https://www.curecmd.org/

Introduction

In 2018, the European Neuromuscular Centre refined the definition of LGMD to include the following criteria:

Defnition:

Limb girdle muscular dystrophies are a group of genetically inherited muscle disease that primarily affects skeletal muscle leading to progressive, predominantly proximal muscle weakness at presentation. To be considered a form of limb-girdle muscular dystrophy the condition must be described in at least two unrelated families with affected individuals achieving independent walking, must have an elevated serum creatine kinase activity, must demonstrate degenerative changes on muscle imaging over the course of the disease, and have dystrophic changes on muscle histology, ultimately leading to end-stage pathology for the most affected muscles.

Changed nomenclature:

• D- dominant 

• R-recessive

• Number according to order gene discovered. 

New Nomenclature

• Autosomal dominant

  • LGMD D1/LGMD1D DNAJB6 

  • LGMD D2/LGMD1F TNPO3 

  • LGMD D3/LGMD1G HNRNPDL 

  • LGMD D4/LGMD1I CAPN3 

  • LGMD D5 COL6A1 (Collagen type VI alpha 1 chain)

• Autosomal recessive

  • LGMD R1/LGMD2A CAPN3 

  • LGMD R2/LGMD2B DYSF

  • LGMD R3/LGMD2D SGCA

  • LGMD R4/LGMD2E SGCB

  • LGMD R5/LGMD2C SGCG 

  • LGMD R6/LGMD2F SGCD 

  • LGMD R7/LGMD2G TCAP 

  • LGMD R8/LGMD2H TRIM32 

  • LGMD R9/LGMD2I FKRP

  • LGMD R10/LGMD2J TTN 

  • LGMD R11/LGMD2K POMT1 

  • LGMD R12/LGMD2L ANO5 

  • LGMD R13/LGMD2M FCMD 

  • LGMD R14/LGMD2N POMT2 

  • LGMD R15/LGMD2O POMGnT1 

  • LGMD R16/LGMD2P DAG1 

  • LGMD R17/LGMD2Q PLEC1 

  • LGMD R18/LGMD2S TRAPPC11 

  • LGMD R19/LGMD2T GMPPB 

  • LGMD R20/LGMD2U CRPPA 

  • LGMD R21/LGMD2Z POGLUT1  (review)

  • LGMD R22 COL6A1/2/3 Collagen VI subunits A1, A2, or A3

  • LGMD R23 LAMA2 Laminin subunit alpha 2

  • LGMD R24 POMGNT2 Protein O-linked mannose N-acetylglucosaminyltransferase 2 (beta 1,4-)

Left out: 

Genes, Protein Products, and Old Nomenclature of Other Myopathies With Limb-Girdle Muscular Dystrophy Phenotype

• • Autosomal dominant

    • MYOT Myotilin LGMD1A

    • LMNA Lamin A/C LGMD1B

    • CAV3 Caveolin 3 LGMD1C

    • DES Desmin LGMD1E

    • RYR1 Ryanodine receptor 1

    • VCP Valosin containing protein

  • Autosomal recessive

    • DES Desmin LGMD2R

    • GAA Acid alpha-glucosidase LGMD2V

    • LIMS2 LIM zinc finger domain containing 2 LGMD2W

    • BVES Blood vessel epicardial substance LGMD2X

    • TOR1AIP1 Torsin 1A interacting protein 1 LGMD2Y

    • RYR1 Ryanodine receptor 1

  • X-linked

    • DMD/BMD Dystrophinopathies

    • FHL1 Four and a half LIM domains 1

Old Classification of Muscular dystrophies

X-linked Recessive Dystrophies

• DMD/BMD, Xp21, Dystrophin

• EDMD, xq28, Emerin

Autosomal Dominant Dystrophies

• LGMD1A, 5q22-31, Myotilin

• LGMD1B with cardiopathy/AD-EDMD, 1q11-12, Nuclear lamin A/C 

• LGMD1C, 3p25, Caveolin-3

• MD1, 19q13.2, DMPK

• DM2/PROMM, 3q, ZNF9 (a.k.a CNBP) 

• LGMD1D/LGMDD1, 6q23, DNAJB6

• LGMD1E/LGMDD1, 7q, DNAJB6

• LGMD 1F/LGMDD2, 7q32.1-32.2. Transportin 3 (TNPO3).

• LGMD 1G/LGMDD3, 4q21, Heterogeneous nuclear ribonucleoprotein D-like protein (HNRNPDL; HNRPDL)

• LGMD 1H, 3p25.1-p.23

• FSHD

• OPMD

• Bethlem myopathy 1

• Bethlem myopathy 2

Autosomal recessive LGMD (LGMD2)

• 2A: Calpain-3 ;15q15:

• 2B: Dysferlin; 2p13

• 2C: γ-Sarcoglycan; 13q12

• 2D: α-Sarcoglycan; 17q21

• 2E: β-Sarcoglycan; 4q12

• 2F: δ-Sarcoglycan; 5q33

• 2G: Telethonin; 17q12

• 2H: TRIM32; 9q33

• 2I (MDDGC5): FKRP; 19q13

• 2J: Titin; 2q24

• 2K (MDDGC1): POMT1; 9q34

• 2L: ANO5; 11p14

• 2M (MDDGC4): Fukutin; 9q31

• 2N (MDDGC2): POMT2; 14q24

• 2O (MDDGC3): POMGnT1; 1p32

• 2P (MDDGC9): DAG1; 3p21

• 2Q: Plectin 1f; 8q24

• 2R: Desmin; 2q35

• 2S: TRAPPC11; 4q35

• 2T: GMPPB; 3p21

• 2U (Cerebellum small): ISPD; 7p21

• 2V: GAA; 17q25

• 2W: LIMS2; 2q14

• 2X: POPDC1; 6q21

• 2Y: TOR1AIP1; 1q25

• 2Z: POGLUT1; 3q13

Limb Girdle Muscular Dystrophy

• LGMD is a genetically inherited condition that primarily affects skeletal muscle leading to progressive, predominantly proximal muscle weakness at presentation caused by a loss of muscle fibers. To be considered a form of limb girdle muscular dystrophy the condition must be described in at least two unrelated families with affected individuals achieving independent walking, must have an elevated serum creatine kinase activity, must demonstrate degenerative changes on muscle imaging over the course of the disease, and have dystrophic changes on muscle histology, ultimately leading to end-stage pathology for the most affected muscles.

• LGMDs stem from genetic defects in genes that provide instructions for making proteins that are involved in muscle maintenance and repair.  The protein defects occur throughout the muscle fiber, including the nucleus, sarcoplasm, sarcomere, sarcolemma, and extracellular matrix.

• Old Nomenclature: 

  • Autosomal dominant forms of LGMD are categorized as LGMD1, followed by a letter

  • Autosomal recessive form of LGMD are categorized as LGMD2, followed by a letter.

• New Nomenclature: 

• The most prevalent LGMD subtypes are due to  defects in the following proteins in muscle:

  • Calpain, dysferlin, the sarcoglycans, fukutin-related protein, anoctamin 5, and lamins A/C: Seen in U.S

  • Calpain (LMGD2A/LGMD R1),  LGMD2I (FKRP), LGMD2L (ANO5): UK, U.S.

  • LGMD2I, ANO5: Scandinavians and part of England. 

  • Dysferlin: Southern Europe, SE Asia - India.

  • Dominant group: Laminopathy:  important to test this as it is broad in its presentation.  rigid spine, contractures, sudden cardiac death in family.  

  • Calpainopathy: Scapular winging, contracture, FVC is well preserved, posterior muscle involvement in leg (MRI) 

  • Some patients have cardiomyopathy: commonly seen in sarcoglycan-related LGMDs, also in FKRP-related and telethonin-related LGMDs.  Diaphragmatic involvement  is more common in sarcoglycan-realted LGMDs and some alpha-dystroglcyanopathies.

  • Anoctamin 5; mild, adult life, men more women, high CK.

• As a group, limb-girdle muscular dystrophies (LGMDs) are the fourth most prevalent genetic muscle disease after myotonic dystrophy, DMD, and FSHD.

• M: F equal. 

• World-wide prevalence rate: 0.8 - 6.9 cases per 100,000 individuals with 3000 to 25,000 affected individuals in the United States. 

• Limb-girdle muscular dystrophy present with shoulder and hip girdle weakness which progresses very slowly at an average rate of less than 5% annually, occurring over the years to decades.

• Facial and ocular muscles are usually spared.

• Muscle Bx shows dystrophic changes (degeneration and regeneration)

• CK levels are usually elevated.

• Before considering LGMD, always rule out an X-linked dystrophinopathy like DMD or BMD and others including POMPE

  • CK levels are informative:  In face of a normal CK, one can exclude the AR type LGMD2, except laminopathy, MFM overlap with LGMD myopathy.  Amongst the AR type of LGMD, Dysferlinopathy, ANO-5 mutation have massive elevations of CK.

  • Try to find out when the disease first started (symptom onset) in the patient. 

    • LGMD2B (dyferlinopathy) has a mixed proximal and distal presentation; walking on tip toes in early 20s

  • Pattern of muscle involvement, scapular winging (common in calpainopathy, sacroglycanopathy) and (less common in dysferlinopathy)

  • Contractures (laminopathy, calpainopathy)

  • Hypertrophy (dystrophinopathy), sarcoglycanopathy, FKRP-pathy.

  • Muscle biopsy and genetic testing.

The AAN and AANEM, emphasize the importance of genetic testing to identify specific types of dystrophy. The guideline provides algorithms for diagnosis:

• Clinical picture

• Ethnicity

• Family history

• Cardiac and respiratory symptoms

• History of progressive, proximal muscle weakness that usually starts in childhood to young adulthood. 

  • Pelvic muscle weakness is most often the first symptom.

  • Abnormal walk

  • Lower back pain

  • Loss of muscle mass and distribution

    • Calf hypertrophy (pseudohypertrophy)

    • Anterior and posterior compartment of leg

  • Shoulder weakness and scapulohumeral weakness. 

  • Scapular winging

  • Neck, elbow, hip, and heel contractures. 

  • Facial weakness, dysphagia.

• CK levels.

  • High in AR, not high or normal in AD

Autosomal dominant LGMD: usually late onset, slower course, CK is not as much elevated as in AR LGMD.  Less cardiac or respiratory involvement when compared to autosomal recessive forms.  Represent 10% of all LGMDs.

LGMD1A (Myotilin) MYOT

• • Onset: Early or late adult life (teens - 80s)

  • Spontaneous mutations are common, so absence of family history should not exclude the diagnosis.

  • Predilection for scapular-humeral-pelvic muscles.  Distal leg (foot drop) and arm weaker than proximal muscles. Muscles are atrophic, and early contractures of the elbows and heel cords develop early.  It is associated with cardiomyopathy.  Calf hypertrophy is rare.  Dysarthria or hypernasal speech or hoarseness (vocal cord involvement) occurs.  

  • CK is normal or mildly elevated.

  • MRI of skeletal muscle: fibrofatty replacement and edema: Medial gastrocnemius, soleus, hip adductors, biceps femoris. Sparing of semitendinosus

  • Muscle Bx: Frequent occurrence of rimmed vacuoles, and occasional nemaline-rod-like inclusions.  May appears like Myofibrillar myopathy (MFM) and h-IBM.

  • Molecular genetics: AD.  Myotilin (MYOT) located on 5q31.2.  Spontaneous mutations are common.

LGMD1B (Lamin A/C)

• • AD; mutations in the LMNA gene cause limb-girdle muscular dystrophy type 1B.

  • Late teens

  • Hip and shoulder muscle weakness or humeral-peroneal distribution of weakness.  It is associated with cardiac conduction defects.  The cardiomyopathy and associated arrhythmias can result in SCD.  Patients need PPM or AICD implantation or even cardiac transplantation.

  • Resembles clinical phenotype of autosomal-dominant EDMD2 being caused by mutations in lamin A/C gene.  Both have similar phenotype: proximal arm weakness with preferential involvement of humeral muscles, both proximal and distal weakness in the lower extremities, ankle and elbow contractures and spine rigidity (especially neck).  However, contractures are not apparent until late in the disease course or not at all, which is a feature that helps distinguish it from X-linked EDMD (emerin) which has early contractures as a feature of the disease.  

  • CK is normal or elevated up to 25 times normal

  • MRI of skeletal muscle: Fatty infiltration of the posterior compartment of the thigh and calves. In AD-EDMD: hamstrings severely involved and quadriceps relatively spared. 

  • Muscle Bx: Variation of fiber size, increased endomysial connective tissue, normal dystrophin, sarcoglycan, and emerin staining. Occasionally, rimmed vacuoles are seen.  Emerin and lamin A/C expression on nuclear membrane are typically normal with immunohistochemistry.

    • On EM, myonuclei exhibit loss of peripheral heterochromatin or its detachment from the nuclear envelop, altered interchromatic texture, and few nuclear pores compared to normal.

  • Molecular Genetics and Pathogenesis: Mutation in LMNA lamin A/C on 1q22

  • The lamin A/C gene has alternative splice products that are involved in nuclear membrane function and interact with emerin; mutations are associated with multiple and varied phenotypes. 

    • Neuromuscular patterns include: Emery–Dreifuss muscular dystrophy type 2; autosomal dominant, limb-girdle muscular dystrophy 1B; autosomal recessive, axonal Charcot–Marie–Tooth disease (CMT2B1); congenital muscular dystrophy with rigid spine; and quadriceps myopathy with dilated cardiomyopathy, familial partial lipodystrophy (Köbberling–Dunnigan syndrome), mandibuloacral dysplasia, and progeria, Hutchinson-Gilford progeria syndrome, restricting dermatopathy are also allelic disorders associated with LMNA mutations. 

LGMD1C (Caveolin-3)

• • Mutations in the caveolin-3 (CAV3) gene, 3p25.3

    • Caveolae are small, flask-shaped invaginations of cell membrane observed in many cell types, including skeletal muscle.  They play an important role in maintaining sarcolemmal integrity and regulating vesicular trafficking and signal transduction. It also function to facilitate organization of signalling complexes, and the sodium channels, may contribute to the pathogenesis of rippling muscle disease. 

  • Two sets of proteins, caveolins and cavins, are the main constituents of caveola.

  • Heterogenous phenotype:  Affected individuals present in childhood or adult life with proximal weakness or exertional myalgias. Calf hypertrophy is seen.  Patients sometimes present with rippling muscle disease, distal weakness (anterior tibial or gastrocnemius) in the form of foot-drop, or asymptomatic hyperCK-emia and rarely myoglobinuria.  Generalized percussion-induced rapid contractions (PIRCs) are apparent in extremities, face, neck in affected patients (rippling muscle disease). 

  • Spontaneous mutations are not uncommon, so lack of family history does not exclude the diagnosis.

  • CK is elevated 3 - 30 times normal.

  • Muscle Bx:  Nonspecific myopathic features with normal dystrophin, sarcoglycan, and merosin staining.  Reduced caveolin-3 staining may be appreciated along the sarcolemma.  EM reveals a decreased density of caveolae on the muscle membrane as well.

  • Cavinopathy is related disorder caused by Cavin which encodes for gene PTRF (polymerase 1 and transcript release factor) which plays a role in the formation of caveolae and stabilization of caveolins. It results in muscular dystrophy and generalized lipodystrophy.  Patients may get generalized or distal weakness, muscle hypertrophy, muscle mounding, and rippling.  There is impaired GI motility and hypertrophic pyloric stenosis in some children due to smooth muscle hypertrophy.  Impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability.  They may have elevated CK.

• Cardiomyopathy or cardiac arrhythmia has been reported in both of the caveolar protein–associated muscular dystrophies.

• Rippling muscle disease (RMD) is a muscle hyperexcitability disorder, clinically characterized by painful muscle stiffness, rippling of the muscle, and percussion-induced muscle mounding or rapid contraction. Muscle rippling is generally electrically silent, but associated electrical activity has been occasionally reported.  RMD can be hereditary, as result of mutations in the caveolin-3 or cavin-1 encoding gene, or acquired, due to an immune-mediated process. The mosaic pattern of sarcolemmal caveolin-3 deficiency, detected by immunocytochemical study, distinguishes the immune-mediated RMD from the hereditary RMD, which is characterized by a more homogeneous loss of caveolin-3 immunoreactivity.

LGMD D1/LGMD1D  (DNAJB6)

• • AD.  DNAJB6,  7q36

  • Autosomal dominant LGMD1D is relatively rare, accounting for only 5-10% of all LGMD cases.  Mutations in the DnaJ homolog, subfamily B, member 6 (DNAJB6) gene have been described in patients with LGMD1D  (new nomenclature: LGMD D1).

  • Rare dystrophy, slow progression, onset: 3rd to 6th decade, may be seen in teens.  

  • Proximal muscle weakness in lower extremities (hamstrings worse than quadriceps) with normal or mild proximal upper extremity muscle strength weakness.  Variable phenotype and some may develop distal lower extremity weakness with preferential posterior compartment involvement more than anterior compartment. 

  • Cardiac and ventilatory muscles are usually spared. 

  • CK: normal to 10 x normal but usually 2-3 times ULN.

  • Muscle Bx: rimmed vacuoles and other features suggestive of MFM.

LGMD1E  (Desmin)

• • AD, DES.  Allelic to LGMD2R (desminopathy; AR)

  • Mutations in desmin (DES) is a common cause of MFM.

  • Late adult onset (5th to 6th decade)

  • Limb-girdle pattern of weakness; most have more distal involvement and can present as progressive foot drop.  Some have equal proximal and distal weakness, or a scapuloperoneal distribution.  

  • Dysphagia or dysarthria can also occur.  

  • Ventilatory muscle weakness and cardiac involvement are common and may precede skeletal muscle weakness.  Cardiac arrhythmias, AV conduction block, AF, and SCD.  Some patients required PPM or AICD.  DCM appears more frequent than HCM or restrictive CM; some patients need cardiac transplantation. 

  • CK levels are normal or 5 x nl.  

  • EMG is myopathic with muscle membrane irritability (increased insertional and spontaneous activity), pseudomyotonic discharges. 

  • MRI of skeletal muscle: Distal leg shows involvement of TA, peroneal muscles, MG, and soleus.  In thighs the earliest muscle to become involved is semitendinosus and sartorius. 

  • Muscle Bx: rimmed vacuoles and features suggestive of MFM.  

LGMD 1F (Transportin 3)

• • Mutation in TNP03, gene on 7q32.1-32.2, encodes for transportin-3, a nuclear import receptor for precursor-mRNA splicing factors. 

  • Onset from infancy to adulthood

  • Proximal greater than distal weakness.   Legs more than arms.  

  • CK level is moderately elevated. 

  • Muscle Bx:  Rimmed vacuoles similar to MFM.

LGMD 1G

• • 4q21

  • Heterogeneous nuclear ribonucleoprotein D-like protein (HNRNPDL; HNRPDL) ; Chromosome 4q21.22; Dominant 

LGMD 1H

• • 3p25.1-p.23

  • Gene unknown

Autosomal recessive LGMD (LGMD2)

• Thee are  >14 types of LGMD2s.  Constitute 90% of all LGMDs.

LMGD2A/LGMDR1 - calpain-3 deficiency (CAPN3 gene). 15q15.1

• • It is the most common form of LGMD in the US and among population of eastern Europe, Netherlands, northern England, Italian, Spanish, and Brazilian  ancestry.

    • 28% of LGMD cases in Italy; 26.5% of LGMD cases in northern England, and 21% of all LGMD cases in Netherlands. 

  • Calpain-3 is a muscle-specific, calcium-dependent, non-lysosomal, proteolytic enzyme.  Mutations in the CAPN3 gene lead to absence or reduction in calpain enzyme.   How it results in a dystrophic process is not clear.  

  • Calpainopathies is the most common form of LGMD and accounts for 20-35% of LGMD. 

    • 60% of patients with calpainopathy manifest as a BMD phenotype.

    • 10% of patients with calpainopathy manifest as a DMD phenotype.

    • 3% of patients with calpainopathy manifest as a distal myopathy phenotype.

    • 6% have asymptomatic hyper-CK-emia.

    • Eosinophils are typically seen in muscle biopsy

  • Onset is from early childhood to mid-adult life.

    • About two thirds of patients present at 8-15 years of age, with a range of 2-40 years.

    • Men are more severely affected than women.

  • Muscle weakness in the lower extremities follows a relatively distinct pattern.  Knee flexors, hip adductors and extensors are weaker than their paired antagonist muscles across the joints.  Weakness is predominantly symmetric.  Scapular winging occurs in approximately 20% of cases.  There is mild weakness of neck muscles.  Gait is lordotic.   Scoliosis occurs due to truncal weakness.  Facial and ocular muscles are not affected.  Joint contractures are common and affect the elbow, hips, knees, and ankles in more than half of patients.  Women tend to be less severely affected than men.  

  • Tendon reflexes are absent or diminished.  

  •  Calf hypertrophy is not common.  

  • No cardiac involvement. Ventilatory function is moderately affected.  No intellectual impairment.

    • The combination of symmetrical scapular winging, severe weakness of hip adductors and elbow flexors, normal respiratory function, and contractures has specificity for LGMD2A (calpainopathy).

  •  Progression is steady and variable.  There is variability of phenotypic expression within families.  

  • Earlier the onset, faster the progression

    • • ~50% of patients are non-ambulatory by the age of 20 years, but some are able to walk late in life.

      • Wheelchair use begins 11-28 years after the onset of symptoms.

  • Normal life-expectancy.

  • CK levels are approximately 2000 U/L to 6000 U/L but range from normal early in the disease and decreases close to normal range later when patients are wheelchair bound.

  • Rarely peripheral eosinophilia seen is affected children.

  • Prenatal diagnosis of LGMD 2A is possible through DNA analysis of fetal cells obtained by amniocentesis or CVS.

  • MRI of skeletal muscles demonstrate fat and connective tissue replacement of normal muscle fibers.  There is predilection for the posterior thigh muscles and adductors in the thighs, as well as the soleus and medial gastrocnemius muscles in the lower leg. 

  • Muscle Bx:  Variation of fiber size - increased endomysial connective tissue.  Lobulated muscle fiber appearance on NADH stain is seen; not a specific finding for calpainopathies and can be seen in other dystrophies.  Eosinophilic infiltrate is sometimes seen in muscle bx specimen confusing it for eosinophilic myositis.

  • Why does peripheral eosinophilia and eosinophilic infiltrates are noted in some affected individuals?

    • Hypothesis:  Calpain-3 is highly expressed in T lymphocytes, and these cells secrete IL-5 and IL-3, cytokines that are required for the growth and differentiation of eosinophils.  Perhaps, the mutation in the gene causes not only LGMD but also a perturbation of T-cell function leading to eosinophilia.

  • Calpain-3 is a cytosolic enzyme, immunostaining cannot be done for diagnosis.  Western blot can be used and may show reduced calpain-3 in most biopsies, but in 20% of cases the Western blot is normal.  The mutation in the gene may not alter the size and amount of calpain-3, but may affect the enzyme activity.  There are no readily available test to show reduced enzyme activity at this time. 

  • Definite diagnosis requires demonstration of a mutation in calpain-3 gene as secondary deficiency in calpain-3 can be seen in other dystrophies, most notably in dystrophinopathies and titinopathies. 

  • LGMD1I (CAPN3) - LGMDD4 is autosoomal dominant calpainopathy is reported. 

LGMD R2/LGMD2B - dysferlin (DYSF gene)

• • It is an autosomal recessively inherited form of LGMD caused by a  lack of dyferlin.  Dysferlin protein is highly expressed in skeletal muscle and also in the myocardium. 

  • It accounts for 6% of all LGMD.  It is the 2nd most common LGMD in US after calpainopathy.  It is Allelic to Miyoshi myopathy (MM or MMD1)

  • Dysferlin gene shares amino acid sequence homology with Caenorhabditis elegan spermatogenesis factor FER-1, thus the origin of its name.  

  • Dysferlin is located in the subsarcolemmal surface of the muscle membrane, but it has a small transmembrane spanning tail.  It does not appear to have a significant interaction with the dystrophin-glycoprotein complex, and immunostain for dystrophin, dystroglycan, merosin, and sarcoglycans is normal.  One role of dysferlin is in patching defects in skeletal membranes such that mutations in the gene result in defective membrane repair. 

  • Age of onset is late teens to early twenties, although onset as late as 48 years has been reported. 

  • Phenotypic variability is present in dysferlinopathies and is broken down as follows: 80% manifest with distal weakness, 8% had LGMD phenotype, and 6% present with asymptomatic hyper-CKemia. 

    • Distal weakness is common.  Anterior tibial weakness, initially followed by posterior calf involvement (Miyoshi type myopathy).  There is posterior calf muscle weakness - atrophy of gastrocnemius and soleus muscles (Miyoshi type myopathy).   Patients have difficulty walking on their tip-toes.   Involvement of gastrocnemius, soleus and thigh adductors is in all cases.  Hamstrings and glutei involvement occurs later in disease.

    • Limb-girdle weakness is less commonly seen.  At onset, leg muscles exhibit the greatest weakness, but this lower extremity weakness can be proximal, distal, or both.  Hip extensors, hip adductors, knee extensors, and ankle plantar flexors are most affected, with relative preservation of hip flexors and hip abductors. 

    • Of note, if someone with LGMD cannot stand on his or her toes within the first few years of disease onset, strong consideration should be given to LGMD2B (and LGMD2L).

    • Involvement is usually asymmetric.

    • Uncommonly paraspinal muscles are involved leading to rigid spine syndrome or, conversely, a lax spine with hyperlordosis or kyphosis. 

    • Scapular winging can be seen.

    • Early loss of Achilles' tendon reflexes (key finding in exam and is helpful to differentiate from other LGMD where it is preserved).

    • No calf hypertrophy or pseudohypertrophy seen as in other types of LGMD.

  • Interestingly, prior to onset of symptoms, a disproportionate number of patients with LGMD2B were better athletically than their peers. However, it has now been reported that exercise in the teenage years is associated with earlier onset of weakness in patients with LGMD2B.

  • Usually progression is slow, but if subacute it causes confusion and at least 25% of cases are initially misdiagnosed as polymyositis.

  • Cardiac involvement usually does not occur but need monitoring as abnormal atrial conduction is reported in some cases.  Respiratory insufficiency is seen late in disease.

  • Recommended method for diagnosis of LGMD2B is Western blot analysis on WBC (dysferlin is present on WBC) or for evaluation of the dysferlin protein on muscle biopsy

  • CK levels (mean of 5000 U/L with a range from normal to >30,000 U/L).

  • Muscle MRI of the legs reveals early involvement of the medial gastrocnemius in the calves, the hamstrings in the thighs, and the paraspinal muscles.  MRI of the legs in patients with dysferlinopathy with LGMD or Miyoshi myopathy demonstrates similar patterns of muscle involvement as the disease progresses despite predominantly proximal and distal weakness, respectively.

  • Muscle biopsy:

    • Fiber size variability, scattered necrotic and regenerating fibers, and increased endomysial connective tissue. 

    • Diminished or absent sarcolemmal immunostaining for dysferlin antibodies.  They may be increased cytoplasmic staining.

    • Western blot needs to be performed on the muscle or WBC for confirmation of dysferlin deficiency. 

    • Mononuclear inflammatory cell infiltrate in endomysium and surround blood vessels.  This picture may be misdiagnosed as polymyositis. However, in contrast to PM, the inflammatory cells do no typically appear to invade non-necrotic fibers.  

    • Deposition of MAC complexes on the sarcolemma of non-necrotic muscle fibers.  This is an early finding seen in dyferlinopathies and other dystrophies including FSHD associated with inflammation, and not seen in inflammatory myopathies such as PM, DM, and IBM.  

    • Amyloid deposition in blood vessel walls, around the sarcolemma and in the endomysial or perimysial connective tissue may be seen with Congo red staining.   

    • On EM, duplication of the basal lamina, disruption in the sarcolemma, invagination of papillary exophytic defects of the muscle membrane, and subsarcolemma vesicles may be appreciated. 

LGMD2C, 2D, 2E, and 2F - sarcoglycanopathies

• Age of onset 6 - 8 years, DMD/BMD like, proximal leg and arm weakness, calf pseudo-hypertrophy, high CK, normal IQ, cardiomyopathy, restrictive airway disease. Difficulty walking or running.

• LGMD R3/LGMD2D SGCA

• LGMD R4/LGMD2E SGCB

• LGMD R5/LGMD2C SGCG

• LGMD R6/LGMD2F SGCD

  • 10% of LGMD

    • Alpha-sarcoglycans (SGCA) 6.6% - LGMD2D, 17q21.33

    • Beta-sarcoglycans (SGCB) 3.1% - LGMD2E, Amish, 4q12

      • It is autosomal recessive, patients can have calf hypertrophy, scapular winging, cardiac abnormalities.

    • Gamma-sarcoglycan (SGCG) 1.5% - LGMD2C, North African, Gypsies, 13q12.12

    • Delta sarcoglycan (SGCD) <1% - LGMD2F, Brazilian, 5q33.3

    • Disease onset ranges from infancy through adulthood but occurs in the first decade in most cases.  Milder cases with ater onset have been reported.

    • Weakness begins in the proximal lower extremities and then involves the proximal upper extremities. Scapular winging, calf hypertrophy, macroglossia, ankle contractures, and scoliosis are common features in early-onset, more severe cases.  

    • Loss of ambulation occurs in the second through fourth decades, with the majority of patients wheelchair dependent in their teenage years. 

    • Dilated cardiomyopathy afflicts a minority of patients, but respiratory insufficiency necessitating nocturnal noninvasive ventilation affects many patients later in the disease course.  Left ventricular systolic dysfunction occurs less often in α-sarcoglycanopathies than the other sarcoglycanopathies.

    • CK levels are elevated 4 to 100 times the normal level.  

    • MRI reveals principal involvement of lumbar paraspinal, gluteal, and thigh muscles with sparing of calf muscles until late in the disease course after loss of ambulation.  In the anterior thighs, a predictable proximal to distal gradient of fatty and fibrous replacement occurs with relative sparing of the distal vasti muscles.  

    • Muscle biopsies reveal dystrophic findings with diminished or absent staining for the sarcoglycans. When immunostaining for the four sarcoglycans (γ-sarcoglycan, α-sarcoglycan, β-sarcoglycan, and δ-sarcoglycan), the level of diminished staining does not predict which sarcoglycan gene is mutated. Complete absence of immunostaining correlates with earlier onset of disease, a more severe phenotype, and earlier loss of ambulation.

LGMD2G - Telethonin, (TCAP) 17q12 

• • Telethonin is localized to skeletal and cardiac muscles, and it is a substrate of the serine kinase domain of titin.   It is also known as titin cap.  The interaction of telethonin with titin appears to be important in myofibrillogenesis.   Telethonin is the most abundant protein in muscle and also overlaps with myosin. 

  • Age of onset is 12–15 years.

  • Weakness affects proximal and distal leg muscles (quadriceps and tibialis anterior) and proximal arm muscles. Facial and neck muscles are usually spared.  Some may present similar to Miyoshi myopathy with calf weakness.  Some have calf hypertrophy. 

  • Patients progress to a nonambulatory state in the third or fourth decade of life in 40% of cases.

  • Cardiomyopathy occurs in 50% of cases.

  • The CK level increases 3-fold to 30-fold.

  • Muscle pathology usually shows dystrophic myopathy, lobulated fibers, rimmed vacuoles, and absent Telethonin staining.

  • Genetic advances have made muscle biopsy not the first diagnostic option. Most LGMD genetic panels test for Telethonin mutations.

LGMD2H - E3-ubiquitin ligase, 9q33.1, TRIM 32 defect.

• • Originally reported in a families of Manitoba Hutterite origin.  

  • Also known as sarcotubular myopathy. 

  • Age of onset from birth to 7th decade of life

  • Individuals have exercise-induced myalgias and exam reveals a limb-girdle pattern of weakness with scapular winging, facial weakness, calf hypertrophy, and heel cord contractures.  Exercise induced myalgias are note in some patients. 

  • Slowly progressive myopathy and most affected individuals are still ambulatory without assistance in the 4th decade of life. 

  • CK are elevated 5 to 50 fold.  

  • Non-specific ECG changes.  

  • Muscle biopsy: dystrophic features.  Most of type 2 muscle fibers contain many small vacuoles which immunostain for sarcoplasmic reticulum-associated ATPase.  These vacuoles abut the T-tubules and appear to be membrane bound on EM.  Most the small vacuoles coalesce to form larger  vacuoles, often with degeneration of their muscle membranes. 

  • TRIM-32 may function ubiquitinating proteins that need degradation by proteosomes. 

LGMD2I/ LGMDR9 (FKRP), 19q13.3

• • Initially described in a large consanguineous Tunisian family with 13 affected members. 

  • Most common form of LGMD in northern Europe, Denmark, account for 4-30% of LGMDs. 

  • It is allelic to congenital muscular dystrophy (MDC type 1C) which is the most common MDC in the West.  

  • Onset can range from infancy (MDC type 1C) to 4th decade of life.

  • Mutations in FKRP is also responsible for causing MDC type 1C (congenital muscular dystrophy).  FKRP is a glycosyltransferase and it deficiency is associated with abnormal glycosylation of alpha-dystroglycan, which apparently disrupts the dystrophin-glycoprotein complex.  Abnormalities in alpha-dystroglycan glycosylation is a recurring theme in the MDCs, as it the causative mechanism of Fukuyama disease, MEB, WWS, and LARGE related CMD (MDC 1D).  FKRP localizes in the rough endoplasmic reticulum, while fukutin localizes in the cis-Golgi compartment of ER.  Fukutin and FKRP appear to be involved at different steps in O-mannosyglycan synthesis of alpha-dystrogycan, and FKRP is most likely involved in the initial step in this synthesis.  ER retention of mutant FKRP may play a role in the pathogenesis of these dystrophies and potentially explain why the allelic disorder LGMD2I is milder, because the mutated protein is able to reach the Golgi apparatus. 

  • Weakness most commonly presents in the proximal lower extremities, with hip flexion and hip adduction most affected.  Scapular winging occurs in less than half of cases, calf hypertrophy is commonplace, and hypertrophy also occurs in the tongue sometimes. Exercise-induced muscle pain and myoglobinuria afflict as many as two-thirds and one-third of patients with LGMD2I, respectively.  

  • Interestingly, patients with LGMD2I can experience abrupt, reversible weakness in conjunction with a febrile illness.  This acute illness-associated weakness sometimes occurs in children prior to onset of weakness associated with LGMD2I, lasts for a few days to a more than a month, may occur more than once, and has an associated increase in CK levels (often more than double baseline) during the weakness.

  • CK elevated 10 - 30 times normal in some younger patients but may be normal in older individuals.  

  • PFT: reduced FVC.  NIV required. 

  • TTE: DCM, myocardial fibrosis on cardiac MRI.

  • Thigh MRIs reveal abnormal signal with fatty and fibrous infiltration in the iliopsoas, adductors, and gluteus maximus with relative conservation of the anterior thigh muscles.

  • Muscle biopsy: non-specific dystrophic changes.  Immunohistochemistry demonstrates normal dystrophin and sarcoglycan and occasionally merosin and alpha-sarcoglycan are reduced or absent.  

    • In the United States, c.826C>A mutation was present in 72% of alleles, and more than 95% of patients with LGMD2I had at least one copy of this c.826C>A pathogenic variant.  Patients homozygous for the c.826C>A mutation always present with the LGMD phenotype or with milder disease.  Patients heterozygous for the c.826C>A mutation have a more severe, Duchenne muscular dystrophy–like disease with onset in the first decade, loss of ambulation in the second decade, and need for ventilator support by the fourth decade.

LGMD2J - Titin (TTN gene mutation), 2q31.2 - Finnish population

• • Mutations in titin (TTN) are associated with 3 different clinical phenotypes:

    • AR, LGMD2J

    • AD, (Udd type distal myopathy).  Presents in later adult life as a foot-drop.

      • Most common phenotype

    • AD hereditary myopathy with early respiratory failure (HMERF), can also have a foot drop, but early onset.

  • Clinical features of LGMD2J (Titin):

    • Onset first 3 decades of life.  

    • Proximal leg and arm with milder distal (AT, MG, forearm and hand muscles) weakness. 

    • Affected individuals are wheelchair dependent within 20 years of onset. 

    • Scapular winging is uncommon but can be seen. 

    • Another presentation is an early-onset, proximal, and distal weakness leading to delayed motor milestones that is associated with a severe DCM.  Some children exhibit hypertrophy of thighs, calves and atrophy of arms. Spinal rigidity and moderated joint contractures appear in the first decade.  Affected patients develop CHF and suffer SCD from malignant arrhythmias.

  • CK: 3-5 x normal.  TTE: DCM, PFTs: ventilatory muscle weakness. 

  • MRI of skeletal muscle: fatty replacement of thigh (hamstrings more than quadriceps) and lower leg muscle (anterior more than posterior compartment).

  • Muscle biopsy: dystrophic features.  Rimmed vacuoles are rare.  

Hereditary Myopathy with Early Respiratory Failure (HMERF) (Titin)

• • AD.  Reported in Sweden and England. 

  • Clinical phenotype overlaps LGMD2J and Udd type distal myopathy. 

  • Like Udd type distal myopathy, HMERF presents with early progressive foot drop and tends to affect in early adulthood.  It may affect the proximal muscles (legs more than arms), as seen in LGMD2J.  Calf hypertrophy, associated with severe ventilatory muscle weakness.  However, cardiomyopathy is not a common feature. 

  • CK levels are mildly elevated.  

  • MRI of skeletal muscles: commonly affected muscles are semitendinosus, peroneus longus and obturator externus. 

  • Muscle biopsy: dystrophic features, rimmed vacuoles and eosinophilic inclusions.  Extensive myofibrillar degeneration with Z-disc as seen in MFM. 

Secondary alpha-dystroglycanopathies:

• LGMD2K, 2M, 2N, 2O

LGMD2K (POMT1)

• • Associated with WWS (MDC), and some milder LGMD phenotypes.

LGMD2L/LGMDR12- ANO5 gene mutation,  Miyoshi myopathy type 3, 11p14.3

• • Prevalence 20-25% of undiagnosed LGMD in Northern Europe - Finnish descent.

  • Affected individuals present with three distinct phenotype

    • Limb-girdle weakness pattern (LGMD2L)

    • Distal weakness resembling Miyoshi myopathy (Miyoshi myopathy type III or MM3).  

    • Asymptomatic hyperCKemia.

  • Onset is late 20-55 years (mean: 30s) for both phenotypes.

  • There is slow progression of asymmetric quadriceps and biceps brachii muscle atrophy and weakness.  This is a diagnostic hallmark.

  • Quadriceps involvement precedes biceps brachii weakness, and creatine kinase (CK) is >10 the upper limit of normal (mean 4,500 IU/L). No significant cardiac or respiratory muscle involvement has been reported.  They can have muscle pain.  

  • MMD3 presents with calf atrophy and plantar flexion weakness starting before asymmetrical quadriceps weakness, while LGMD 2L presents with asymmetric quadriceps and biceps brachii atrophy and weakness with mild plantar flexion weakness. Other authors note that initial symptoms of predominant distal or proximal weakness may vary, but LGMD 2L and MMD3 phenotypes overlap substantially over time.

  • The majority of patients with LGMD2L remain ambulatory most of their lives but may need canes, walkers, or wheelchairs 20 to 40 years after symptom onset.

  • CK levels are usually elevated to around 1500 U/L to 4500 U/L (range of 200 U/L to 40,000 U/L) and tend to diminish over time.  Myoglobinuria with exercise or exercise intolerance can occur before onset of weakness. 

  • Anoctamin 5 is also expressed in cardiac muscle, an increased number of patients with LGMD2L have ventricular premature complexes and some develop cardiomyopathies with reduced left ventricular ejection fractions.

  • MRI of skeletal muscles: Atrophy and fatty replacement of biceps long-head, MG, soleus, adductors, hamstrings, TFL, and  the quadriceps in the legs often asymmetrical pattern.  

  • Muscle biopsies may be relatively normal prior to onset of weakness but later reveal nonspecific myopathic changes such as variability in fiber size, increased internal nuclei, fiber splitting, and endomysial fibrosis. Noteworthy, amyloid deposition may be seen in the endomysium and in walls of intramuscular blood vessels in some biopsies.

  • LGMD2L is caused by mutations in ANO5 that encode anoctamin-5 protein which is located in the endoplasmic reticulum.  The exact function of anoctamin-5 is unclear but it belongs to a family of proteins found in calcium active chloride channels.  The phenotype of LGMD 2L includes adult onset (ages, 20–50 years; mean, 30 years) with slow progression of asymmetric quadriceps and biceps brachii muscle atrophy and weakness.  Quadriceps involvement precedes biceps brachii weakness, and creatine kinase (CK) is >10 the upper limit of normal (mean 4,500 IU/L).  No significant cardiac or respiratory muscle involvement has been reported.

LGMD2M - FKTN, 9q31.2, Fukuyama muscular dystrophy

• • Mutations in the fukutin gene that causes Fukuyma muscular dystrophy (CMD).  However, mutations may rarely be associated with a more benign LGMD phenotype. 

LGMD2N - POMT2, 14q24.3

• • Mutations in the POMT2 gene that encodes for protein-O-mannosyltransferase, causes MEB disease; rarely a more benign form of LGMD

LGMD2O - POMGnT1

• • Mutations in POMGnT1 also usually results in MEB disease, but have been associated with more benign LGMD2O that has later onset of weakness and spared cognition.  

LGMD2P (alpha-dystroglycan), DAG1

• • Mutations in the DAG1 gene that encodes for alpha-dystroglycan.  The disorder is a primary alpa-dystroglycanopathy in which mutations lead to impaired binding to merosin and destabilization of dystrophin-dystroglycan complex. 

  • Reported in a child age 3 years who had difficulty climbing stairs and an unsteady gait.  Microcephaly and intellectual development delay was noted, and IQ at age 16 was 50.  

  • CK levels elevated at >4,000 U/L.

  • MRI of brain is normal in the reported case. 

  • Muscle biopsy: dystrophic features with a reduction of alpha-dystroglycan on immunohistochemistry. 

LGMD2Q - PLEC1, 8q24.3

• •  Mutations in the gene PLEC1 that encodes for plectin 1, a scaffolding protein important for the formation of muscle fibers and neuromuscular transmission and also for the structural integrity of skin.  

  • It is referred to as muscular dystrophy associated with epidermolysis bullosa which is a characteristic feature in infancy or early childhood.  It manifests as blisters of the skin and mucous membranes, and nail dystrophy.  Later in life, progressive weakness may ensue.  

  • Other phenotype is limb girdle weakness in later childhood and upto 4th decade; without skin abnormalities. 

  • It is also allelic to a form of congenital myasthenia.  Manifest as ptosis, ophthalmoplegia, and facial weakness. 

  • Other features described: dental caries, scarring alopecia, urethral strictures, pyloric atresia, esophageal strictures, respiratory distress, and rarely, cardiomyopathy. 

  • CK is slightly to markedly elevated.  

  • EMG: myopathic features with muscle membrane irritability.  RNS in case of congenital myasthenia has shown decrement. 

  • Muscle biopsy:  type 1 fiber predominance and irregular oxidative staining.   Immunohistochemisty: loss of sarcolemmal staining using the antibody for the rod domain of plectin-1 in type 1 fibers, whereas type 2 fibers retained activity.  Plectin-1 deficiency may also be demonstrated on skin biopsy.   EM may show nonspecific, myofibrillar disarray and Z-disc  streaming.  In those with congenital myasthenia like features, the end-plates had focal degeneration of the junctional folds, but AChR content was normal.

LGMD2R, 2q35, Desmin

• • Progressive proximal muscle weakness and ventilatory failure in early childhood or adulthood.  CK levels are mildly elevated.  

  • In contrast to most cases of primary desminopathy, it is associated with autosomal recessive inheritance as opposed to autosomal dominant. 

  • Allelic to LGMD1E and MFM.

LGMD2S, 4q35.1, TRAPPC11

• • LGMD reported in Syrians and Hutterites.  

  • Characterized by an infantile onset of choreiform, athetoid or dystonic movements, seizures, truncal ataxia, and mental intellectual disability.  

  • Proximal weakness in childhood along with scoliosis and hip dysplasia.  

  • CK is mild to moderately elevated.

  • TRAPPC11 gene encoding transport protein (trafficking) between endoplasmic reticulum and Golgi complex. 

LGMD2T GMPPB, 3p21.31, GDP-mannose pyrophosphorylase B

A congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and mental retardation. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia .

LGMD R21/LGMD2Z caused by POGLUT1 mutation

• The most striking characteristic associated with POGLUT1 mutations is on MRI of muscles, especially at the level of the thigh, the muscle imaging pattern resembles an “inside-to-outside” fatty degeneration because the most affected segment is in the inner region of each muscle in the anterior and posterior compartment of the thigh.  Proximal > distal weakness.  Legs > Arms, scapular winging, respiratory: 4th decade,. Course: Slow progression is slow and some require wheel-chair.  Dowling-Degos disease-4 (DDD4) is autosomal dominant genodermatosis caused by heterozygous mutation in the POGLUT1.  This condition is characterized by progressive and disfiguring reticulate hyperpigmentation primarily involving flexural surfaces and skin folds, in combination of reddish-brown papules that are partly erosive and partly hyperkeratotic.   

• Another diagnostic hint in these cases is that most cases show normal CK levels. This could serve as a differential diagnosis to other autosomal recessive LGMDs, most of which usually show very high CK levels.

Facioscapulohumeral Muscular Dystrophy (FSHD):

General Information: Muscular dystrophies are genetic, progressive, degenerative disorders of muscle. 

FSHD is an autosomal dominant disorder.  Although 70% to 90% of patients have a family history of FSHD, up to 20% of cases are sporadic.  It is one of the most prevalent muscular dystrophies, with a world-wide prevalence range of 2–7:100,000). It is considered the 3rd most common muscular dystrophy after DMD (Duchene), and DM1 (Myotonic dystrophy). 

Incidence: 4 per million.  Prevalence: 50 per million.   

Symptoms and Signs: Muscle weakness is the primary symptom. Weakness spreads rostrocaudally with onset in the face, then the scapular region, followed by the proximal arms, and lasting the legs.

Onset of disease usually occurs in the patient’s teens, and 90% of patients show signs of disease by 20 years of age.   Range (3-44 years), but onset as late as age 75 has been reported.   They are cases of incomplete penetrance, however.  There is a variable degree of penetrance of clinical findings within families, while around 30% of affected family members are unaware of their deficits.  Thus, it is very important to examine family members of patients suspected to have FSHD.

In FSHD, there is predominant involvement of facial, periscapular, biceps, and triceps muscles. The facial involvement commonly manifests as decreased brow furrow; inability to close the eyes or bury the lashes in forced eye closure; a flattened, transverse smile; inability to purse lips or sucking through a straw, or blowing balloons, and inability to tense the platysma. Facial weakness may be strikingly asymmetric and may mimic a seventh cranial nerve palsy (Bell's palsy).  EOM are not impaired.  During sleep the eyes may remain slightly open and the globe may be rolled up (Bell's phenomenon). Ptosis and dysphagia are uncommon.  The mouth loses the normal contour and appears widened with a more horizontal appearance due to the loss of the normal upward curvature of the lower lip.  When viewed from the side, the lips have a pouting (bouche tapir) appearance.  Sometimes a dimple may be seen on either side of the angle of mouth, which deepens when the patient attempts to smile.   Muscles of mastications and EOM are spared. 

Pectoral muscles are distinctly weak, but the deltoid muscles tend to be spared.  Unlike many other muscular dystrophies, asymmetries are typical in FSHD.  Since subtle perioral and periocular weakness is functionally non-limiting early in disease, weakness in the arms, especially in overhead activities, often brings patients to medical attention.  In the shoulder girdle, scapular winging is prominent, and pectoral muscle atrophy leads to reversal of the anterior axillary folds.  Usually, the anterior axillary folds slant outward, toward the shoulder. In FSHD, due to pectoral atrophy and scapular laxity, the anterior axillary folds point inward, toward the neck, and the shoulders often slope downward.  Additionally, patients may have the triple-hump sign, composed of the deltoid muscle, the bones of the shoulder, and the high-riding, winged scapula. These findings are depicted in the figures. There is wasting of the neck muscles and the medial end of the clavicles jut forwards, forming a distinct step at the base of the neck.  The droop in the shoulders result in the clavicles to run horizontally or to slope downwards.  The deltoid is spared, while the biceps and triceps are wasted. The arm may look slender with a bulky cap formed by the deltoid and bulky forearm giving the description of "Popeye" arm.  In severe cases (infantile and juvenile), the wrist extensors may be weak and produces a wrist drop. The wrist flexors have normal strength and maintain it while the lower extremity muscles are affected.  The inability to extend the wrist results in another characteristic posture adopted by patient with FSHD, the so-called "praying mantis" position.  

The pattern of shoulder and arm weakness in FSHD is different from that of limb-girdle dystrophy. The selective weakness of biceps and involvement of deltoid in LGMD is helpful to make the differentiation.  A study of 108 facioscapulohumeral muscular dystrophy patients with scapular involvement that used magnetic resonance imaging found that scapular muscles were affected in the following percentage of patients: trapezius 100%, serratus anterior 85%, rhomboids 55%, supraspinatus 4%, subscapularis 3%.

FSHD often involves the limbs in a very asymmetric fashion. It is not unusual to see one arm or leg severely involved while the other maintains reasonable strength. In the lower extremities, the ankle dorsiflexors weaken before proximal leg muscles in most patients.  The posterior compartment muscles are relatively preserved and therefore, the gastrocnemius is much stronger than the anterior tibialis and peronei muscles. There is preservation of the posterior tibial muscle which often leads to intorsion of the the foot while walking and , eventually, to a permanent equinovarus deformity of the foot. 

Patients with FSHD have trouble getting up when laying in a supine position. They tend to roll side-ways and use their arms to pull themselves up. There is presence of a positive Beevor's sign. This is elicited by asking the patient with FSHD to lift their heads and shoulders from the bed, when in laying in supine position. One will notice that the umbilicus of the patient is drawn several inches rostrally, dramatically. This affect is due to lower abdominal muscle weakness seen in FSHD and in contrast selective sparing of upper abdominal muscle.  The Beevor sign is associated with spinal cord (T10) lesion, but in FSHD it is present because of the uneven involvement of the abdominal muscles. It is quite specific of FSHD.

Pain is common in FSHD. Shoulder girdle laxity leads to muscle and joint pain, but also to neurogenic pain from the weight of the arm tugging downward and stretching the brachial plexus and nerve roots. Neck and back pain due to paraspinous muscle weakness, with kyphosis and exaggerated lumbar lordosis, is also common. 

Up to one-third of patients with FSHD who are nonambulatory have respiratory involvement. The greatest impairment is found in those who are wheelchair dependent and have kyphoscoliosis.  Early manifestations include nocturnal hypoventilation.  Respiratory insufficiency requiring ventilator support is rare.  Cardiomyopathy is not associated with FSHD.

Hearing loss is reported in 75% of patients with FSHD (infantile form), and retinal vascular abnormalities (Coats syndrome) in 60%. Cardiac arrhythmias are present in a slightly higher proportion of FSHD patients than controls but are generally asymptomatic. Due to the lack of significant bulbar, respiratory, and cardiac involvement in FSHD, life expectancy is normal; however, 20% of patients eventually require wheelchair use.

Coats syndrome: Subtle retinal vascular changes (peripheral telangiectasias) can be found in up to one-fourth of patients with facioscapulohumeral muscular dystrophy on retinal examination.  A more severe retinal vasculopathy known as Coats syndrome can be found in less than 1% of patients and is characterized by aneurysmal dilations, exudation, and, if untreated, can cause retinal detachment or blindness. Idiopathic Coats syndrome is typically unilateral and occurs in males; however, in facioscapulohumeral muscular dystrophy,  Coats syndrome is often bilateral, is found more commonly in females, with variable age of onset, and is associated with large contractions (less than 15 kb) and the smallest number of residual D4Z4 units (1 to 3 units remaining).

Pathogenetics: The genetic basis of FSHD1 has been linked to a reduction in the number of tandem repeats of a stretch of DNA which is 3.3 kb long (termed D4Z4) just below the telomere of chromosome 4q35.  In normal individuals the D4Z4 repeats exceed 11 (11-100), while in affected individuals it is between 1 - 10 repeats. Each D4Z4 repeat contains an open reading frame coding for a transcription factor known as DUX4 (double homeobox 4). Normally this region is highly methylated, and expression of the DUX4 gene is blocked.  In FSHD there are  1 to 10 D4Z4 repeats. are present.  This deletion of repetitive units is associated with hypomethylation of the region.  With hypomethylation, the chromatin is relaxed, allowing transcription of the normally dormant gene DUX4 from the terminal D4Z4 repeat.  However, for the DUX4 transcript to be polyadenylated and stabilized, the deletion must be in the correct context of one of two alleles (A and not B).  In this setting, FSHD1 ensues.  95% of all FSHD is FSHD1.

Thus, in FSHD, the smaller number of repeats results in decreased methylation and opening of the chromatin structure in the D4Z4 region, allowing the DUX4 gene to be expressed. This expression in muscle tissue is highly toxic.  DUX4 encodes for double homeobox 4, which itself is a transcription factor controlling the expression of other genes.  This in turn likely leads to the under or overexpression of other genes. 

FSHD2 is a rare form of FSHD caused by mutation in structural maintenance of chromosomes, flexible hinge domain containing 1 (SMCHD1) gene with resulting hypomethylation of the same sub-telomeric region of chromosome 4q and derepression of DUX4,

FSHD2 requires inheritance of two unlinked genetic factors: a permissive 4q A type (SNP) allele and a loss of function mutation of the SMCHD1 gene, which is found on chromosome 18p11.  FSHD 2 presents similarly to FSHD 1.  Onset age is usually older, though (more than 30 years).  Patients with severe weakness may have both FSDH 1 and FSHD 2 mutation.  Facial sparing, occurs in 15% of cases and is usually associated with smaller deletions.  Muscle inflammation, occurs in 75% of cases.

Diagnosis: The distinctive reversal of the anterior axillary folds along with scapular winging, asymmetries, triple-hump sign, and facial weakness guide the diagnosis. CK levels range from normal to 1000 U/L (if >1500 U/L; consider alternate diagnosis). EMG reveals myopathic motor units with or without muscle membrane instability. Definitive diagnosis of this autosomal dominant disorder is based on genetic analysis of a nonprotein-coding region of chromosome 4q. The deletion has to be on a form of chromosome 4q35(A).  A total of 95% of FSHD patients have deletion of the D4Z4 gene on chromosome 4.  Severity of the disease inversely correlates with the size of the D4Z4 repeat in FSDH 1.  Patient with 1 to 3 units are usually severely affected and often represent isolated (de-novo mutations) cases, whereas patient with 4 to 10 units typically have an affected parent.  False positives may occur due to nonpathogenic contraction of the D4Z4 gene.  In atypical cases of FSHD, the pathogenicity of D4Z4 mutations should be confirmed by looking for a permissive distal sequence (4qA).  

In FSHD the muscle biopsy shows inflammation and appears similar to PM with endomysial infiltrates. The differentiating feature is that in FSHD there is no evidence of invasion of non-necrotic muscle fibers.

Genetic test: FSHD

https://myfshd.org/    

FSHD COM

Treatment: AAN Guideline for management of FSHD

The management of FSHD focuses on conservative care to: limit the effects of weakness on the joints and bones, manage comorbidities (including monitoring for retinal vasculopathy), and optimize functional ability and quality of life. Specific therapy does not currently exist for FSHD. Several short-term open studies found that low-intensity aerobic exercise is beneficial. Scapular retraction orthoses and lumbosacral corsets can provide support in selected patients with axial weakness and back pain. There may also be a role for surgical intervention with scapulothoracic fixation in carefully selected patients. Ankle-foot orthoses provide dorsiflexion assist and ankle stabilization in those with significant foot drop. Management also includes psychological support aimed at improving patients' mental outlook and providing state of the art information to them about their condition.

Clinical trials: Losmapimod

Scapuloperoneal muscular dystrophy

• Caused by mutations and DES gene on 2q35, encoding for desmin and in FHL1 on Xq26.3 encoding for four and a half LIM protein.  Mutations in these genes are also associated with MFM.  

• Patient with scapulo-peroneal muscular dystrophy present with foot drop followed by scapular weakness within the first 2 decades of life.  

• Weaknesses is often asymmetric, and patient sometimes are diagnosed as having a peroneal neuropathy.  Some patients have a neuropathy or motor neuronopathy.  

• A few patients with myopathic scapuloperoneal syndromes may demonstrate compensatory hypertrophy of the extensor digitorum brevis with the ability to dorsiflex the foot more effectively than the big toe, an unlikely observation in neurogenic foot drop.  Ankle contractures are prominent features of the disease secondary to weak anterior compartment muscles.  

• The weak scapular muscles give appearance of the shoulder girdle similar to that seen in FSHD.  However, unlike FSHD, the humeral musculature is usually relatively spared.  On the other hand, the peroneal muscles are typically more severely affected and scapuloperoneal muscular dystrophy compared to FSHD.  

• Some patients may rarely manifest mild weakness of the facial muscles.  However, facial muscle weakness is less prominent than that seen in FS HD.  

• The muscle weakness is slowly progressive.

• Serum CK levels may be normal or moderately abnormal.

• EDX: Motor and sensory nerve conductions studies are normal aside from reduced CMAP amplitudes in the more severely affected muscles.  Needle EMG may demonstrate sparse fibrillation potentials and myopathic units.

Oculopharyngeal Muscular Dystrophy (OPMD):

• Inherited autosomal dominant with almost complete penetrance.  

• Expansions of a short GCG repeat in the gene encoding for PABPN1 (poly-adenylate binding protein nuclear-1), formerly called PABP2 (poly-A binding protein-2) on 14q11.  Normally they are 6 GCG repeats encoding for a polyalanine tract at the N terminus of the protein, but approximately 2% of the population has polymorphism with 7 GCG repeats.  In OPMD there is an expansion of 8–13 repeats.  These expansions are meitotically stable, unlike myotonic dystrophy, therefore, anticipation is not observed in OPMD. The expanded repeats lead to formation of misfolded protein that cannot be degraded and cleared so it ends ups to form neurotoxic inclusion bodies.

• Patient who are homozygous for GCG expansions may manifest at an earlier age and have more severe weakness.  Also, patients who are heterozygous for GCG and the GCG polymorphisms are also more severely affected.  Interestingly, late onset, autosomal recessive form of OPMD can develop in patients who are homozygous for the GCG polymorphism.  The GCG allele within PABPN1 with the first example of the polymorphism that could act as a modifier of a dominant phenotype or a recessive mutation. 

• The PABPN1 protein is found mostly in dimeric and oligomeric forms with the nuclei.  PABPN1 is involved in polyadenylation of mRNA and is adjoined to the polyadenylate mRNA complex for transport through the nuclei pores into the cytoplasm.  In the cytoplasm, the PABPN1 detaches from the mRNA.  The mRNA is translated into protein and the PABPN1 is actively transported back into the nuceli.  The expansion of GCG repeats probably results in abnormal binding of the polyalanine domains of PABPN1.  The misfolded proteins are ubiquitinated but are resistant to nuclear proteosomal degradation.  The mutated PABPN1 oligomers then accumulate as the 8.5 nm intranuclear tubulofilamentous inclusions apparent on EM.  The more severe clinical phenotypes are associated with a large number of myonuclei containing intranuclear inclusions.  The aggregation of mutated PAPBN1 may lead to disruption of various nuclear or cytoplasmic processes leading to cell death. 

• Presents present 40-60 with increasing ptosis which is almost always bilaterally but present initially with asymmetrically,  due to asymmetric involvement of levator palpebrae muscles.  

• Frequent in French-Canadian inheritance (Montreal)

• Ophthalmoplegia occurs in 50% of cases, but diplopia is rare due to chronicity and suppression of one image by the brain.  Pupils are spared.  Other causes of peripheral ophthalmoplegia, such as CPEO and CMS,  and MG should be considered.

• Ptosis is usually is followed or accompanied (but seldom preceded; only less than 25% of case present with dysphagia initially) by dysphagia—first for solid food and later for liquids as well.  Dysphagia is slowly progressive leading to weight loss and aspiration.  These patients have normal palatal movements but can have slight impairment of gag reflexes, suggesting that the dysphagia and accompanying regurgitation result from impaired esophageal motility.  In a small number of patients, when dysphagia is severe and they are at risk of aspiration pneumonia, cricopharyngeal myotomy has resulted in significant improvement.  

• Laryngeal involvement leads to dysphonia (nasal/spastic). 

• Facial and masticatory muscles may be slightly weak.  Gag reflex is impaired.   Pharyngeal weakness results in dysphagia, dysphonia, and dysarthria. 

  • The most common cause of premature death in oculopharyngeal muscular dystrophy (OPMD) is complications related to lack of treatment of dysphagia 

• Mild neck and proximal limb weakness is seen.

• Distal muscles involvement in distal variant of OPMD.

• Normal sensation, MSR: diminished or absent. 

• Normal studies demonstrate impaired pharyngeal and esophageal motility.

• No myotonia.  No abnormal reflexes.  No sensory abnormalities or facial weakness.  No history of visual or cardiac problems. 

• Sensation is normal: But muscle stretch reflexes can be reduced or absent.

• CK and aldolase levels are normal

• Muscle biopsy is not necessary for the diagnosis, but if obtained, it would show chronic myopathic features and red-rimmed vacuoles similar to the ones seen in inclusion body myositis (IBM).

• EM shows 8.5 nm intranuclear tubulofilament inclusions that are arranged in tangles and palisades (~9%) that contain PABPN1 proteins, and fiber size variation.  In addition, 15 to 18 nm tubulofilaments may be evident in the cytoplasm, as seen on IBM, h-IBM, in the form of the distal myopathies. 

• EMG is abnormal in affected muscles.

• There is a variant where distal muscles are affected (distal OPMD).

• There is no cure.  Eye crutches on glasses, taping of eyelids.  Oculoplasty for ptosis and cricopharyngeal myotomy for dysphagia are helpful if appropriately timed.  Patients with severe dysphagia resulting in aspiration or significant weight loss required PEG-T placement.  Patients have normal survival rates.

• Variants of OPMD: Infantile or early childhood onset of ptosis, ophthalmoparesis, and severe generalized weakness with respiratory failure is reported.  Oculopharyngodistal myopathy (mostly in Japan) but can be seen in other ethnic groups.  Weakness develops earlier than classic OPMD, with onset usually in the first decade of life in some cases.  It can present with chronic intestinal pseudo-obstruction.  

OPMD Surveillance:

• Neuromuscular: Annual surveillance by neuromuscular specialist to check for overall disease progression and to assess presence and severity of proximal weakness and other neurologic findings.

• PT/OT: To assess gross motor and fine motor skills, gait ambulation, need for adaptive devices, PT, and OT.

• Oculomotor: Neuro ophthalmology evaluation and ophthalmology examination.  To assess best corrected visual acuity.  Determine presence and severity of ptosis and range of extraocular movement.  Surgery is an option for severe ptosis if it obscures vision. Consider frontal suspension of the eyelids as permanent option as the frontalis muscle, which is relatively preserved in OPMD.

• Pulmonology: PFT, chest CT as baseline and when symptomatic.  

• Sleep medicine: Nocturnal polysomnography for features of OSA. 

• Speech pathologist: Swallow evaluation.

• Dysphagia: Food should be cut into small pieces.  Report frequent choking when eating.  Cricopharyngeal dilatation (preferred) or if needed cricopharyngeal myotomy 

• Nutritionist: Nutritional status and diet.  Weight monitoring. 

• Psychiatry/neuropsychologist: To assess cognitive dysfunction if needed.

• Pain and fatigue: Perform evaluation as needed.  BDI-PC, CIS, McGill's pain questionnaire, symptom checklist 90; sickness Impact profile-136.

• Genetic counseling: Inform patient that the family is about nature and implications overall PMD in order to facilitate medical and personal decision making.

• Anesthesia: General anesthesia is not contraindicated, although individuals with OPMD may respond differently to certain anesthetics (Caron MJ, Girard F, Girard DC, Boudreault D, Brais B, Nassif E, Chouinard P, Ruel M, Duranceau A. Cisatracurium pharmacodynamics in patients with oculopharyngeal muscular dystrophy. Anesth Analg. 2005;100:393–7.)

• Family support/resources: Use of community or online resources.  Need for social work involvement for caregiver support. https://rarediseases.org/rare-diseases/oculopharyngeal-muscular-dystrophy/

Oculopharyngodistal myopathy

Oculopharyngeal distal myopathy (OPDM) is a group of genetically heterogenous muscle diseases, characterized by onset in adulthood and slowly progressive weakness affecting ocular, bulbar, and distal limb muscles, and pathologically by the presence of rimmed vacuoles and intranuclear inclusions.

Expansion of CGG repeats in the 5' undtranlated region (5' UTR) of LRP12 (OPDM1), GIPC1 (OPDM2), NOTCH2NLC (OPDM3), and RIPL1 (OPDM4) have been reported to cause OPDM in Japan in China.  The disease was first described in for Japanese families more than 4 decades ago, and subsequently was also reported from other countries.

OPDM1 is the most common OPDM subtype in Japan, accounting for 31.25% of Japanese OPDM patients, while OPDM2 is the most common OPDM subtype in China, accounting for 37.3% of Chinese OPDM patients.  LRP12 low-density lipoprotein receptor related protein 12 is a transmembrane protein that is expressed in various organs, including skeletal and cardiac muscle.  The normal number of CGG repeats in LRP12 ranges between 13 and 45, whereas affected patient's  process more than 50 repeats.  The presence of CTG repeat expansions in all 4 OPDM subtype suggests that they have a common pathogenic mechanism.

The 2 possible mechanisms are: 

1. RNA dependent gain of function, triggering the formation of cytotoxic RNA foci causing myodegeneration

2. Repeat associated non AUG (RNA) translation, producing a toxic protein containing polyglycine stretch.  

OPDM1 is likely transmitted in autosomal dominant fashion with incomplete penetrance, has some families had multiple symptomatic individuals and in consecutive generations while other families had asymptomatic individual with disease range expansions.  An inverse correlation between the length of CCG repeats and age of onset was observed.

Duchenne muscular dystrophy (DMD)

Becker muscular dystrophy (BMD)

Congenital Muscular Dystrophy

• Heterogenous group of AR disorders characterized by the perinatal onset of hypotonia and weakness, dsytrophic muscle biopsies and exclusion of other recognizable myopathy of the newborn.   Abbreviation MDC is assigned by the Human Genome Organization.  MDC stands for muscular dystrophy congenital.  The major categories of MDCs include:

1. Those associated with mutations in genes encoding structural proteins of the basal lamina, extracellular matrix, or sarcolemmal proteins that bind to basal lamina. 

2. Those associated with impaired glycosylation of alpha-dystroglycan

3. Those associated with selenoprotein 1 mutations. 

MDC 1A (MDC with Laminin  alpha2 or merosin deficiency), LAMA2, 6q21-22

• 30 - 40% of patients with MDC have absent or severely reduced merosin.  

• Some have partial merosin deficiency which are known to be secondary deficiencies from glycosylation defects in alpha-dystroglycan.  Merosin binds to alpha-dystroglycan and alpha7-beta 1-delta integrin. Merosinopathies may result in a disruption and loss of integrity of the dystrophin-glycoprotein complex.  

• Merosin is also present in the basal lamina of myelinated nerves.  Abnormal expression of merosin may interfere with myelinogenesis and may account for the hypomyelination evident in the central and peripheral nervous system.  It is also expressed in the skin and thus, merosin-negative MDC can be diagnosed on skin biopsy.  

• Merosin-negative congenital muscular dystrophy (MDC1A) is the most common  form of congenital muscular dystrophy.

  • It is caused by mutations in the laminin α2 gene (LAMA2) linked to chromosome 6q22-q23.  It is inherited in an autosomal recessive pattern.

  • Children manifest at birth with generalized weakness and hypotonia.  Predilection of weakness is for neck, shoulder, and hip-girdle muscles.  Calf hypertrophy may be appreciated early in the course.  Contractures develop but severe arthrogryposis is rare.  Breathing and feeding problems occur but are not severe enough to need ventilatory support and tube feeding.  Some children develop cardiomyopathy.  Some EOM impairment is noted in later stages of life.  

  • Merosin negative is more severe than merosin positive cases.  Most children with merosin-negative MDC  typically have severe weakness and is associated with a poorer prognosis compared with merosin-positive cases.  Merosin negative MDC1A never ambulate independently.  

  • Individuals with partial merosin deficiency have a milder course and can be present in childhood with a DMD phenotype or in early adulthood with a phenotype similar to BMD or LGMD. 

  • Most children with MDC1A have normal intelligence despite abnormal white matter changes apparent in MRI.  There is high incidence of epilepsy (12-30%) as well as some reported cases of occipital dysplasia in merosin-deficient MDC.  Epilepsy can also occur in patients with partial merosin deficiency.  Rare patients with MDC1A with epilepsy and occipital gyri also have mental retardation.  

  • CK levels are markedly elevated, usually over 2,000 in merosin negative infants, while partial merosin myopathies are associated with normal or mildly elevated serum CKs.  

  • MRI of brain demonstrates diffuse white matter abnormalities in T2WI suggestive of demyelination in most children after the age of 6 months.  Occipital polymicrogyria/agyria and hypoplasia of pons and/or cerebellum are evident in rare cases.  Patients with partial merosin deficiency may or may not have cerebral hypomyelination on MRI.  

  • VEP and SSEPs may reveal delayed latencies in MDC1A.  

  • Slowing of NCV is also commonly observed.  

  • Muscle biopsy:  variation in muscle fiber size, increased endomysial connective tissue, and decreased or absent merosin. 

  • Skin biopsy. 

  • Prenatal diagnosis: CVS

• Merosin positive classic MDC is clinically more benign than Merosin negative MDC.

  • Genetically heterogeneous.

  • Some partial merosin deficiency cases (MDC 1B) on 1q42.  Some cases of partial merosin deficiency or MDCs with normal merosin are due to mutations in glycosyltransferases which causes secondary alpha-dystroglycanopathy.  

  • Mutations of the alpha7-subunit of integrin gene, ITGA7, located on 12q13 have been demonstrated in 3 patients to date with merosin positive MDC. 

  • Children who are affected present with congenital onset generalized weakness or hypertonia and delayed motor milestones.  Mental retardation was reported in 1 child who had a normal MRI of the brain after EEG.

  • Serum CK is mildly elevated less than 5 times normal.

  • Muscle biopsy:  mild variation of fiber size with normal Merosin expression on immunohistochemistry.

Ullrich Disease

Ullrich congenital muscular dystrophy (UCMD) is associated with weakness at birth or early infancy, contractures of the proximal joints (elbows and knees), hyperextensibility of the distal joints, high arched palate, and protuberant calcanei.  It is associated with congenital muscle weakness, delayed motor milestones, proximal joint contractures, scoliosis, and marked distal joint hyperextensibility.  Intelligence is normal. Loss of ambulation by age 10 years and respiratory compromise even earlier.  

• It is allelic with a more benign Bethlem myopathy.

• UCMD can be autosomal recessive or autosomal dominant inheritance, unlike Bethlem myopathy which is autosomal dominant.

• Serum CK is normal or mildly elevated.

• Muscle biopsy:  Variation in muscle fiber size, scattered regenerating and degenerating fibers, and increase in endomysial connective tissue.  Immunohistochemistry reveals that collagen 6 is present in the interstitium but absent from the sarcolemma.  EM demonstrated collagen 6 in the interstitium fails to anchor normally to the basal lamina surrounding muscle fibers.  

• Collagen 6 is composed of 3 chains: alpha-1, alpha-2, and alpha 3 and is ubiquitously expressed extracellular matrix protein.  The 3 chains are encoded by COL6 A1 and COL6A2  on 21 q22.3 and COL6A3 on 2q37.  UCMD and the less severe Bethlem myopathy are caused by mutations in these genes.

• Collagen VI is an important component of the extracellular matrix of many tissues including muscle, skin, tendon, cartilage, and adipose tissues and has an important role in maintaining structural stability by anchoring the basement membrane to the extracellular matrix.  Mutations in any of the three genes encoding collagen VI can result in collagen VI–related muscular dystrophy phenotypes. The triple helical region contains a repeated Gly-X-Y motif common to all collagens that allows tight coiling of the three chains and is particularly sensitive to mutation.

• UCMD has been considered a recessive condition caused by homozygous or compound heterozygous mutations in COL6A2 and COL6A3,  In contrast, the milder disorder Bethlem myopathy has autosomal dominant inheritance caused by a single mutation in COL6A1, COL6A2, and COL6A3.  Some studies however have demonstrated that a UCMD can be inherited in an AD fashion.  There is a correlation of collagen 6 deficiency and the clinical severity in UCMD.   Collagen VI mutation can be absent in some cases suggesting that a mutation involving other proteins that potentially interact with collagen VI. 

• The COL12A1 gene is associated with autosomal recessive Ullrich congential muscular dystrophy 2 (UCMD2).

Collagen type VI-related disorders 

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1736127/pdf/v042p00673.pdf 

• Cardiac involvement is not reported in collagen VI disorders. 

• Spontaneous pneumothoraces have been reported. 

• https://www.curecmd.org/

Bethlem myopathy (LGMD D5) Collagen VI–Related

• Autosomal dominant, allelic to UCMD. 

• Onset is usually at birth or early childhood with history of decreased fetal movements which may be noted in-utero, and neonates may demonstrate generalized hypotonia.  Motor milestones are often delayed but eventually are reached.  Weakness may not be evident until early adulthood.  

• Phenotypic variability is seen with an affected family members.  

• There is proximal greater than distal muscle weakness, with the legs being more severely affected than arms.  Extensor muscles are weaker than flexor muscles.  They can be mild neck and trunk involvement.  Cranial muscles are spared.  Muscle strength can be asymmetric.  Calf hypertrophy may be seen.  As in EDMD, contractures at the elbows and ankles are seen early in the course before any significant weakness.  Eventually, contractures develop in the wrists and fingers.  Some patients present with only proximal hip and shoulder girdle weakness without evidence of contractures, resembling LGMD.  Muscle stretch reflexes may be normal or reduced.  It was thought, earlier, that the heart was spared in Bethlem myopathy as most patients do not present it as a notable feature.  However, some patients have been reported to have abnormal echocardiograms and ECGs.  These include atrial fibrillation, accelerated atrial rhythm, intraventricular conduction delay, right bundle branch block, and pathological Q waves and atrial dilatation.  Thus, detail cardiac investigations and Bethlem myopathies do reveal abnormalities in 10% of cases.  Ventilatory muscles appear to be involved in Bethlem myopathy.  There is reduced vital capacity.  Some have progressive ventilatory insufficiency due to diaphragmatic muscle involvement.

• Serum CK is normal or mildly elevated.  Cardiac studies may be abnormal.  Motor and sensory nerve conduction studies are normal.  Needle EMG may show normal insertional and spontaneous activity, although a mixture of small amplitude, short duration polyphasic MUP with large amplitude, long duration MUP can be seen.  Skeletal muscle MRI of the thigh in patients with Bethlem myopathy reveals moderate involvement of the thigh muscles with the "central shadow" within the rectus femoris (preferential involvement of the muscle and replacement with fatty tissue in the anterior aspect of the muscle), atrophy and increased abnormal signal at the periphery of the vastus lateralis, and fatty replacement between the vastus lateralis and the vastus intermedius.

• Myopathy has been linked to dominant heterozygous mutations of the genes:  COL6A1 and COL6A2  on 21 q22.3 and COL6A3 on 2q37. 

• The COL12A1 gene is associated with autosomal dominant Bethlem myopathy 2 (BTHLM2)

• Muscle biopsy shows nonspecific features such as variability in fiber size, increased splitting, central nuclei, and mild endomysial fibrosis.  Lobulated type I fibers and moth-eaten fibers may be apparent on NADH-TR stains. 

• Treatment: Physical therapy is indicated to prevent progressive contractures that can impair mobility and function.

Laing Distal Myopathy

MDC associated with impaired glycosylation of alpha-Dystroglycan

Alpha-dystrocylcanopathies are the result of mutation and alpha dystrophy glycan (DAG1) gene, and at least 13 other genes to date that are involved in the glycosylation pathway (POMT1, POMT2, POMGnT1, FK RP, Fukutin,  LARGE, ISPD,  GTDC2, B3GALNT2, B3GNT1, TMEM 5, GMPPB, , SPK196, and DPM1, DPM2, DPM3, RXYLT1).  All of these are enzymes that are involved in post-translation glycosylation of alpha-distrogycan.  Not only is glycosylation of alpha-dystroglycan important for proper muscle function, but its impaired glycosylation leads to defects in neuronal migration and abnormalities in the central nervous system.

• WWS (Walker-Warburg Syndrome), MEB (Muscle-eye-brain disease) is now known as Muscular dystrophy-dystroglycanopathy with brain and eye abnormalities (type A) or MDDGA1 caused by POMT1 gene .  

• MDDGA2 is caused by mutations in the POMT2 gene.

• MDDGAD3 is caused by mutations in the POMGnT1 gene.

• MDDGA4  is caused by mutations in the FKTN gene.

• MDDGA5 is caused by mutations in the FKRP gene.

• MDDGA6 is caused by mutations in the LARGE gene.

• MDDGA7 is caused by mutations in the ISPD gene.

• MDDGA8 is caused by mutations in the GTDC2 gene.

• MDDGA10 is caused by mutations in the TMEM5 gene.

• MDDGA11 is caused by mutations in the B3GALNT2 gene.

• MDDGA12 is caused by mutations in the SGK196 gene.

• MDDGA13 is caused by mutations in the B3GNT1 gene.

• MDDGA14 is caused by mutations in the GMPPB gene. 

Muscle biopsy findings are nonspecific from other forms of MDC using routine stains.  Inflammatory infiltrate is occasionally present, which may lead to the erroneous diagnosis of a  congenital inflammatory myopathy or polymyositis.

Abnormal glycosylation of alpha dystroglycan can be appreciated by reduced immunostaining of the sarcolemmal membrane with antibodies directed against alpha-dystroglycan and meerosin.

Fukuyama Congenital Muscular Dystrophy

It was first described in Japan where it is the most common form of MDC.  

Clinical features: Generalized proximal greater than distal weakness and hypotonia in infants.  Mothers of affected children retrospectively recall decrease in fetal movements. There is an increased frequency of spontaneous abortions of affected fetuses.  Pseudohypertrophy of the calves occurs in approximately half of the children.  Muscle stretch reflexes are reduced.  Some children are born with arthrogryposis and contractures that are progressive.  In addition to the myopathy, FCMD is associated with severe structural abnormalities of the brain, including microcephaly, cortical dysplasia, lissencephaly, pachygyria, polymicrogyria, and hydrocephalus.  Intellectual function is markedly compromised. 50% of the children affected have seizures.  Physical and mental development is delayed, with the majority never being able to stand or ambulate independently.  Most children die by age of 10 to 12 years of age from ventilatory failure.  CK is usually elevated 10-50 times normal values.  EEG is often abnormal demonstrating epileptiform activity and generalized slowing.  MRI and CT scans of the brain reveal structural abnormalities and evidence of hypomyelination.

FCMD  is caused by mutations in the fukutin gene, FKTN on 9q 31.  Fukutin is a secretory enzyme that localizes to the cis-golgi compartment is thought to have a role in post-translation glycosylation of alpha dystroglycan.  In addition to the skeletal muscle involvement, the disruption of normal glycosylation of alpha-dystroglycan or other proteins leads to defects in neuronal migration and differentiation, which accounts for the many abnormalities seen with of the central nervous system.

Walker Warburg syndrome (WWS) or cerebro-ocular dysplasia.

It is the most severe alpha-dystroglycanopathy and is associated with a life expectancy of less than 3 years.

Infants presented with severe generalized weakness and hypotonia.  They are usually born blind secondary to ocular malformations, which include fixed pupils, hypoplasia of the optic nerves, microphthalmia, corneal opacities, cataracts, shallow anterior chambers, ciliary body abnormalities, irido-lental synechia, retinal dysplasia and detachment.  It is also associated with migrational and developmental disturbances of neurons of the brain, which include lissencephaly, polymicrogyria, hydrocephalus, hypomyelination of the subcortical white matter and hypoplasia of the brainstem and vermis.  Seizures are common.  CK levels are elevated.  MRI of the brain reveals structural abnormalities as mentioned above.  EEG is often abnormal, revealing slowing of the background and epileptiform activity.

WWS  is caused by mutations in several genes (POMT1, POMT2,  FKRP, FKTN, ISPD, CTDC2, TMEM5, POMGnT1, B3GALNT2, GMPBB, B3GNT1,  SGK196).  Mutations of the POMT1 gene are the most common and account for 20% of the cases of WWS.  Rare cases being reported with LGMD and mild mental retardation (LGMD2K).

Muscle-eye-brain disease

First described in Finnish patients and later reported in other populations.  

MEB is commonly caused by mutations in POMGnT1 on 1p32-p34..  Mutations in this gene have also been associated with a milder myopathy, and LGMD 2M.  Mutations in the FKRP, FKTN, ISPD, and TMEM5 genes can also cause MEB.

Similar to WWS, brain and eye abnormalities are accompanied by muscle weakness; however MEB is less severe than WWS.  Infants are weak and motor development is slow but most affected children eventually can sit and stand and some are able to walk.  Severe cognitive impairment is associated with structural abnormalities of the brain, which include pachgyria, polymicrogyria, abnormal midline structures, and hypoplasia of the vermis and pons.  MEB is also associated with progressive myopia, glaucoma, and late cataracts. Serum CK levels are elevated.  MRI of the brain may demonstrate polymicrogyria, abnormal midline structures, hypoplastic vermis, and pons.  

 MDC 1C or MDDGA5

 MDC 1C also known as MDDGA5 is allelic to LGMD 2I and is caused by mutations in the genes that encode for FKRP.  The myopathy is very common, especially among patients of Norther Europe including English ancestry, and give rise to the largest phenotype spectrum of muscular dystrophy so far connected to mutations of a single gene.  The age of onset can range from infancy to the fourth decade of life, with a pattern of weakness similar to MDC 1A.  Early involvement of cardiac and respiratory muscles is common.  CK levels are always very elevated (10-75 times normal).  TTE: DCM.  PFTs may reveal reduced forced vital capacity and inspiratory pressures.  MRI of the brain may reveal microcephaly, cerebellar cysts, and hypoplasia of the vermis, and also white matter abnormalities.

MDC 1D

Very rare dystrophy caused by mutations in LARGE gene which is also required for glycosylation of alpha-dystroglycan.

It is associated with generalized weakness, mental retardation, and global developmental delay.  Motor milestones are delayed but individuals who are affected may be able to ambulate.  Nystagmus may be seen on examination but no other ocular abnormalities are typically identified.  Serum CK is mild to moderately elevated.  MRI of the brain show mild structural abnormalities. 

MDC associated with Selenoprotein N1 mutations.

Rigid spine syndrome or rigid spine muscular dystrophy (RSMD) is heterogeneous disorder.  

Some cases are autosomal recessive and have been linked to the gene that encodes for selenoprotein N1 (SEPN1) on 1p35-36.  Mutations in this gene have also been shown in some patients with multi/minicore myopathy and MFM.  Selenoprotein N1 is an endoplasmic reticulum glycoprotein. 

RSMD1 manifest in infancy with hypotonia, proximal weakness, and delayed motor milestones.  Affected individuals develop progressive limitation of spine mobility often associated with scoliosis and contractures at the knees and elbows.  Initially many clinical features with EDMD and UCMD/Bethlem myopathy.  Frequently misdiagnosed with multi/minicore congenital myopathy.  Respiratory weakness can develop due to stiffness of the rib cage and involvement of the diaphragm.  Many patients need noninvasive ventilatory support.  Serum CK is normal or slightly elevated.  ECG may show conduction defects.  PFT showed reduced vital capacity.  EMG demonstrated myopathic appearing motor unit potentials, while insertional activity is typically normal and abnormal spontaneous activity is sparse.  

Muscle biopsy is nonspecific and shows myopathic features including variability in fiber size, increase internal nuclei, type I predominance, and moth-eaten fibers and lobulated fibers on NADH-TR stains.  Some cases are associated with multiple minicores.  Cytoplasmic bodies, Mallory bodies, increased desmin expression, and sarcoplasmic and intranuclear tubulofilamentous inclusions may also be present similar to MFM.   Endomysial fibrosis is apparent, particularly in the axial muscles (rectus abdominis and paraspinal muscles).  Immunostains for dystrophin, sarcoglycans, and the dystroglycans are normal.

Welander (Later Adult onset distal myopathy type I)

• Defect on 2p13, (TIA1 gene - cytotoxic granule-associated RNA binding protein). Available as blood test

• Welander distal myopathy has an autosomal dominant inheritance and a late onset, usually in the 5th decade of life (mean age of onset: 47).. 

• Almost exclusively seen in patients with Nordic (Swedish or Finnish) heritage.

• Starts in hands, primarily affecting the fingers and wrist extensors.

• The onset of symptoms is in the hands (wrist and finger extensors) and gradually distal muscles of the lower extremities are involved; ankle dorsiflexors  more than plantar flexors.  In 10% it starts in the legs or simultaneously in distal arms and legs.  Flexor muscle groups are less involved but do get involved in ~40% of cases. 

• Sensation is normal

• MSR is preserved initially, but the brachioradialis and ankle reflexes diminish or disappear over time. 

• CK-values are normal or slightly elevated. 

• There is never any cardiac involvement in Welander distal myopathy. 

• Neurophysiological findings are myopathic in character. 

• Histopathological findings in muscle biopsies are mainly of myopathic type and include rimmed vacuoles which correspond to autophagic vacuoles on the ultrastructural level. Tubulo-filamentous inclusions with a diameter of 16-21 nm, i.e. of the same type as found in patients with Inclusion Body Myositis, are found in the sarcoplasm and in myofiber nuclei. 

• A neurogenic component in Welander distal myopathy has been suggested, on the grounds of a sensory dysfunction, neuropathic findings on neurophysiology and muscle biopsy and a decrease of A-delta nerve fibers on sural nerve biopsy. 

• Genetic analysis has excluded linkage to other defined distal myopathies and hereditary Inclusion Body Myopathy.

Udd Distal Myopathy

• Autosomal dominant distal myopathy associated with mutations in the TTN gene on 2q31-33 and encoding for titin. 

• Usually presents after the age of 35 years (5th-7th decade) with weakness of the anterior compartment of the lower legs resulting in unilateral or bilateral foot drop.  It is slowly progressive, beginning in the toe extensors and gradually involving anterior tibial muscles.  Occasionally, the proximal legs and distal upper limbs (predominantly the hand intrinsics and wrist extensors) are affected.  

• Rare presentations include arms affected more than legs, posterior calves involvement with sparing of the anterior tibial muscles, or patients with LGMD distribution of weakness.  Facial muscles are usually spared, although bulbar weakness has been reported.  Sensation is normal.  Ankle reflexes are reduced.  Unlike other forms of titin myopathy, cardiac and ventilatory muscles are usually spare in Udd distal myopathy.

• Normal CK or only slightly elevated.  

• Motor and sensory NCS are normal.  EMG reveals fibrillation potentials and positive sharp waves as well as small amplitude, brief duration motor unit potentials with early recruitment.  

• Muscle MRI shows fatty infiltration of the anterior tibial and extensor digitorum longus more than gastrocnemius muscles; proximal pelvic muscles, gluteus medius and minimus may be affected later.  

• Allelic to autosomal recessive LGMD 1 and autosomal dominant HMERF.

Markesbery-Griggs Distal Myopathy

• ZASP

• Similar to UDD type.

• AD

• Progressive foot

• CM is common

• MFM 

GNE myopathy, a.k.a Nonaka myopathy (Autosomal recessive hereditary inclusion body myopathy)

• A rare (1:million) prevalence, but progressive distal myopathy which starts distally and then progresses proximally.

• It is a distal myopathy characterized by presence of rimmed vacuoles in muscles. 

• The muscle biopsy results are also quite similar to those of Markesbery-Griggs, Udd, and Welander myopathies in that rimmed vacuoles are observed. 

• Further EM reveals 15- to 18-nm tubular filaments typical of inclusion body myositis. 

• However, unlike inclusion body myositis, no significant inflammatory process occurs in hIBM.

• Mild or no elevation of CK

• Pathogenesis:

  • GNE encodes a single protein with 2 enzyme activities in the sialic acid synthetic pathway:

    • Epimerase

    • Kinase

  • Sialic acid are monosaccharides in the terminal portion of glycoproteins and glycolipids. They are crucial for cellular interactions and function. 

  • Hyposialylation appears to be important in the pathogenesis of GNE myopathy.

• Adult-onset (3rd decade of life) distal myopathy in Japanese, middle eastern Jews, Iranian Jews, and certain pockets in India. 

• Nonaka myopathy is caused by mutations in the gene encoding for UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase, or GNE gene, on chromosome 9p1-q1 

• The clinical phenotype is similar to that of Markesbery-Griggs (ZASP gene) and Udd myopathies, with weakness initially involving the anterior tibial muscles, axial muscles, and flexor forearm muscles.

  • Foot drop 

• Quadriceps sparing

• Skeletal muscles affected only.

• Facial, EOM, bulbar, intercostal, and diaphgram muscles are spared

• Progressive muscle weakness results in wheelchair dependence in 10-20 years. 

• Cardiac involvement is very uncommon (<10%)

• Tx: IVIG (high load of sialic acid), vector gene therapy.

Miyoshi myopathy (Early adult onset distal myopathy type II)

• Autosomal recessive, or sporadic.

• Mutation in the gene on 2p13; it is allelic to LGMD type 2B, dysferlin (DYSF gene)

• ANO5.

• Presents early in adult life

• Myopathy that affects the posterior compartment of the legs.  Gastrocnemius and soleus are involved.  

• Weakness eventually involves more proximal muscle groups.

• Pts have high CK, 10 to 100 times that of normal

• 25% of cases are misdiagnosed as PM.

• Bx of hamstring muscles (semitendinosus) is most useful and usually shows dystrophic changes. Gastrocnemius would show only endstage histological abnormalities and would not be revealing, whereas the quadriceps would be normal or show only minimal changes.

• Myoshi distal myopathy is to be distinguished from Nonaka distal myopathy, which is characterized by predominant tibial muscle involvement and rimmed vacuoles.

Emery-Dreifuss Muscular Dystrophy (EDMD):

• X-linked, AD, or AR (rare) forms.  

• X-linked due to mutation in the gene  EMD on Xq28, which encodes emerin (nuclear membrane protein).  EDMD-X1

• Autosomal dominant form of EDMD2 is due to mutation in the LMNA gene on 1q21, which encodes lamin A/C (nuclear membrane protein).  

  • Allelic with LGMD1B (chromosome 1)

  • AD form of EDMD2 is more common than X-linked EDMD.

  • Less likely to have contractures and if they do is not early on as in X-linked EDMD.

  • De novo mutations are responsible in 76% of cases 

• Autosomal recessive EDMD  is a rare muscular dystrophy with contractures and severe rigidity of the spine.  Onset is usually in the first 2 years of life and children are unable to walk by the age of 8 years.  There is no cardiac abnormalities.  Serum CK is moderately elevated.  It is caused by mutations in LMNA.

• About 60% of patients with the EDMD do not have mutations of the case including emerin or lamin A/C.  Mutations in the genes that code for an Nespirin 1 and Nesprin 2 have been reported in several sporadic cases and autosomal dominant families with EDMD like phenotypes.  

• Nesprin-1 and Nesprin-2 are transcribed from 2 genes, SYNE1 on 6q24 and SYNE2 on 14q23.  

• Rare causes of autosomal dominant EDMD are caused by mutations in TMEM43 that encodes for transmembrane protein 43 or LUMA. 

• There is reduced mobility of the spine.  EDMD is in the differential diagnosis of the "rigid spine syndrome."

• Patient have difficulty flexing the neck and trunk.  The contractures of the Achilles tendons, elbows, and paraspinal muscles are evident before there is any significant weakness, which helps distinguish X-linked form of EDMD from autosomal dominant EDMD where weakness precedes contractures.  

• Patients with EDMD are born normal usually.  There is an early predilection for weakness and atrophy affecting the humeral peroneal muscles (biceps brachii, triceps, anterior tibial, and peroneal muscles).  Pes-cavus deformities of the feet are common.  Weakness is slowly progressive and eventually the shoulder and pelvic girdle muscles can become involved.  Most affected individuals are able to ambulate into the third decade.  There is no calf hypertrophy.  Muscle stretch reflexes are diminished or absent early in the disease.

• Woman carriers  do not manifest muscle weakness or contractures, however, there may appear to develop cardiomyopathy.  Affected individuals with FHL 1 mutations unlikely to develop ventilatory muscle failure.

• Serum CK levels may be normal or moderately elevated.

• ECG frequently reveals sinus bradycardia, prolongation of the PR interval, or more severe degree of conduction block.

• EDX: Motor and sensory conduction studies are typically normal in these patients.  EMG reveals myopathic motor unit potentials.

• Muscle biopsies in patients with FHL 1 mutations (EDMD-X2) can be distinguished from those with more common EMD mutations, (EDMD-X1) 

• Annual cardiac work-up including ECG on all patient including possible female carriers and a 24-hour Holter monitoring.  Affected individuals may require pacemaker or AICD at there is an increased risk for sudden cardiac death.  Physical therapy is aimed at minimizing contractures.

Bent Spine/Dropped Head Syndrome

Myofibrillar Myopathy (MFM)

• Mutations in genes encoding the structural proteins of the Z-disk or the proteins that maintain Z-disk functions typically cause myofibrillar myopathies (MFMs).  The pathologic hallmark of MFMs is the presence of sarcoplasmic aggregations of myofibrillar degradation products as a result of Z-disk disintegration

• Mutations in several genes (BAG3, CRYAB, DES, DNAJB6, FHL1, FLNC, HSPB8, MYOT, and ZASP) have been identified in MFM patients, although approximately half of MFM cases lack a molecular diagnosis.  Skeletal muscle a-actin (ACTA1), lamin A/C (LMNA), nebulin (NEB), plectin (PLEC1), and titin (TTN) are not constituents of the Z-disk, but they interact with Z-disk proteins, and mutations in these proteins occasionally give rise to MFM pathology.

• Desminopathy is likely the most common form and αβ-crystallinopathy is the least common form. 

• Age at onset varies from 7-77 years, with a mean of 54 years, except for patients with mutations in selenoprotein N who have onset at birth and the 1 described patient with a lamin A/C mutation who presented at age 3 years. Patients with desminopathy often present in early adulthood, while patients with myotilinopathy and filaminopathy often present after age 50 years

• Clinically, this group of disorders is heterogeneous, with slowly progressive weakness affecting the proximal and distal muscles in most patients, but about 25% present with distal predominant weakness (common in myotilinopathy), and 25% present with only proximal weakness (common in filaminopathy). 

• Muscle MRI may help to distinguish distinct subtypes.  In patients with desminopathy, the semitendinosus was as least equally affected as the biceps femoris and the peroneal muscles were never less involved than the tibialis anterior. In patients with myotilinopathy, the adductor magnus was more affected than the gracilis and the sartorius was as least equally affected as the semitendinosus. In patients with filaminopathy, the biceps femoris and semitendinosus were at least equally affected as the sartorius, the medial gastrocnemius was more affected than the lateral gastrocnemius and the semimembranosus was more affected than the adductor magnus.

• Rare findings include the following:

  • Facial weakness

  • Asymmetric weakness

  • Severe atrophy

  • Respiratory failure, which may be severe or at presentation

  • Contractures

  • Distal sensory deficits (neuropathy diagnosed in about 20%)

  • Cardiac disease (especially common in desminopathy) may be present either as cardiomyopathy or arrhythmias and conduction block, and is present in about 50%.

• Specific mutations

  • Desminopathy (MFM1): Onset is generally in the 20s or 30s with slow progression. Patients often present with distal weakness that progresses proximally, but limb-girdle, scapuloperoneal, and distal weakness combined with proximal weakness have all been described. Inter- and intrafamilial variability exists. Those with autosomal recessive disease may have an early onset. Cardiac disease (cardiomyopathy or atrioventricular conduction abnormalities) occurs in about 60% and may follow or precede myopathy, may be isolated, and may be severe. Respiratory failure may be severe and may be present at presentation. Facial and bulbar weakness may occur late. About 75% of patients eventually need assistance with ambulation.

  • αβ-crystallinopathy (MFM2): Onset varies from early to mid adulthood. Patients present with proximal more often than distal weakness. They may also present with respiratory failure. Patients may have neuropathy, cardiac failure, conduction abnormality, and congenital posterior polar cataracts.

  • Myotilinopathy (MFM3): The first mutations described were in 2 patients with an LGMD phenotype (see LGMD1A). Since then, several patients have been found with a myofibrillar myopathy. Onset is usually in mid-to-late adulthood. Most patients present with distal greater than proximal weakness, often with early foot drop. Neuropathy occurs in about 50%. Cardiomyopathy affects about 50%. Dysarthria, joint contractures and myalgias are present in about 33%. One family with spheroid body myopathy, a congenital myopathy, has been found with a mutation in the myotilin gene.

  • Z-band alternatively spliced PDZ motif-containing protein (ZASPopathy) (MFM4): Onset is at age 44-73 years, and patients most often present with distal more than proximal weakness, though proximal weakness can occur alone. Cardiac disease occurs in about 25% of patients and may be the presenting or predominant feature. Neuropathy affects approximately 45% of patients. Mutations are allelic with Markesbery distal myopathy, and dilated cardiomyopathy +/- isolated noncompaction of left ventricular myocardium.

  • Filamin C (γ-filamin) myopathy (MFM5): Age at onset is 24-57 years, with proximal greater than distal weakness. Respiratory failure occurs in about 50% of patients. Neuropathy affects about 40%. Cardiac disease may be present in up to 33%.

  • BCL2-associated athanogene 3 (BAG3) myopathy (MFM6): Age of onset is from childhood to early teens with proximal and distal weakness with progression that often causes respiratory failure and wheelchair dependency.[40, 41] Other features include contractures, scoliosis, and rigid spine. Peripheral neuropathy may be present. Cardiomyopathy is common and often severe, requiring transplantation in some patients.

  • Selenoprotein N myopathy: Selenoprotein N mutations were originally found in patients with congenital muscular dystrophy with rigid spine syndrome or minicore congenital myopathy. A study has shown that some patients with Mallory-body desmin-related myopathy also have a mutation in the selenoprotein N gene. Onset is at birth with hypotonia as well as axial and proximal weakness. Contractures and scoliosis are common and cardiac disease may occur. Death or the need for ventilatory support occurs before adulthood due to progressive respiratory failure.

  • Laminopathy: Besides presenting with a limb girdle phenotype (see LGMD1B), a recent case was described with a myofibrillar myopathy. The patient presented at age 3 with difficulty running and at age 5 was noted to have limb-girdle weakness

 Algorithm in Assessment in the assessment of weakness in muscular dystrophy and differential diagnosis

The assessment of 4-week infant less than 2 to 3 years of age.

• If it is mostly weakness assess if the initial weakness is minor and initial motor milestones may be normal.  

• If the infant has predominantly head lag consider SEPN1 and consider in the DDx: congenital myopathy, congenital myasthenic syndromes, congenital MD1.

• If the infant has transient progression of muscle weakness consider LAMA2, LMNA.  DDx: Intermittent deterioration of congenital myasthenic syndrome.

• If the infant has associated spasticity and upper motor neuron features consider alpha-dystroglycanopathy.  DDx:  Perinatal trauma/hypoxic ischemic encephalopathy, metabolic disease with muscle and CNS involvement.

• If infant has prominent facial weakness, early ophthalmoplegia, respiratory failure at birth, congenital cardiomyopathy; DDx: congenital myopathy, congenital myasthenic syndrome, congenital MD1, rarely metabolic (Pompeii, mitochondrial).  Very uncommon in CMD.

• If congenital contractures and mostly distal consider LAMA2.  If the contractures are proximal and axial consider COL6 in combination with distal laxity.  DDx: congenital myasthenic syndrome inclluding Escobar syndrome, neonatal myasthenia (maternal antibody), neurogenic, including congenital CMT, fast twitch thin filament disorders (distal arthrogryposis syndromes).

• If congenital hip dislocation consider COL6.  DDx: RYR1 related myopathy 

• If excessive laxity consider COL6 (may be present in conjunction with contractures).  DDx: Fibrillinopathies, EDS forms, Larsen syndrome.

• Associated malformations including abnormal head shape such as macrocephaly, macrocephaly and encephalocele consider possible alpha-dystroglycanopathy with DDx: Meckel-Gruber syndrome if encephalocele is present.  If cleft palate and structural abnormalities of eyes consider possible eval for alpha-dystroglycanopathy.  DDx: MSS for cataracts, 

The  assessment of weakness beyond infancy.  Assess the distribution, and progression of the weakness.

• Proximal weakness: alpha dystroglycanopathy, COL6, late MDC 1A.  DDx: LGMDs, various congenital myopathies, DOK 7, SMA 2+3, MD type II, inflammatory myopathy.

• If weaknesses is distal consider COL6.  DDx: Neurogenic, distal myopathies, myotonic dystrophy type I.

• if weaknesses is scapuloperoneal distribution consider LMNA with DDx: FHL 1 disorders, FSHD, myosin storage.

• The distribution of weaknesses is diffuse consider COL6 with DDx: various congenital myopathies, congenital myasthenic syndrome, and acid maltase deficiency

• If the weakness is axial and the patient presents with dropped head.  Consider LMNA, SEPN 1; DDx: various congenital myopathies, congenital myasthenic syndrome, acid maltase deficiency.

• If weakness is nonprogressive/stable which can be often seen in nonprogressive or improving, consider LMNA and MDC 1A with initial phase of progression.  Also consider in DDx: various congenital myopathies.  

• If there is later progression of weakness, consider alpha-dystroglycanopathy, other LGMD, metabolic myopathies.  

• If the weakness is steroid responsive consider FKTN or inflammatory myopathies.  

• If the progression of weakness is intermittent consider congenital myasthenic syndromes, myasthenia gravis and metabolic myopathies.

Assessment of muscle size:

• Atrophy: SEPN1 (thin neck), COL6, LMNA (with decreased subcutaneous fat).  DDx: congenital myasthenia syndrome, neurogenic, congenital myopathies.

• Calf muscle hypertrophy:  consider alpha-DG, LAMA2.  DDX: Other muscular dystrophy's including dyferlinopathies and sarcoglycanopathies. 

Muscle contracture: COL6 (with or without laxity) LMNA (spine, knees, feet), LAMA2 (EDMD-like); congenital myasthenic syndromes (DOK-7, RAPSYN); Escobar, RYR1.  CAPN3, dermatomyositis, AR titinopathy. 

Rigid spine: SEPN1, LMNA (with lumbar lordosis), COL6, and LAMA2 (complete and partial); DDx: Acid maltase, CAPN3, EDMD, RYR1, DNM2, FHL1, skeletal dysplasias. 

Laxity: COL6 (common), fibrillinopathies, EDS forms, core disorders, SMA2 and 3.  

CNS inovlvement:

• MR/cognitive delay: Mostly alpha-DG with and without abnormal brain MRI.  DxX: Mental retardation syndromes, with or without brain malformations.  Perinatal injury.

• If associated with seizures in addition to MR/cognitive delay: LAMA2, with similar differential diagnosis as above.

• If associated with seizures without mental retardation: LAMA2 with differential diagnosis of unknown related to complex partial seizures.

Unexpected respiratory failure: SEPN1, COL6 (possible and still ambulatory patients), LMNA.  DDx: CMS (CHAT), acid-maltase, and nemaline myopathy. 

Tests:

• CK levels consistently elevated: LAMA2

• CK levels elevated but rarely normal: alpha-DG

  • Consider DDx in both of above: Muscular dystrophy, inflammatory myopathies, acid maltase deficiency.

• CK levels variably elevated: COL6, LMNA

• CK levels normal: SEPN1

  • DDx of both of above: Congenital myopathy, congenital myasthenic syndromes, neurogenic conditions.

MRI of the brain showing white matter abnormalities, sparing dense fiber tracts, less commonly occipital pachygria, cerebellar involvement, white matter cysts: LAMA2.  Consider in DDx: disorders of myelinization (hypomyelination syndromes, leukodystrophies).

 MRI of the brain showing pachygyria, lissencephaly with anterior to posterior gradient, white matter abnormalities.  Prominent infratentorial involvement: Cerebellar atrophy, cerebellar cysts, hypoplastic pons, thick tectum: alpha-DG.  DDx: disorders of migration (lissencephaly-LIS 1, DCX, ARX, RLn, TUBA1), Liss-CH, polymicrogyria.  Pontocerebellar hypoplasias (CDG1A, PCH1/VRK1, PCH1&4-TSEN complex)

Muscle biopsy

• Can be normal, or close to normal in non-neuromuscular, congenital myasthenic syndromes, channelopathies, some metabolic myopathies.

• Mild to severely myopathic, with variable dystrophic pathology, abnormal fiber type distribution frequent (SEPN1, COL6); consider DDx:  RYR1, TPM3.

• Occasional inflammatory infiltrates but no fiber invasion: Fiber invasion suggests inflammatory myopathies.

• Core-like lesions compatible (SEPN1, COL6, RYR1)

• Desmin positive inclusions in SEPN1, myofibrillar myopathies.

• Immunohistochemistry is suggestive in LAMA2, alpha-DG, and COL6.  immunohistochemistry is not helpful in LMNA, SEPN1, and COL6. 

The inverted diagnostic approach

If there is a clinical suspicion of LGMD:

1. Check CK, HGMCR-ab, anti-SRP, myositis panel (myomarker-3)

2. Perform genetic testing: panel, WES, WGS.

3. Check MRI to indentify pattern of muscle involvement or US.  Also ,imaging can help target  suitable affected muscle (do not select end-stage atrophied muscle which appears homogeneously hyperintense, on T2 or STIR; pick a muscle which has some islands or striations of normal looking muscle - helps reducing sampling error), EMG, muscle biopsy if genetic test is negative, indeterminate (comes back VUS).

4. Muscle biopsy

What to do when VUS are reported?

• Refer to medical genetics/genetic counsellor - quick exit strategy OR

• The first step is to reassess the patient and determine whether the presentation fits the genetic testing result; if not, an alternative diagnosis should be considered.  

• Prevalence of VUS: For example, a patient with no family history of LGMD may be found to have 2 variants in alpha-sarcoglycan that have not been previously linked to LGMD for an autosomal recessive condition caused by a loss of function mutation, the presence of 2 variants in one gene is sufficient to cause disease, whereas the presence of one variant does not.   Less common variants may be reported on testing as "not detected in the general population" or seen in less than 0.001% which suggest that they are possibly disease causing mutations.  Reports provide computational analysis of VUS to predict whether the variant represents a pathogenic or benign mutation, thereby determining the need for continued monitoring as most population frequency includes for VUS were performed in people of European descent, these should be applied cautiously (data on other populations are lacking)

• Variants predicted to cause disease should lead to muscle biopsy and staining for the presence or absence of protein in question should be performed to confirm that the variant is deceased closing.  

• Another approach is to order genetic testing of the parents to make sure each parent has only 1 (not both) of the 2 VUS, genetic counselors can be helpful in interpreting complex test results.  In the United States efforts are being made to reduce the number of VUS reported for LGMD.

Distinguishing Features in muscular dystrophies:

• Early development of foot drop (MFM, hIBM, hIBM-PFD)

• Asymmetry in muscle weakness (e.g., LGMD1A, LGMD2L, MFM) FSHD (although not a LGMD)

• If considering DMD and the family history reveals a sister or 1st degree relative female with severe involvement, then the diagnosis is unlikely DMD.

• LGMD 2A and 2B do not cause cardiomyopathy.  LGMD2B starts at an earlier age.

• Sarcoglycanopathies are autosomal recessive LGMDs and represent 20-25% of all LGMDs.

  • Clinical picture varies from Duchenne like dystrophy to mild weakness.

  • LGMD2E is a rare form of sarcoglycanopathy.

  • In the vast majority of cases, weakness is proximal with legs affected more severely.

  • Axial and distal weakness occurs as the disease progresses.

  • Contractures of tendons is common.

  • Cardiac involvement occurs in 50% of cases, usually in a form of dilated cardiomyopathy and 28% of patients develop arrhythmias and conduction abnormalities.

  • Severe respiratory involvement occurs in 19% of cases

• Limb contractures (lamin A/C myopathies, EDMD, BAG3). Muscle strength may be relatively good in face of contractures. In humero-peroneal patttern. Includes rigid-spine syndrome.

• Prominent muscle cramps, rippling muscle phenomenon and percussion-induced muscle contractions (LGMD1C) CAV3 caveolinopathies

• Ancestry (e.g., northern European for LGMD2I) FKRP; Southern European (spanish), Italian descent think LGMD2A calpainopathy.

• Family/personal history of frontotemporal dementia, Paget disease, or familial ALS:  hIBM-PFD VCP gene

  • hIBMPFD is a rare autosomal dominant disorder usually caused by mutations in VCP that encodes for valosin-containing protein (VCP).  It is characterized by adult onset (range late 1st to 9th decade, with mean in the 40s) of limb girdles, distal, or scapuloperoneal weakness.  There also appears to be a mild asymmetry  and variability in the patterns of muscle weakness.  FTD is seen in approximately 30-50% with onset approximately 10 years after weakness (average age 54 years).  Paget disease (PDB) of the bone tends to occur earlier than in the more sporadic forms of PDB and is seen with variable frequency.  The complete triad of h-IBM, PDB, and FTD occurs in only about 1/3rd of cases.  In addition, mutations in the same gene cause a form of familial amyotrophic lateral sclerosis (fALS) with or without FTD.  A dilated cardiomyopathy (DCM) may be seen in a quarter of patients.  Ultimately, the cause of death is through progressive muscle weakness and ventilatory failure.  There is significant heterogeneity in clinical phenotype and severity both between and within families. 

  • Lab Features:  Serum CK are normal to slightly elevated.  Serum alkaline phosphatase levels can be a screening test but may not be elevated in those without PDB.  EMG shows myopathic changes with muscle membrane irritability. 

  • Histopathology: Rimmed vacuoles and inclusions that immunostain with ubiquitin.  TDP-43, and VCP.  Neurogenic features of type grouping and angulated fibers, which is notable .  VCP mutations can also associated with motor neuron disease.  EM may show paired helical filaments in muscle and in PDB osteoclasts. 

  • Molecular  Genetics and Pathogenesis

    • h-IBMPFD is caused by mutations in the gene encoding VCP, a member of the AAA-ATPase superfamily.  VCP is associated with a variety of cellular activities, including cell-cycle control, membrane fusion, and the ubiquitin-proteasome degradation pathway.  VCP normally localizes to nuclei and is specifically near nucleoli.  Mutations in VCP gene may disrupt in nuclear structure or normal translation of mRNA.  In addition, mutations in SQTM1, HNRPA2B1, and HNRNPA1, have been noted to cause hIBM and fALS, while mutations in SQTM1 can also cause PDB.  Some have termed these disorders as "multisystem proteinopathies. "

• Scapular winging: FSHD (usually asymmetrical), LGMD1B (laminopathy), LGMD2A (calpainopathy), sarcoglycanopathies (LGMD2C-F), EDMD, Desmin, centronuclear, myotubular, nemaline, central core, PFK deficiency, ALS, SMA, scapulo-peroneal syndromes, long-thoracic nerve palsy, spinal accessory neuropathy, dorsal scapular neuropathy.

• Calf hypertrophy: BMD, DMD (pseudohypertrophy), LGMD1C (caveolin), LGMD2A (calpain), LGMD2I (FKRP), sarcoglycanopathy (LGMD2C-F), Anoctamin (LGMD2L), telethoninopathy (LGMD2G).

• Limb contractures: Brody disease, glycolytic/glycogenotic enzyme defects, McArdle-disease, PFK deficiency, PGK deficiency, PGM deficiency, LDH deficiency, debrancher enzyme deficiency, hypothyroid myopathy, PMC, rippling muscle disease, Bethlem myopathy, EDMD,  LGMD1G, LGMD1B (lamin A/C myopathies), LGMD1A (calpain), DMD.

• Quadriceps selective weakness:  BMD, LGMD1B (Lamin A/C), 2B (DYSF), 2H (E3-ubiquitin ligase), 2L (ANO5), EDMD; Lamin A/C, hIBM.  sIBM, PM, focal myositis, myopathy with ring fibers, SMA types III and IV, femoral neuropathy, diabetic amyotrophy (DLRPN), L3-L4 radiculopathy, lumbosacral plexopathies. 

• Cardiac involvement: LGMD1B (Lamin A/C) LMNA, EDMD, LGMD1A (Myotilin) MYOT, dystrophinopathies, DM1 and DM2, caveolinopathy (LGMD1C), LGMD2G (Telethonin) TCAP, LGMD2I (FKRP),  sarcoglycanopathies (LGMD2C-F), LGMD2I ((Anoctamin) ANO-5,  MFM, Danon disease, mitochondrial myopathy, Pompe disease, nemaline myopathy, amyloidosis, carnitine disorders, POEMS syndrome, lyme radiculoneuritis. 

• Ptosis with ophthalmoparesis: centronuclear myopathy, mitochondrial myopathy (CPEO), multicore disease, myosin heavy chain myopathies, MFM, nemaline myopathy, OPMD, oculopharyngodistal myopathy, MG, LEMS, botulism.

• Ptosis without ophthalmoparesis: congenital myopathies,  central core myopathy, desmin (MFM), myotonic dystrophy.

• EMG: myotonic and pseudomyotonic discharges (MFM). It tends not to be useful in the diagnosis of LGMD.

• Muscle biopsy features: 

  • Rimmed vacuoles (AR-hIBM/Nonaka, GNE, hIBMPFD-VCP, hIBM3- hyaline body myopathy, OPMD, Marksberry-Griggs/Udd distal myopathy, Welander distal myopathy, MFM (desmin), postpolio syndrome, chronic denervation, LGMD1D-DNAJB6) 

  • Reducing bodies/cytoplasmic bodies (Inclusions that reduce NBT-EDMDX2/MFM- FHL-1) 

  • Hyaline bodies ( type I fibers, eosinophilic, green on Gomori, -Laing DM-MyHC7) 

  • Derangement of myofibrils (MFM)

  • Nemaline rods (Nebulin distal myopathies) 

  • Eosinophils: calpainopathy LGMD2A.

  • Reductions of specific proteins on immunohistochemistry (confirm with genetic testing)

Treatment recommendations for patients with limb-girdle muscular dystrophy

1. Medical management through multidisciplinary neuromuscular clinics

2. Cardiology, pulmonary, and orthopedic evaluation and treatment

3. PT/OT/SLP/RT/orthotics/assisted devices - DME

4. Genetic testing and genetic counseling. 

5. Encouragement for patients to remain active and lead fulfilling lives.

It is an exciting time for research in the LGMDs as small molecule, gene replacement, gene editing, and cell replacement therapies are in various stages of development and implementation.  Already, just as viral vector gene therapy has been successful in infants with spinal muscular atrophy, proof of concept and efficacy for viral vector gene replacement strategies in the LGMDs have been successful in animal models for β-sarcoglycan and dysferlin, along with phase 1 and 2 first in human studies.  Viral vector gene therapy via systemic delivery in humans is in various stages of development for a number of LGMD genes.  Additionally, the promise of gene editing through CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR associated-9) and other technologies may allow for perinatal correction of disease. Some patients with late stage LGMD may not benefit from gene correction therapies because of the extensive preceding loss of muscle mass with concomitant fatty and fibrous replacement of muscle.  For these patients, myoblast, satellite, and stem cell therapies hover more distantly on the horizon.  However, further progress in those areas may be much closer than previously expected.

https://practicalneurology.com/articles/2019-aug-july/differential-diagnosis-of-distal-myopathies/pdf 

Genes commonly associated with a limb girdle muscular dystrophy phenotype

• Dominant: CAPN3, CAV3, COL6Ax, DES, DNAJB6, HNRNPDL, LMNA, MYH2, MYH7, MYOT, RYR1, TNPO3, VCP, ZNF9

• Recessive: ANO5, BVES, CAPN3, COL6Ax, CRPPA, DAG1, DES, DYSF, FCMD, FKRP, GAA, GNE, GMPPB, LAMA2, LIMS2, PLEC1, POGLUT1, POMGnT1, POMGnT2, POMT1, POMT2, PRTF, RYR1, SGCA, SGCB, SGCD, SGCG, TCAP, TOR1AIP1, TRAPPC11, TRIM32, TTN

• X linked: DMD, FHL1, TAZ

Cases

A 42-year-old man presented to the neuromuscular center for leg weakness and a family history of muscular dystrophy.  He did not walk until nearly 2 years of age.  In high school, he was slower than the other children, but participated in varsity sports (football as an offensive guard and wrestling in the heavyweight class) because of his size (1.9 m [6 feet 4 inches] tall and 116 kg [255 pounds]).  As a teen, he was able to bench press more than 135 kg [300 pounds], but could only lift perhaps 55 kg [120 pounds] when doing squats.  By his 30s, he was having trouble ascending stairs and started to note episodes of his heart racing.  At present, he has a cardiac pacer-defibrillator and remains able to traverse stairs (except when tired at the end of the day).  His father also had a muscular dystrophy requiring use of a wheelchair at around 41 years of age.  His father had a pacemaker for an arrhythmia and died at age 52 years from sudden cardiac arrest.

On examination, the patient had a paced heart rate. Interestingly, his body habitus was of relative truncal adiposity with a relative paucity of subcutaneous fat in his lower extremities.  His strength (MRC [Medical Research Council] scale) was 4 to 4+ in a humeroperoneal pattern. There were mild contractures of the ankles, elbows, and neck extensors. His gait was mostly normal, but he was not able to walk well on his heels.  Evaluation revealed a creatine kinase level of 475 U/L. His nerve conduction studies (NCS)/electromyogram (EMG) showed normal motor and sensory responses, no decrement on repetitive stimulation, and a proximal myopathy with minimal muscle membrane instability, but no myotonic discharges.  The next step in the evaluation was genetic testing 

The diagnosis in this patient is:

1. LGMD 1A caused by a pathogenic variant in the gene for myotilin, MYOT.

2. LGMD 1B caused by a pathogenic variant in the gene for lamin A/C, LMNA.

3. LGMD 1C caused by a pathogenic variant in the gene for caveolin 3, CAV3.

4. LGMD 1D caused by a pathogenic variant in the gene for DNAJB6-related protein, DNAJB6.

5. LGMD 1E caused by a pathogenic variant in the gene for desmin, DES.

As expected from his history, phenotype, and examination, genetic testing revealed a pathogenic variant in LMNA, c.1130G>A (p.Arg377His).  This variant has been reported to segregate in families with LGMD with atrioventricular conduction disturbances and in families with dilated cardiomyopathy with quadriceps weakness.  Through alternate splicing of the gene, LMNA produces the proteins lamin A and lamin C, integral proteins of the inner nuclear envelop.  LMNA-related disease involves a myriad of phenotypes (often overlapping), including limb girdle and Emery-Dreifuss muscular dystrophies, axonal polyneuropathy, arrhythmogenic and dilated cardiomyopathies, lipodystrophy, progeria, restrictive dermopathy, mandibuloacral dysplasia, and others.  This patient had muscular dystrophy, cardiac conduction disease, mild lipodystrophy, and contractures of the neck extensor, biceps, and Achilles tendons.  Patients with LGMD 1B often have symptoms in the first decade, but weakness can progress at variable rates.  Some infants have early and progressive weakness requiring wheelchair use. Others, like the patient in case 1, may remain ambulatory and active through the later decades of life.  Although age of onset of weakness is broad, the median age in a large cohort was in the third decade.  Weakness tends to be in a humeroperoneal pattern but may also involve the quadriceps.  Contractures of the ankle plantar flexors, elbow flexors, and neck extensors are common.  Scoliosis can occur with onset of weakness at an early age.  Although respiratory insufficiency is not common, up to 10% of patients require noninvasive ventilation in their lifetimes.  Creatine kinase levels may be normal and up to 10-fold the upper limit of normal.  Cardiac involvement in LGMD 1B is not universal, but is nearly so in a lifetime.  There is a family history of heart disease in most patients with LGMD 1B. Motor weakness generally precedes cardiac symptoms by around a decade, but cardiac symptoms may be the first symptom bringing the patient to medical attention.  The incidence of cardiac manifestations increases with age, being uncommon in the first decade and nearly uniform by the sixth decade.  Sudden cardiac death may account for more than 25% of mortality in LGMD 1B, which underscores the importance of routine cardiac surveillance (electrocardiogram, Holter/Zio monitor, and echocardiogram) starting no later than the second decade of life in patients with LGMD 1B.  Placement of cardiac pacer-defibrillators for arrhythmogenic disease and cardiac transplant for cardiomyopathies with heart failure are both indicated for LGMD 1B.

A 32-year-old man presented for evaluation for muscle pain and cramping since his early teenage years.  From age 20 years onward, he has noted increased weakness with trouble arising from the floor or ascending steps.  In his job as a heavy equipment mechanic, he needs assistance for tasks above his head and for twisting or unscrewing pipes, screws, or bolts. With physical activity, he notes his muscles wear out more rapidly, hurt more after use, and cramp with less and less exertion.  Now, his muscles feel tight and sore nearly all the time, even interfering with sleep.  Interestingly, he describes that sometimes he feels and sees a rolling of the muscles of his calves or quadriceps before cramping, when contracting a muscle, or when he bumps a muscle.  He recalls dark urine on 2 occasions after sporting activities.  He does not have shortness of breath, palpitations, chest pain, or episodes of syncope. Noteworthy, his mother and maternal grandfather have a similar disorder.  His mother now uses a wheelchair for distances, and his maternal grandfather was wheelchair dependent late in life.  

On examination, his strength was fairly well preserved with normal strength except as follows (MRC scores, right/left): shoulder abductors, 4+/4+; elbow flexors, 4+/4+; finger flexors, 4+/4+; finger abductors, 4+/4+; hip abductors, 4+/4+; hip adductors, 4+/4+; knee flexors, 4+/4+; ankle dorsiflexors, 5/5; toe flexors, 4/4.  Sensation, coordination, and reflexes were normal.  His gait was initially stiff legged, then transitioned to normal after 8 to 10 steps.  Interesting features on his examination included male pattern baldness, mild percussion myotonia at the thenar eminences, and a rippling of his muscles when struck by the reflex hammer.  His only evaluation before genetic testing was a creatine kinase level of 544 U/L .

The diagnosis in this patient is:

1. LGMD 1A caused by pathogenic variants in MYOT, the gene for myotilin.

2. LGMD 1C caused by pathogenic variants in CAV3, the gene for caveolin 3.

3. Myotonic dystrophy type 1.

4. Myotonic dystrophy type 2.

5. A thymoma.

Genetic testing in this patient confirmed the diagnosis of LGMD 1C with the known pathogenic variant, CAV3, c.80G>A (p.Arg27Gln).  This variant has been reported in families with a proximal, LGMD pattern of weakness, distal weakness, autosomal dominant rippling muscle disease, and asymptomatic hyperCKemia.  One of the unique clinical examination findings in LGMD 1C is increased muscle membrane irritability, which manifests as percussion-induced rapid contractions, muscle mounding when struck or bumped, and muscle rolling or rippling.  Remarkably, when muscles ripple, they roll perpendicularly to the long axis of a muscle. Muscle pain, cramps, and stiffness are common concerns of patients.  Weakness in LGMD 1C ranges from asymptomatic to wheelchair dependence.  Because pathogenic variants in CAV3 have been reported in families with hypertrophic cardiomyopathy, patients with LGMD 1C should undergo cardiac evaluation at diagnosis and intermittently thereafter.

Creatine kinase levels range from 3 to 30 times the upper limit of normal.  MRI of the thigh often reveals preferential involvement of the rectus femoris and semitendinosus, often with a peripheral predilection for fatty and fibrous replacement in a ring like pattern.  In the diagnostic evaluation of a person with an autosomal dominant family history of weakness along with rippling and rolling of muscles, the first step should be to check a muscle enzyme level and then move directly to genetic testing.

A woman presented for further evaluation at 52 years of age.  In her teenage years, friends commented that her walk was unusual.  By 17 years of age, she was noted to have a waddling gait, walking erect and with her arms somewhat hyperextended behind her.  She noted difficulty with stairs.  During an evaluation at age 27 years, her creatine kinase level was found to be 2616 U/L, with several subsequent, contemporaneous levels in the 1200 to 5300 U/L range.  Subsequently an EMG revealed myopathic motor units with fibrillation potentials and positive sharp waves in proximal muscles, and a quadriceps muscle biopsy revealed so-called moth-eaten muscle fibers.  Over the next 2 decades, she had greater difficulties in walking independently, and by age 45 years began to use a Rollator walker regularly.  Around age 50 years, she used a power wheelchair most of the time and anytime outside her home. Once using the wheelchair regularly, she gained a substantial amount of weight, with her body mass index exceeding 40 kg/m2.  Around this time, she was started on nocturnal bilevel positive airway pressure at night because of a forced vital capacity (FVC) of 72% predicted in the upright position, an FVC of 58% in the supine position, and an overnight polysomnogram with an apnea-hypopnea index at 99 events per hour and with oxygen saturation less than 89% for 35% of her sleep time. There is no family history of a similar disorder.

On examination, her general and mental status examinations were normal except for obesity.  Cranial nerves were normal with normal extraocular and perioral strength and the ability to whistle normally.  Strength was graded as follows (MRC scale, right/left): shoulder abductors, 3/3; elbow flexors, 2/3; elbow extensors, 3/3; wrists/fingers, 5/5; hip flexors, 3/3; hip extensors, 2/2; hip abductors, 5/5; hip adductors, 2/2; knee extensors, 5/5; knee flexors, 2/2; ankles/toes, 5/5. There was prominent scapular winging, bilaterally.  Sensation and coordination were normal.  She was able to arise from a chair without the use of her arms.  Her gait was hyperlordotic with her arms held behind her and her legs splayed apart, and she was able to walk without an ambulatory aid for 6 to 15m(20–50 feet).  At age 52 years, genetic testing confirmed the diagnosis suspected in this woman.

The diagnosis in this woman is:

1. LGMD 2A/R1 caused by pathogenic variants in CAPN3, the gene for calpain 3.

2. LGMD 2B/R2 caused by pathogenic variants in DYSF, the gene for dysferlin.

3. LGMD 2L/R12 caused by pathogenic variants in ANO5, the gene for anoctamin 5.

4. Manifesting dystrophinopathy carrier caused by a pathogenic variant in DMD.

5. Facioscapulohumeral muscular dystrophy caused by a truncation in the number of D4Z4 repeats on chromosome 4.

This patient has LGMD 2A/R1 caused by compound heterozygous pathogenic variants in CAPN3, c.550delA and c.1250C>T.  Calpainopathies are the most prevalent LGMD in the United States.  Symptoms generally begin in LGMD 2A/R1 between 5 and 15 years of age.  Weakness has a distinct pattern with marked disparities in strength in antagonist muscles across the hip and knee joints.  Thus, the hip adductors, hip extensors, and knee flexors are substantially weaker than the hip abductors, hip flexors, and knee extensors.  Retained quadriceps strength allows patients to walk much longer. Nearly half of patients have scapular winging, sometimes prominent.  In general, cardiopulmonary function is not affected early in the disease course.  Later, respiratory insufficiency requiring nocturnal noninvasive ventilation occurs in around 20%.  Although most patients with calpainopathy inherit their disease in an autosomal recessive fashion, up to one-third of patients may have disease with only 1 pathogenic variant in CAPN3.  In autosomal dominant calpainopathy, onset of disease tends to be 10 to 20 years later than in LGMD 2A/R1.  In LGMD 2A/R1, creatine kinase levels range from normal late in disease to in excess of 20,000 U/L. Muscle biopsies often reveal lobulated fibers on oxidative enzyme stains.  In this patient with obesity, the question arose as to whether bariatric surgery would be appropriate. There is mounting evidence that bariatric surgery is safe in the LGMDs, and that subsequent weight loss may improve function without worsening the disease course.

A man initially presented at 48 years of age for evaluation of a 3-year history of progressive weakness of his bilateral biceps and left leg.  As a youth, he was athletically gifted, winning the state wrestling championship in his weight class.  Through his 20s and 30s, he remained physically active and was able to bench press 135 kg (300 pounds), squat 180 kg (400 pounds), and bicycle 4830 km (3000 miles) per year.  Around 47 years of age, he noted left calf hypertrophy, but, ironically, noted greater difficulty standing on his toes, bilaterally.  Over the ensuing decade, his strength declined such that he could not traverse stairs, arise from the floor, and now uses a walking stick regularly.  His past history is significant for gynecomastia surgery when younger.  He also experiences frequent premature ventricular contractions (>10,000 on 48-hour Holter monitor) since his early 30s.  Noteworthy, his unaffected parents are first cousins.  Of 6 siblings, 2 younger brothers also have milder weakness; 1 younger sister has persistently increased aspartate transaminase, alanine transaminase, and creatine kinase levels, but no weakness, and 2 sisters have multiple sclerosis.  No aunts, uncles, or grandparents have neurologic disease.

On examination at 58 years of age, his motor examination revealed the following strengths (MRC scale, right/left): deltoid, 5/5; biceps, 2/4; triceps, 3/4; wrist and finger muscles, 5/5; hip flexors, 4/4; hip extensors, 2/2; hip abductors, 5/4+; hip adductors, 2/2; knee extensors, 4/3; knee flexors, 2/2; ankle dorsiflexion, 5/5; and ankle plantar flexion, 4/4.  He was able to walk on his heels bilaterally, but unable to stand on his toes bilaterally.

In terms of evaluation, at 48 years of age, his creatine kinase level was 4852 U/L, and, at age 58 years, his creatine kinase level was 1374 U/L.  NCS/EMG revealed a nonirritable, proximal myopathy both at age 48 years and again at age 58 years.  His MRI of the thighs and calves at age 58 years revealed bilateral marked fatty and fibrous replacement of his hamstring, adductor, and vasti muscles with sparing of the rectus femoris muscle in the thighs, and marked fatty and fibrous replacement of the bilateral gastrocnemius muscles and left soleus muscle with sparing of the anterior compartment of the calves.  A right biceps muscle biopsy at age 53 years revealed end-stage muscle with a few muscle fibers among fatty and fibrous tissue.  A deltoid muscle biopsy at age 58 years revealed nonspecific myopathic changes.

The diagnosis in this patient is:

1. LGMD 2A/R1 caused by pathogenic variants in CAPN3, the gene for calpain 3.

2. LGMD 2B/R2 caused by pathogenic variants in DYSF, the gene for dysferlin.

3. LGMD 2L/R12 caused by pathogenic variants in ANO5, the gene for anoctamin 5.

Becker muscular dystrophy caused by a pathogenic variant in DMD.

5. Bulbospinal muscular atrophy or Kennedy disease caused by the gynecomastia with a CAG repeat in the gene for the androgen receptor.

This patient has LGMD 2L/R12 caused by homozygous pathogenic variants in ANO5, c.172C>T (p.R58 W). LGMD 2L/R12 is highly prevalent in persons of northern European ancestry.  Patients with 2 pathogenic variants in ANO5 can present with a proximal, limb girdle pattern or with a distal pattern (Miyoshi-like muscular dystrophy type 3).  Onset of weakness is later than in most LGMDs, often in the third to fifth decades.  In persons with the same pathogenic variants, women tend toward less weakness than men.  The muscles most affected include the quadriceps and biceps muscles.  Early inability to walk on the toes can occur, similar to LGMD 2B/R2. Cardiac arrhythmias are more prevalent than in the general population, but heart failure is less common.  Muscle enzyme levels generally are 10-fold to 50-fold the upper limit of normal at diagnosis, but may exceed 30,000 U/L.  MRI shows fatty and fibrous replacement in the posterior thigh muscles along with the biceps muscle.  Muscle biopsies may be nearly normal early in disease, or in less affected muscles, but later show fatty and fibrous (dystrophic) changes.

A 54-year-old woman initially noted greater fatigue in middle school and high school.  At that time, she was never able to accelerate quickly, and had trouble running the 50-yard (46-m) dash with any speed.  She could never jump very high.  In her 20s, she noted greater difficulty running. In her 30s, she noted difficulty with ascending stairs, using her arms over her head, and some mild foot drop.  At that time, she was diagnosed with LGMD.  By her early 50s, she was unable to ride a bicycle, hike, play golf, or walk any significant distance.  She was falling perhaps once a month.  There was no family history of a similar disorder.

On general examination, she had enlarged calves, but did not have tongue hypertrophy.  Mental status and cranial nerves were normal (specifically, she had no ptosis and no diplopia). Strength testing revealed symmetric weakness graded as follows (MRC scale) in the upper extremities: shoulders and elbows, 4 to 4+; wrists and fingers, 5.  Her lower extremity strength was: hip flexors, 4; knee extensors, 5; ankle dorsiflexors, 3; ankle plantar flexors, 5; hip extensors, adductors, and abductors, 2; knee flexors, 4+.  Station and gait revealed a camptocormic thoracic spine with forward hip posture.  She had trouble standing erectly.

Her evaluation extended over 3 decades.  Creatine kinase levels ranged from 900 to 2700 U/L.  EMGs in her 30s were consistent with a myopathy.  Muscle biopsies in her 30s revealed myopathic changes and a mildly dystrophic pattern with fatty and fibrous replacement.  At age 54 years, ultrasonography of her muscle was consistent with a generalized myopathy without a distinct pattern.  MRI of her lumbar spine revealed complete fatty replacement of the lumbar paraspinal muscles with relative preservation of her iliopsoas muscles.  MRI of the brain was normal.  Pulmonary function tests revealed an FVC at 74% of predicted in the upright position, but only 56% of predicted in the supine position.  Echocardiogram was normal.  Electrodiagnostic testing at age 54 years revealed a myopathic pattern, mostly in proximal muscles, but also repetitive stimulation at 3-Hz stimulation of the spinal accessory nerve to the trapezius muscle revealed a decrement of 23%.  This decrement repaired with treatment with pyridostigmine.  The patient was started on pyridostigmine and her strength and endurance improved and she no longer had falls.

The diagnosis in this woman is:

1. Myasthenia gravis caused by antibodies to the acetylcholine receptor.

2. LGMD 2A/R1 caused by pathogenic variants in CAPN3, the gene for calpain 3.

3. LGMD 2I/R9 caused by pathogenic variants in FKTN, the gene for Fukutin-related protein.

4. LGMD 2T/R19 caused by mutations in GMPPB, the gene for guanosine diphosphate (GDP) mannose pyrophosphorylase B.

5. Congenital myasthenic syndrome caused by pathogenic variants in DOK7, the gene for DOK7-related protein.

Genetic testing in this patient revealed 2 pathogenic variants in GMPPB: c.79G>C (p.Asp27His) and c.1099G>A (p.Gly367Arg). GMPPB encodes the protein GDP mannose pyrophosphorylase B, one of 18 genes associated with glycosylation of alpha-dystroglycan. Two pathogenic variants in GMPPB may lead to the spectrum of phenotypes including congenital muscular dystrophy with brain and eye involvement, congenital myasthenic syndrome, and a milder muscle phenotype (LGMD2T).  In some cases, there are components of more than 1 phenotype.  This case had predominant limb girdle pattern muscular dystrophy with proximal weakness and fatty and fibrous replaced muscles but also had a partially reversible neuromuscular junction component.  Progressive muscle weakness in the disease course with myopathic changes on muscle biopsy, along with evidence for abnormal transmission at the neuromuscular junction, may also be seen in other myopathies, such as BIN1, DES, DNM2, MTM1, and PLEC, as well as in other congenital myasthenic syndromes, such as DOK7, ALG2, ALG14, COL13A1, DPAGT1, and GFPT1.  For this reason, evaluation for abnormalities of the neuromuscular junction, either repetitive nerve stimulation or single-fiber EMG, should be performed in all patients presenting with weakness, even in the presence of myopathic motor units.

The age of onset in LGMD 2T/R19 ranges from congenital weakness to later adult life.  Calf hypertrophy commonly occurs in LGMD 2T/R19.  Lumbar paraspinal, adductor, hamstring, and medial gastrocnemius muscles is the pattern that tends to be most involved.  Creatine kinase levels are increased, running from 300 to 10,000 U/L.  Lumbar paraspinal muscles tend to be the most affected on total-body MRI of muscles.  In terms of genetics, there are genotype/phenotype correlations.  The common c.79G>C pathogenic variant tends to be associated with milder weakness and more so with a myasthenic syndrome phenotype.  Treatment with pyridostigmine and/or salbutamol improves the strength and endurance in some patients with LGMD 2T/R19

A 22-year-old man of Asian and northern European ancestry presents for an evaluation of his muscle weakness. In high school he was very athletic and was awarded a college scholarship for his abilities in the high jump.  Unfortunately, shortly after his sophomore year he began to experience difficulty maintaining the height of his high jump.  He recalls in retrospect that his calf raises in the gym had become more challenging at about the same time.  By midway through his junior year he had developed mild difficulty running, which eventually required that he quit track and field.  Despite a slow, progressive decline in leg strength over the subsequent year he delayed seeking medical attention until he developed difficulty performing arm curls in the gym.  By then he noted that he was losing muscle bulk in his calves and biceps brachii.  He was evaluated by a family practice physician and underwent initial laboratory screening that included a complete blood count, a comprehensive metabolic panel, and tests of blood levels of thyroids stimulating hormone, vitamin B12, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and creatine kinase (CK).  Results were remarkable for a markedly elevated CK (5,432 U/L; normal CK levels < 300 U/L but varies by sex and ethnicity).  ECG and echocardiogram were normal.  A muscle biopsy was obtained at the local community hospital and reportedly demonstrated endomysial inflammatory infiltrates. He was initially diagnosed with polymyositis and was started on oral prednisone 60 mg/d.  After 6 months without benefit and further subtle progressive decline in strength, he was referred to a regional referral center and evaluated by a general neurologist.  Repeat CK level was 15,234 U/L.  Nerve conduction test was normal, whereas an EMG demonstrated the presence of myopathic potentials with early recruitment in most muscles tested, most prominently in the calves and biceps femoris.  He was subsequently referred to a tertiary care facility for specialty evaluation. 

His past medical and surgical history are otherwise insignificant.

The only medication he is currently taking is prednisone 60 mg/d. He has no known drug allergies. 

Social history is notable for occasional alcohol use but no more than 2 to 3 beers per week. He denies prior tobacco or illicit drug use. He is a graduate student studying sports physiology and has maintained a 4.0 grade point average since starting high school. His childhood development history is otherwise unremarkable, both physically and cognitively. 

Family history is without any suggestion of neuromuscular disease and is otherwise noncontributory. Of some interest is his northern European and Asian ancestry. 

In addition to that reported in the history of present illness, a complete review of 14 systems is otherwise unremarkable. 

On physical examination, he is a well-developed and well-nourished male in no distress. Temperature is 36.7º, blood pressure is 123/66, pulse is 62, and respiratory rate is 14. No bruits are noted over his carotids, and heart sounds are normal. He is alert and oriented to person, place, and date. Both short-term and delayed memory are intact. Speech is fluent with intact naming, repetition, and comprehension. Insight and thought content are appropriate for age and education. Pupils are equally reactive to light and accommodation. Visual fields are full to confrontation, and extraocular muscles are intact. Facial sensation and strength are normal. Hearing is intact bilaterally to finger rub. Palate, tongue, and uvula are midline. Sternocleidomastoid and trapezius strength are normal. On motor examination, there is atrophy of bilateral gastrocnemius and biceps femoris muscles. There is no scapular winging. No myotonia or fasciculations are noted. Motor strength testing reveals the following: neck flexors 5; limb muscles (right/left): deltoid 5- /5-, biceps 4/4+, triceps 5/5, brachioradialis 4+/4, wrist flexors 5/5, wrist extensors 5/5, interrossei 5/5, iliopsoas 4/4, gluteus medius 5-/5-, quadriceps 5-/5-, hamstrings 4+/4+, tibialis anterior 5/5, gastrocnemius 4+/4, extensor hallucis longus 5/5. Sensation is preserved normal to pinprick, touch, vibration and joint sense. Deep tendon reflexes are 2+ in the upper extremities and at the knees. Ankle jerks are 1+ bilaterally. Plantar responses are flexor. Station is normal. Casual gait also is normal, but the patient is unable to walk on his toes on the left. He has mild difficulty rising from the floor. 

Additional diagnostic studies include an MRI of the lower extremities that demonstrates fibrous and fatty degeneration of the gastrocnemius and soleus muscles. The patient is counseled about a possible diagnosis of muscular dystrophy and the suspicion of a dysferlinopathy on the basis of his history and pattern of weakness. Genetic testing is performed and confirms a mutation in the dysferlin gene (DYS). You tell the patient that he has limb-girdle muscular dystrophy type 2B (LGMD2B). Prognosis is discussed. He is counseled with regard to this being an autosomal recessive disorder so he would not likely pass it on to his children unless his wife also carries the same gene mutation. He is referred for physical and occupational therapy. 

A 20-year-old woman presents with a 6-month history of weakness in her legs.  She has difficulty climbing stairs and rising from chairs.  On clinical examination, she has mild hip-girdle weakness (MRC grade 4+/5), her hamstrings are 4/5, and ankle plantar flexors are 3/5.  Her knee extensors and ankle dorsiflexors are normal, as are her arms.  There is no scapular winging or muscle hypertrophy, although she has atrophy of the medial gastrocnemius muscles bilaterally and is unable to stand on her tip toes.  Sensation is intact.  Muscle stretch reflexes are 2/4 and symmetric throughout except at the ankles, where these reflexes are absent.  Her serum CK level is 12,000 U/L. 

Which of the following would be the most appropriate next step? 

A. Perform an EMG/nerve conduction study (NCS) 

B. Obtain a dried blood spot analysis for alpha-glucosidase activity, as it would be important not to miss a possible treatable condition (e.g., late-onset Pompe disease) 

C. Order a Western blot for dysferlin analysis on peripheral monocytes or sequencing of the DIS gene for mutations 

D. Perform a gastrocnemius muscle biopsy, as this muscle is the most severely affected E. Treat the patient empirically with prednisone 1.0 to 1.5 mg/kg daily for presumed polymyositis 

The correct answer is C. The age of onset and pattern of weakness is classic for Miyoshi myopathy/dysferlinopathy and is supported by the markedly elevated serum CK level. The clinical impression can be confirmed noninvasively by performing Western blot analysis on peripheral monocytes or direct mutation analysis of the DYS gene that encodes for dysferlin. The clinical phenotype and markedly elevated CK levels do not suggest Pompe disease.  EMG/NCS are useful in localization, although with a CK of 12,000 U/L it has to be a myopathy. EMG can at times help narrow the diagnosis of the type of myopathy (e.g., if there were myotonic discharges); however, in this case the EMG is not likely to assist in the diagnosis. One could consider a muscle biopsy to confirm the diagnosis of a dystrophy or exclude another cause.  If the results are dystrophic, one could do immunostaining or immunoblot of muscle tissue for dysferlin. 

A 24-year-old man presents with a 4-year history of progressive weakness in his proximal arms and legs.  He is of Spanish descent but has no family history of any neuromuscular problems.  On examination, he has scapular winging.  No muscle atrophy or hypertrophy is appreciated.  Manual muscle testing reveals weakness in the proximal legs more than in the proximal arms.  Sensation and muscle stretch reflexes are normal.  

His serum CK is 5,300 U/L.  A biceps brachii muscle biopsy reveals variability in muscle fiber size, mild increase in endomysial connective tissue, scattered necrotic and regenerating fibers, lobulated muscle fibers on NADHTR stain, and rare, small foci of endomysial inflammatory cells composed of many eosinophils.  Which of the following would be the most appropriate next step? 

A. Perform genetic testing for CPN3 (calpain-3) mutation 

B. Order a Western blot for dysferlin analysis on peripheral monocytes or sequencing of the DYS gene 

C. Perform genetic testing for facioscapulohumeral muscular dystrophy (FSHD) given the prominent scapular winging and inflammation on biopsy 

D. Order genetic testing for all available limb-girdle muscular dystrophies (limb-girdle muscular dystrophy [LGMD] panel), as it is impossible to guess which type of LGMD he is most likely to have 

E. Begin treating the patient with prednisone 1.0 to 1.5 mg/kg daily for presumed eosinophilic polymyositis 

The correct answer is A.  The clinical phenotype is typical of LGMD2A that is caused by a mutation in CPN3 that encodes for calpain-3.  LGMD2A is the most common form of LGMD in patients from Spain and southern European backgrounds.  There are several reports of patients having been erroneously diagnosed with eosinophilic myositis who actually had calpainopathy.  The limb-girdle pattern of weakness, high CK level, and inflammation on biopsy can be seen in dysferlinopathies, but scapular winging is not typical.  Rarely, patients with FSHD can have a limb-girdle pattern of weakness and inflammation on biopsy mimicking myositis, although CK is not usually as elevated, making calpainopathy most likely. 

Myofibrillar myopathy has been associated with mutations in the genes that encode for which of the following proteins? 

A. Desmin 

B. Myotilin 

C. BAG-3 

D. Z-band alternatively spliced PDZ motif-containing protein 

E. All of the above 

The correct answer is E.  Mutations in the genes that encode for filamin-C, myotilin, ZASP, BAG-3, desmin, alpha B crystallin, and titin have been associated with myofibrillar myopathy. 

A 26-year-old woman is referred for evaluation of slowly progressive weakness she has been experiencing for 3 years.  On examination, she has mild atrophy of humeral muscles and MRC grade 4+/5 in her elbow flexion, elbow extension, and foot dorsiflexion.  She also has moderate contractures at her elbows, knees, and ankles and rigidity of her spine.  Family history is notable for sudden cardiac death in her father, who exhibited similar clinical features as she does now.  The most appropriate diagnostic test would be which of the following? 

A. Muscle biopsy 

B. Genetic testing for mutations in the gene that encodes for emerin 

C. Genetic testing for mutations in the gene that encodes for lamin A/C 

D. Genetic testing for mutations in the gene that encodes for dystrophin 

E. Genetic testing for myotonic dystrophy 

The correct answer is C.  The pattern of muscle weakness, early contractures, autosomal dominant inheritance, and cardiac disease are characteristic of autosomal dominant Emery Dreifuss muscular dystrophy or LGMD1B, both of which are caused by mutations in the gene that encodes for lamin A/C. 

RYR1

The RYR1 gene is associated with autosomal dominant and recessive central core disease (CCD), autosomal recessive congenital myopathy with fiber-type disproportion (CFTD), and autosomal recessive multiminicore disease.  It is also associated with autosomal recessive and autosomal dominant centronuclear myopathy (CNM) and malignant hyperthermia susceptibility type 1 (MHS1).  The RYR1 gene also has preliminary evidence supporting a correlation with periodic paralysis.

If two causative variants are present on opposite chromosomes, then this result is consistent with a predisposition to, or diagnosis of, autosomal recessive RYR1-related conditions.  The clinical significance of this result in autosomal dominant RYR1-related conditions is unknown at this time.  RYR1 is associated with a clinically heterogeneous and overlapping group of core myopathies including CCD, CFTD, MmD and CNM.  

CCD is characterized by muscle weakness, hypotonia, and delayed motor milestones .  Onset typically occurs in childhood, though adult-onset cases have been reported.  Muscle biopsy findings consist of large numbers of central cores present in type 1 muscle fibers.  

CFTD is characterized by infantile onset hypotonia, muscle weakness, and the presence of small type 1 fibers with no evidence of cores, rods or central nuclei on muscle biopsy.  

MmD is characterized by proximal muscle weakness, multiple focal areas of reduced oxidative activity in muscle fibers, and highly variable age of onset.  

CNM is characterized by infantile onset facial muscle weakness, external ophthalmoplegia, and central nuclei on muscle biopsy.  Rarely, individuals more severely affected with RYR1-related myopathies may present with symptoms perinatally. 

Pathogenic variants in RYR1 are also associated with increased risk for malignant hyperthermia, a pharmacogenetic disorder of skeletal muscle that can lead to a hyper-metabolic response after exposure to certain environmental factors, such as anesthetic agents. Episodes may include hyperthermia, tachycardia or arrhythmia, skeletal muscle rigidity, respiratory and metabolic acidosis, and/or rhabdomyolysis. Rarely does MH occur in a non-anesthetized patient.

https://www.aan.com/Guidelines/home/GuidelineDetail/670

Muscle MRI in muscular dystrophies - PMC (nih.gov)