Congenital myopathies
Congenital myopathies refer to a genetically and clinically heterogeneous group of inherited skeletal muscle diseases associated with early infantile or childhood onset of motor weakness, hypotonia, and developmental delay, which have a static or slowly progressive course.
There is wide variation in clinical severity within each group and marked clinical overlap with other neuromuscular disorders, including the muscular dystrophies, congenital myasthenic syndromes, metabolic myopathies, and spinal muscular atrophy.
Clinically, the congenital myopathies share a number of common features: generalized weakness, hypotonia and hyporeflexia, poor muscle bulk, and dysmorphic features secondary to the myopathy (e.g. pectus carinatum, scoliosis, foot deformities, a high arched palate, and elongated facies). The pathologic process appears to exclusively affect the striated muscle, and thus congenital myopathies may be distinguished clinically from neuromuscular conditions with multisystem involvement, such as facioscapulohumeral muscular dystrophy, which is associated with hearing defects or retinal vascular pathology, myotonic dystrophy with central nervous system involvement, cataracts and cardiac conduction defects, and a subset of patients with congenital muscular dystrophies (CMD) associated with brain pathology (e.g. Walker Warburg syndrome, muscle-eye-brain disease, Fukuyama CMD).
Epidemiology:
Congenital myopathies are rare disorders; the overall prevalence is estimated at 1 in 25,000 individuals. Previous point prevalence of congenital myopathies ranged from 1.37 per 100,000 of all age groups in northern England, 10 to 5 per 100,000 of the pediatric population in western Sweden. The true prevalence is likely to be higher because of underrecognition of mildly affected individuals as well as a substantial proportion of cases with nonspecific histologic findings. Core myopathies including central core and multiminicore myopathy are the most common histopathologic subtypes of congenital myopathies. Mutations of the ryanodine receptor 1 (RYR1) gene are most often implicated as the cause of congenital myopathies, with a point prevalence of 1 in 90,000 of the pediatric population in the United States.
Clinically, the diagnosis of congenital myopathies remains challenging because of the variable phenotypes. Significant heterogeneity exists even within family members affected by the same genetic mutation. In one large case series of congenital myopathies, approximately one-third of patients remained genetically unresolved. The lack of molecular confirmation was in part related to the nonspecific clinical features (especially during the neonatal period), the genetic heterogeneity of congenital myopathies, as well as the large size of some involved genes, especially TTN and NEB. Recently, a targeted exome sequencing strategy in combination with muscle histology has been proposed to identify disease causing mutations in myopathies of unknown causes. The sequencing includes coverage of each exon of known genes implicated in congenital myopathies to enable more precise genetic diagnosis.
Diagnostic approach:
Age and developmental history is important. The history and neurologic examination are important first steps in the diagnostic approach. Careful review of the pregnancy, birth, growth and development, family history, and direct examination of the parents is essential to exclude other inherited neuromuscular disorders.
In addition to muscle weakness and hypotonia, clues to the diagnosis of congenital myopathies include the early onset of symptoms, static or slow rate of disease progression, the presence of myopathic facies, ophthalmoplegia, or bulbar involvement, as well as associated signs such as muscle atrophy, hyporeflexia, spinal deformity, clubfoot, or other orthopedic complications. Systemic involvement may manifest as cardiomyopathy, malignant hyperthermia, or respiratory insufficiency. Sensation and intelligence are generally preserved. Infants with a prenatal onset of muscle weakness due to severe congenital myopathies often present with a history of reduced fetal movement and polyhydramnios. The consequence of fetal akinesia (or lack of movement in utero) includes craniofacial dysmorphism, multiple joint contractures (or arthrogryposis), pulmonary hypoplasia, hip dysplasia, muscle atrophy, and profound generalized weakness. Severe hypotonia plus bulbar and respiratory insufficiency may necessitate invasive mechanical ventilation and gastrostomy tube feeding from birth.
The most helpful tools for the diagnostic workup of congenital myopathies are serum creatine kinase (CK), nerve conduction study and EMG, muscle imaging, muscle biopsy, and selective biochemical and genetic testing. Serum CK is usually normal or mildly elevated (less than five times the upper limit of normal) in congenital myopathies; significantly raised levels (more than 10 times the upper limit of normal) are suggestive of alternative diagnoses such as muscular dystrophies. Nerve conduction studies often yield normal motor and sensory responses, apart from reduced compound motor action potential (CMAP) amplitudes. EMG may reveal a myopathic recruitment pattern with occasionally nonspecific findings or neurogenic changes due to severe muscle atrophy. Increased jitter or significant electrodecremental responses can be seen in congenital myopathies associated with secondary neuromuscular junction defects, including cap myopathy due to mutations in the TPM2 gene, centronuclear myopathies related to DNM2 or X-linked MTM1 mutations, and congenital fiber-type disproportion caused by TPM3 and RYR1 mutations.
Muscle imaging using MRI or ultrasound provides additional noninvasive diagnostic clues as genetic myopathies are often associated with specific patterns of muscle involvement, particularly early in the course of the disease. In contrast to CT, MRI provides excellent soft tissue contrast without the use of ionizing radiation and is frequently the modality of choice for skeletal muscle imaging, although sedation may be required in young children. Based on a relatively simple algorithm of an anterior versus posterior pattern of muscle involvement of the thighs followed by the same assessment of the lower legs, Wattjes and colleagues proposed the use of MRI to distinguish among the different subtypes of congenital myopathies. The differential diagnosis was further expanded by Quijano-Roy and colleagues. Similar to MRI, muscle ultrasound performed by skilled clinicians can also be used to detect various types of congenital myopathies. This technique is particularly useful as a screening tool in pediatric patients younger than 5 years of age and does not require sedation. In one study, muscle ultrasound was abnormal in 23 out of 25 patients (92%) with core myopathies, with a specificity of 26.3% and a positive predictive value of 62.2%.
The differential diagnoses of hypotonia and severe generalized weakness in the newborn or early infancy period include congenital myopathies, congenital muscular dystrophies, congenital myotonic dystrophy, congenital myasthenic syndromes, myofibrillar myopathies, other myopathies, congenital neuropathies, spinal muscular atrophy, as well as genetic and metabolic conditions such as Prader-Willi syndrome or glycogenstorage disease. The presence of encephalopathy, microcephaly, or upper motor neuron signs such as increased tone, hyperreflexia, sustained clonus, and obligate extensor plantar responses may point to an alternative diagnosis such as hypoxic ischemic encephalopathy or other central nervous system disorders.
Genes and Modes of Inheritance for Congenital Myopathies.
Nemaline Myopathy
TPM3 (autosomal dominant, autosomal recessive)
NEB (autosomal recessive)
ACTA1 (autosomal dominant, autosomal recessive)
TPM2 (autosomal dominant)
TNNT1 (autosomal recessive)
KBTBD13 (autosomal recessive)
CFL2 (autosomal recessive)
KLHL40 (autosomal recessive)
KLHL41 (autosomal recessive)
LMOD3 (autosomal recessive)
The most common genetic causes for nemaline myopathy are mutations in NEB, which can cause up to half of cases, and actin α1, skeletal muscle (ACTA1), which occurs in 20% to 25% of cases.
Central Core Myopathy
RYR1 (autosomal dominant, autosomal recessive)
SEPN1 (autosomal recessive)
ACTA1 (autosomal dominant)
TTN (autosomal recessive)
Multiminicore Myopathy
SEPN1 (autosomal recessive) a.k.a SELENON gene
RYR1 (autosomal dominant, autosomal recessive)
MYH7 (autosomal dominant)
TTN (autosomal recessive)
Cardiac involvement is not reported in multiminicore disease, and heart involvement in combination with multiminicore pathology suggests the possibility of a mutation in TTN or MYH7.
Core-rod Myopathy
RYR1 (autosomal dominant, autosomal recessive)
NEB (autosomal recessive)
KBTBD13 (autosomal dominant)
CFL2 (autosomal recessive)
Centronuclear Myopathy
MTM1 (X-linked)
DNM2 (autosomal dominant)
BIN1 (autosomal recessive)
RYR1 (autosomal recessive)
TTN (autosomal recessive)
MTMR14 (autosomal recessive)
CCDC78 (autosomal dominant)
SPEG (autosomal recessive)
Congenital Fiber-type Disproportion
ACTA1 (autosomal dominant)
SEPN1 (autosomal recessive)
TPM3 (autosomal dominant)
TPM2 (autosomal dominant)
RYR1 (autosomal recessive)
MYH7 (autosomal dominant)
Myosin Storage Myopathy
MYH7 (autosomal dominant)
Cap Myopathy
TPM2 (autosomal dominant)
TPM3 (autosomal dominant)
ACTA1 (autosomal dominant)
Zebra Body Myopathy
ACTA1 (autosomal dominant)
Distal Myopathy With No Rods
NEB (autosomal recessive)
Core myopathies:
These are among the most common form of congenital myopathies and are further divided into central core and multiminicore myopathies.
Autosomal dominant due to gene defect in the ryanodine rcp-1 gene (RYR1) on 19q13.1. Rarely AR.
Allelic with familial malignant hyperthermia.
Ryanodine rcp mediates release of calcium after sarcolemmal depolarization. This should be considered when general anesthesia is needed.
Clinical phenotype:
Symmetrical limb-girdle weakness with variable involvement of facial and neck muscles.
In severe cases early onset weakness, hypotonia soon after birth, and subsequent delay in motor development (sit and walk). Some never achieve independent ambulatory status, while others have mild weakness. Thus, there is variability in severity. Muscle weakness is stable or only slowly progressive. Weakness is proximal, and pelvic girdle is usually affected more than shoulder girdle (i.e. legs are more affected than arms). Gait is wide-based and hyperlordotic. Gower's sign or modified Gower's sign is demonstrated by the patient when arising from the floor after squatting. Mild facial and neck flexor weakness. No ptosis or EOM weakness - distinguishing feature from centronuclear and nemaline myopathies. Muscle atrophy or hypertrophy is not seen. Contractures are uncommon. Muscle stretch reflexes are normal or reduced.
Common skeletal abnormalities such as pes-cavus, pes-planus, kyphoscoliosis, congenital hip dislocation, a long face, and a high-arched palate are common. Recurrent shoulder or patella dislocation and congenital hip dysplasia due to marked ligamentous laxity is reported.
Mild ventilatory muscle weakness with reduced FVC and nocturnal hypoxemia is seen in some patients. No apparent CNS abnormalities.
Labs and diagnostics:
CK is normal or slightly elevated.
EDX:
Motor and sensory NCS are normal. EMG may show fibrillation potentials, positive sharp waves, myopathic appearing MUP with early recruitment in weak muscles. Long duration, polyphasic MUPs with satellite potentials may also be seen.
MRI of skeletal muscle show early involvement of vastii, sartorius, and adductor magnus in thigh with relative sparing of the rectus femoris, adductor longus, and hamstrings.
Muscle biopsy:
Type I fibers show cores on histology. Core myopathies are characterized pathologically by the absence of oxidative enzyme activity in the central area of the myofiber due to mitochondrial depletion. The cores usually are well demarcated, deficient in phosphorylase activity and glycogen, devoid of mitochondria, and do not stain with oxidative enzyme stains. The cores can run the length of muscle fibers.
The abnormal regions are devoid of mitochondria, which correlate with the loss of mitochondrial enzymatic activity in histochemical (eg, NADH, succinate dehydrogenase [SDH], or cytochrome oxidase [COX]) stains.
Type 1 fiber predominance, as well as an increase in internal nuclei, are also common pathologic findings in RYR1-related core myopathies.
RYR1 encodes the channel that mediates calcium release in skeletal muscle during excitation-contraction coupling. Patients with central core disease should be considered at risk for malignant hyperthermia. These patients need to be counseled regarding potentially fatal adverse reaction to volatile anesthetics or muscle relaxants, and wearing a medical alert bracelet is generally advisable in case of any unexpected emergency.
The central core myopathy can be caused by autosomal dominant or autosomal recessive mutation in the skeletal muscle ryanodine receptor (RYR1) gene on chromosome 19q13.1, which is most common cause. Other gene mutations implicated in central core myopathies are in selenoprotein N1 (SEPN1) on 1p36; AR, encodes an endoplasmic reticulum glycoprotein. Mutations in the skeletal muscle -actin 1 (ACTA1) and titin (TTN) can also result in core myopathies. Rarely, mutations of RYR1 or NEB genes have been associated with a combination of rods and cores also known as core-rod myopathy.
Treatment: No treatment, PT/OT, orthotics, avoid GA with (halothane) and NMBA (succinylcholine).
RYR1 (Central core disease)
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 throughout the length of 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.
Clinical features: variable clinical expression. Presents in infancy and early childhood; adult forms have been reported. Infants who are affected are hypotonic and weak; delayed motor milestones but later able to ambulate. Most patients have generalized muscle weakness and atrophy predominantly affecting axial and proximal extremity muscles. Distal muscles are usually normal or only slightly involved. A subgroup of MmD manifests with predominantly distal hand weakness. Facial muscle weakness, ptosis, and occasionally ophthalmoparesis (more common in RYR1 related MmD) can also be seen. It is unclear if these patients represent a distinct subgroup of MmD.
Muscle contractures and multiple skeletal deformities such as kyphoscoliosis, high-arched palate, and club feet are common findings. Weakness is usually stable or only slowly progressive. Neck extensors and trunk muscles may be contracted, leading to rigidity of the spine. Cardiomyopathy and ventilatory muscle involvement can also develop especially in MmD from MYH7 and TTN mutations. Ventilatory involvement can be disproportionate to the degree of scoliosis. Patients may require intermittent or continuous positive pressure ventilation.
Labs: CK is normal or slightly elevated. PFT show reduced FVC. PSG shows nocturnal oxygen desaturation and short apneic spells. NCS are normal. EMG shows normal insertional and spontaneous activity. although early recruitment of short-duration, small MUAPs may be appreciated.
Muscle biopsy: Multiple small regions within muscle fibers of variable size (minicores) formed by disorganization of myofibrils. Similar to central cores but much smaller and do not extend the entire length of muscle fiber as do central cores. They can be seen in either type 1 or type 2 muscle fibers. Type 1 fiber predominance and atrophy as well as fiber size variation are also noted. There is increased endomysial connective tissue as well.
Molecular genetics: Heterogeneous group of disorders. Mostly like AR or spontaneous de novo mutations. Some patients with ptosis, external ophthalmoplegia show mutations in RYR1 gene similar to central core myopathy. Mutation in selenoprotein N gene (SEPN1) located on 1p36, are the most common in individuals with classic MmD. SEPN1 is also involved in congenital muscular dystrophy with rigid spine syndrome and some cases of MFM. Mutations in coflin-2 gene (CFL2) on 14q13 have been reported in patients with nemaline rods and minicores on muscle biopsy. Mutations in myosin heavy chain 7 (MYH7), titin (TTN), and multiple EGF-like domains 10 (MEGF10) can be associated with minicores as well. Minicores can also be seen in other conditions such as muscular dystrophies as well as collagen VI-related myopathies.
Treatment: No treatment. Risk of malignant hyperthermia. Early onset scoliosis is common and may required extensive arthrodesis. Patients may need intermittent or continuous positive pressure ventilation. Results from a recent pilot study and case report suggested that albuterol, beta-2 agonist, may be helpful for the treatment of core myopathies; but further confirmation from a larger prospective study is awaited. Similarly, N-acetylcysteine will be evaluated as part of a clinical trial regarding its role as antioxidant therapy for RYR1- related congenital myopathies.
Centronuclear myopathies are a genetically heterogeneous group of inherited neuromuscular disorders characterized by clinical features of a congenital myopathy and abundant central nuclei as the most prominent histopathological feature.
To date, 8 genes have been associated with centronuclear myopathies, including X-linked recessive mutations in MTM1 encoding myotubularin 1; autosomal dominant mutations in DNM2 encoding dynamin 2, the BIN1 gene encoding amphiphysin 2, and CCDC78 gene encoding coiled-coil domain containing protein; autosomal recessive mutations in BIN1, MTMR14 , RYR1, TTN, and SPEG encoding striated muscle preferentially expressed protein kinase. The majority of mutations related to centronuclear myopathies to date (including MTM1, DNM2, BIN1, and MTMR14). Recently, pathologic recessive mutations of the gene encoding striated muscle preferentially expressed protein kinase (SPEG), an MTM1-interacting protein localized to the sarcoplasmic reticulum, were found to result in severe centronuclear myopathy with dilated cardiomyopathy.
X-linked, or autosomal dominant, or recessive forms
X-link form is severe and presents in neonates
The most severe infantile X-linked recessive form appears to be caused by mutations in the gene for Myotubularin 1 (MTM1).
The X-linked recessive form is severe, presents at birth with severe hypotonia and generalized weakness. Affected infants require ventilatory support and feeding tubes. Polyhydramnios is common complication in mother's pregnancy. Ptosis and ophthalmoparesis, facial and bulbar weakness may become apparent later in infancy. Arthrogryposis is present. It is usually a fatal form of myopathy; but prognosis is not invariably poor. With aggressive medical intervention, the survival rate has increased. Surviving patients can have systemic features including risk for vascular abnormalities of the liver.
There are well described cases manifesting in females, likely due to skewed inactivation (Lyonization) similar to female carrier of dystrophin mutations. These females manifest axial and proximal weakness, skeletal asymmetry, calf pseudohypetrophy, bilateral ptosis, and external ophthalmoplegia with onset in childhood or adult.
AD form: DNM2 is the most common cause of centronuclear myopathy and usually presents as a relatively mild form of autosomal dominant late-childhood or early-adult onset distal myopathy, and de novo mutations with a severe early-onset phenotype have also been described.
Muscle weakness is mid and slowly progressive. The pattern of weakness is variable, with some patients having predominantly proximal weakness, while distal muscles are affected in others. Facial muscles may be weak and some have ptosis and ophthalmoparesis. A facioscapulohumeral pattern of weakness has also been described. Unlike infantile- and childhood-onset cases, dysmorphic facial features and skeletal muscle anomalies are not associated with the adult-form of centronuclear myopathy.
Autosomal recessive centronuclear myopathies caused by BIN1 mutations are generally very rare. Affected individuals usually present as an intermediate form of disease between the severe neonatal-onset X-linked MTM1 and the autosomal dominant late-childhood-onset DNM2 forms of centronuclear myopathy.
Children are a product of normal pregnancy except that in some there is history of in utero, reduced fetal movements and polyhydramnios Mild hypotonia and generalized weakness at birth, or in early childhood; motor milestones may be delayed. Ambulation may be achieved but the gait is hyperlordotic and wide-based. Similar to nemaline myopathy, generalized muscle atrophy, elongated narrow facies, and high-arched palate are often appreciated. Ptosis and EOM weakness,. Proximal and distal weakness; hyporeflexia. Sensation is normal. Some children can develop mental retardation and seizures.
CK is normal or mildly elevated.
Electrodiagnostic:
Patients with centronuclear myopathy may have an associated defect of neuromuscular transmission. In vitro studies have shown that the safety margin of neuromuscular transmission in this disease is compromised by decreased quantal release by nerve impulse and by a reduced postsynaptic response to the released quanta. Individuals with centronuclear myopathies show positive response to anticholinesterase therapy or evidence of impaired neuromuscular transmission based on electrophysiologic (repetitive stimulation or single-fiber) studies. Indeed, defects in neuromuscular transmission have recently been recognized as one of the pathogenic mechanisms among subtypes of congenital myopathies, particularly in cases related to MTM1, BIN1, DNM2, TPM2, TPM3, and RYR1 mutations. The use of pyridostigmine, an acetylcholinesterase inhibitor, can sometimes be associated with significant clinical improvement.
Normal motor and sensory NCS.
Needle EMG is abnormal in the severe X-linked infantile onset form revealing increased insertional activity and abnormal spontaneous activity (fibrillation potentials and PSW), CRDs, and even myotonic discharges. Motor units shows myopathic pattern (early recruitment of short-duration, small amplitude, and polyphasic MUPs).
In some individuals with mutations in dynamin-2 gene the motor and sensory NCS show mild abnormalities in the form of reduced CMAPs and slow CV in motor and sensory NCS. This is not surprising as dynamin-2 (DYN2) gene is also a cause of dominant intermediate CMT type B (DI-CMTB).
Muscle bx shows small type 1 muscle fiber predominance. Central nuclei appear in both type 1 and 2 muscle fibers. These appear as chains when viewed longitudinally. In cases associated with BIN1 mutations, the nuclei often cluster in the center of the fiber rather than forming longitudinal chains. Frequently observed are a predominance and selective hypotrophy of type 1 fibers. Type 2 fibers are normal in size. Typically, a large number of central sarcolemmal nuclei present in 25% to 95% of fibers and are associated with excessive oxidative enzyme activity (with loss of ATPase activity) in the central myocytic zones. The intermyofibrillary network often has a radial appearance like spokes of wheel and is well-seen in NADH histochemistry and in semithin plastic sections in centronuclear myopathy caused by dynamin-2 (DYN2) mutation. The radial arrangement of the myofibrils is due to peripheral attenuation of enzyme activity. Also, necklace fibers, in which there are rings/loops of oxidative enzymes staining internally within fibers, can be found in DYN2 and obligate women carriers with myotubularin 1 (MTM1) mutations. In other centronuclear myopathy caused by other the central areas appear dark. There can be increased endomysial connective tissue as can be seen in muscular dystrophies. On EM there are reduced myofibrils and an excess of mitochondria and glycogen granules in the center of muscle fibers that are not occupied by nuclei.
Molecular genetics and pathogenesis:
The severe X-linked form is caused by mutations in the myotubularin gene (MTM1). It plays a role in muscle growth and differentiation. Terminal muscle fiber differentiation is dependent on the hyperphosphorylation of specific gene regulating proteins. Myotubularin is thought to dephosphorylate these regulating proteins, and mutations in the myotubularin gene lead to loss of function of this phosphatase activity, resulting in maturational disturbances of muscle.
Other gene mutations as mentioned above include dynamin 2 (DNM2), amphiphysin 2 (BIN1) and ryanodine receptor (RYR1) and titin (TTN) have been identified in CNM.
Treatment: Infants with the X-linked form of the disease often require mechanical ventilation and tube feedings to support life. With such aggressive medical intervention, the survival rate has increased.
Congenital myopathy with a structural anomaly.
Autosomal recessive form, most severe, childhood (most common) which is a static or slowly progressive form, and adult onset have been described.
Severe infantile form is characterized by severe generalized weakness and hypotonia at birth. MSR and Moro reflexes are usually absent. Infants with this condition have a weak cry and suck. They often need to be mechanically ventilated. Most die within first year of life due to ventilatory complications. Arthrogryposis, neonatal ventilatory failure, and failure to achieve early motor milestones are associated with early mortality. Most are autosomal recessive, but some autosomal dominant forms have been described.
Childhood form manifest as mild, non-progressive, or slowly progressive weakness beginning in infancy or early childhood. Proximal and distal extremities are affected; generalized reduction in muscle bulk. Some have a facioscapuloeroneal distribution of weakness. Motor milestones are delayed, and children exhibit a wide-based, waddling, hyperlordotic gait. Slight facial and masticatory muscle weakness may be appreciated, ptosis and EOM weakness is present, but not invariably. Many have dysmorphic narrow facies with high-arched palate and micrognathia. Pectus excavatum, kyphoscoliosis, temporal mandibular ankylosis, pes cavus, or club feet are common. MSR are reduced or absent.
Adult onset type is associated with mild proximal and occasionally distal predominant muscle weakness presenting in adulthood. Some patients have minimal skeletal muscle weakness but manifest with a cardiomyopathy. The adult-onset form is not associated with dysmorphic facial features or skeletal deformities typical of early-onset forms.
Labs: CK is normal or mildly elevated. NCS are usually normal. EMG shows myopathic motor units. In early infantile forms, EMG demonstrates increased insertional and spontaneous activity.
All the genes associated with nemaline myopathy that have been identified to date encode structural components of the sarcomeric thin filaments or proteins that help regulate turnover of the thin filament.
Nemaline myopathy is associated with genetic defects of thin filament–associated molecules including alpha-actin, alpha-tropomyosin, beta-tropomyosin, nebulin, troponin, and cofilin.
The number of affected fibers is highly variable and is not correlated with the clinical severity of the disease.
Muscle biopsy in nemaline rod myopathy: Type 1 fibers are smaller than normal and often predominate in infantile form but no hypotrophy is seen in adult forms. Nemaline rods best seen on routine histochemistry with GTS, and appears as small, red or bluish purple staining bodies in the subsarcolemma and occasionally perinuclear region. On EM, the typical "rod-bodies" measure 3-6 um in length and 1-3 um in diameter, appear like thread (nemaline: Grk: thread-like). The nemaline rods have a density similar to Z-disc. intranuclear rods are suggested to represent a marker for severe form of the disease. However, these are not always seen in the severe infantile cases and sometimes seen in the milder adult onset forms. Immunohistochemistry reveals the rods and Z-disc are strongly immunoreactive for alpha-actinin.
Rods are not specific for congenital nemaline myopathy and can also occur as a secondary phenomenon in HIV-associated myopathy, MFM, IBM, hypothyroidism, and even as an acquired response to tenotomy. Nemaline rods are disintegrating Z disc proteins
Molecular Genetics and pathogenesis:
Nemaline rods are secondary to derangement of proteins necessary in the maintenance of normal Z-disc structures.
Genetically heterogeneous: Mutations in genes that encode nebulin (NEB), alpha-tropomyosin (TPM3), (TPN2), troponin T (TNNT1), alpha-actinin (ACTA1), cofilin-2 (CFL2), Kelch repeat and BTB 13 (KBTBD13), and Kelch-like family member 40 and 41 (KLHL40 and KLHL41). Recently, recessive mutations of leiomodin 3 (LMOD3) were found to be associated with a severe and often fatal form of congenital nemaline myopathy.
Most (50%) of AR cases are caused by nebulin gene mutation (NEB). The clinical phenotype can be mild to severe. Most patients with NEB mutations have predominant proximal weakness; however, distal-predominant involvement also has been observed, particularly in late onset cases.
ACTA1 (alpha-actin) gene mutations are the 2nd most common cause of nemaline myopathy (15-30%) but are responsible for about 50% of the severe lethal congenital-onset cases. It is usually AD or AR or sporadic, with no family history. Clinical features range from lack of spontaneous movements at birth, requiring mechanical ventilation to mild disease compatible with life to adulthood. These mutations in ACTA1 are also responsible for the reported cases of "congenital myopathy with excess of thin filaments." The presence of intranuclear nemaline bodies, as opposed to the more common sarcoplasmic location, is exclusive to ACTA1 mutations. ACTA1 is associated with other pathologic features, including nemaline rods, cores or minicores, cap myopathy, intranuclear rod myopathy, and congenital fiber-type disproportion.
TPM3 (alpha-tropomyosin) gene mutations on 1q21-q23 can result in AD or AR nemaline myopathy. Severity of cases range from severe infantile to late childhood-onset, slowly progressive forms. A useful clue for TPM3 mutations is the rods are found only in type 1 muscle fibers since TPM3 is not expressed in type 2 muscle fibers. It is a common cause of congenital fiber disproportion without nemaline rods. Both caps and rods were found in a patient caused by AD mutation in TPM3 gene and cause cap myopathy.
TPM2 (beta-tropomyosin) gene mutations cause AD, rod myopathy that may manifest with neck and distal lower extremity weakness (foot drop) and cardiomyopathy.
TNNT1 (muscle troponin) gene mutations cause AR, severe infantile nemaline myopathy, found in Amish communities.
CFL2 (cofilin-2) gene mutations that encode for actin-binding protein have been identified in nemaline myopathy and minicores.
KLHL40 (Kelch-like family member 40) gene mutations, AR, found by utilizing WES was found to cause nemaline myopathy in 28 apparently unrelated kindreds of various ethnicities, accounting 28% of cases in Japanese.
KLHL41 (Kelch-like family member 41) gene mutations, recessive small deletions and missense mutations using WES.
Treatment: No treatment. Aggressive early management is need in most cases of severe infantile nemaline myopathy. PT and bracing. Morbidity from respiratory tract infections and feeding difficulties frequently diminish with increasing age.
Variants of nemaline myopathy include cap myopathy, zebra body myopathy, and core-rod myopathy.
Treatment of Nemaline myopathy: It is symptomatic, including range of motion exercise, use of orthotics for foot-drop, positive-pressure mechanical ventilation, and nasogastric tube feeding for nutritional support. Regular low-impact aerobic exercise may help to maintain cardiovascular fitness. Tyrosine has been reported as a potentially beneficial supplement for nemaline myopathy; however, the mechanism of action of tyrosine in nemaline myopathies remains unclear. Other experimental therapies for nemaline myopathies involving muscle stem cells, antisense oligonucleotides, and gene replacement will depend on the underlying genetic mutations and ongoing research.
Core-Rod Myopathy
Although central core and nemaline rod myopathies are considered separate entities (genetically and histologically), they have been scattered case reports in literature of simultaneous occurrence of both cores and rods in the same muscle biopsy. Onset of symptoms are variable (congenital or early adult life) as is severity. The weakness can be proximal, distal, or generalized. Some cases have ptosis and/or skeletal deformities (contractures, scoliosis).
Serum CK may be normal or slightly elevated. NCS are normal. Myopathic motor units.
Muscle biopsy shows both cores and rods along with type 1 fiber predominance.
RYR1 mutations account for most cases. ACTA1, NEB, KBTBD13 have also been associated. Kelch repeat and BTB domain containing 12 (KBTBD13) mutations suggest importance of BTB-Kelch family members in maintenance of Z-disc and sarcomeric integrity.
No specific treatment. At risk of malignant hyperthermia (RYR1 mutations).
Late-onset Nemaline Myopathy
Clinical features: It is acquired and not genetically inherited. Associated with SLONM (sporadic late-onset nemaline rod myopathy). It usually presents after the age of 40 years and can begin as late as the 9th decade. Some patients present with isolated neck and paraspinal muscle weakness (head drop or bent spine - axial myopathy) Ventilatory muscle involvement may be cause of death.
Serum CK is usually normal. Motor and sensory NCS are normal. EMG reveals increased insertional and abnormal spontaneous activity with myopathic pattern (early recruitment of short-duration, small amplitudes MUAPs). 50% of cases are associated with a monoclonal gammopathy of undetermined significance (MGUS).
Muscle biopsy: Nemaline rods seen on routine light and electron microscopy. Rods are short and may be missed on routine light microscopy if thickness of the sections in more than 3 um. Rods are almost always appreciated on EM.
Molecular genetics and Pathogenesis:
It is sporadic disorder and there is no genetic mutation reported.
Relationship between nemaline myopathy and MGUS is unclear but causes the clinical entity SLONM.
Response to treatment in SLONM is generally poor, some patients may respond to IVIg, or autologous stem cell-transplantation (ASCT).
Zebra body myopathy
Clinical features: Only few cases of Zebra body myopathy have been reported. One child presented with generalized weakness and atrophy from birth. A second report involved a child with severe hypotonia, dysphagia, and asymmetric weakness of the upper limbs. Muscle weakness was stable or only slowly progressive.
Serum CK is 2-3 times normal. EMG reveals myopathic units without abnormal spontaneous activity.
Muscle biopsies demonstrate variability in muscle fiber size, increased internal nuclei, and occasional vacuoles. The Z bodies appear on EM as osmophilic 280 mm stria, with a periodicity such that they resemble stripes on a zebra. The density of the stria is that of Z-discs measuring up to 2 nm in length. Streaming of the Z-bands and nemaline rods may also be appreciated.
Molecular genetics and pathogenesis: It is associated with mutations in ACTA1. However, they are not a specific abnormality and can be found in normal individuals at myotendinous junctions, and intrafusal fibers (muscle spindles), in EOM, and in cardiac muscles. These may also be found in other pathologic conditions (e.g., myofibrillar myopathy).
Treatment: No specific medical treatment available.
Cap myopathy
Clinical features: The clinical features of this rare myopathy overlap with those seen in nemaline myopathy given the causal genes are similar. It is usually associated with neonatal onset of generalized muscle weakness and hypotonia associated with skeletal deformities and reduced muscle stretch reflexes. Ventilatory muscles are also frequently affected.
Serum CK is normal. NCS are normal, while the EMG demonstrates myopathic MUPs.
Muscle biopsies reveal many muscle fibers that contain a peripheral crescent that reacts strongly to NADH-TR, PAS, and phosphorylase, but not to SDH or myofibrillar ATPase. Immunohistochemistry revealed that these "caps" show increased fast myosin activity, desmin, tropomyosin, and alpha actinin. On EM, there is widening Z bands, disarray of the myofibrils, and lack of thick filaments.
Molecular genetics and pathogenesis: Myopathy is most commonly caused by mutations and TPM2, but also has been reported with TPM3, and ACTA1.
Treatment: No specific medical treatment available.
Dominant, recessive, and X-linked forms
Alpha-tropomyosin (TMP3) - AD; RYR1 - AR; rarely: ACTA1, SEPN1, MYL2, TPM2, and MHC7 gene mutations rarely
Clinical features:
It usually manifests as generalized hypotonia and weakness along with a weak cry and suck in infancy. Motor milestones are delayed, but muscle weakness is usually nonprogressive and functional status improves with age. However, there are cases with progressive and sometimes fatal course secondary to ventilatory muscle insufficiency. Some children who are affected display dysmorphic facial features with a high-arched palate, congenital hip dislocations, kyphoscoliosis, arthrogryposis, and a rigid spine. MSR are reduced. ~ 1/3rd of patients have some type of CNS abnormalities; some of these cases may represent forms of congenital muscular dystrophy with impaired glycosylation of alpha-dystroglycan.
Serum CK is normal or mildly elevated. NCS are normal. EMG can be normal or reveal increased insertional and spontaneous activity and early recruitment of myopathic MUAPs.
Muscle biopsy:
Disproportionate atrophy of type 1 compared to type 2 muscle fibers. It is defined by the presence of type 1 fiber hypotrophy with mean diameter being uniformly smaller than type 2 fibers by more than 35% to 40%, in the absence of other structural abnormalities and accompanied by clinical features consistent with congenital myopathies. The presence of rods, cores, abundant central nuclei, or other structural features of congenital myopathies indicates an alternative diagnosis other than congenital fiber-type disproportion.
Treatment: Supportive measures with mechanical ventilation, tube feeding may be temporarily needed in some patients. PT and orthotic devices may be beneficial.
Clinical features: It is a rare disorder and typically presents as generalized hypotonia, weakness, and muscle atrophy in infancy or early childhood. Muscle strength is stable or only slowly deteriorates over time. MSR are reduced or absent. Some individuals have a reduced intelligence and febrile seizures. In addition, kyphoscoliosis and pectus excavatum may be evident in some cases.
Serum CKs are normal or slightly elevated. NCS are normal. EMG may be normal or may demonstrate myopathic MUPs without abnormal insertional or spontaneous activity.
Muscle biopsy reveals type 1 fiber predominance with type 1 fiber hypotrophy and type 2 fiber hypertrophy. On oxidative enzyme stains, there is a reduced activity in the subsarcolemma and perinuclear regions in type 1 fibers. EM and phase-contrast microscopy demonstrate a complex lamellar pattern resembling fingerprints that are evident in these areas; these fingerprint bodies appear to be composed of cytoskeletal proteins. Fingerprint bodies are nonspecific and have also been noted in myotonic dystrophy, various distal myopathies, nemaline myopathy, dermatomyositis, OPMD, and muscle biopsies from patients with uremia and chronic pulmonary disease.
Molecular genetics and pathogenesis: Most cases are sporadic, although the disease was reported in a pair of male identical twins and in two siblings. The pathogenic mechanism for the formation of the fingerprint bodies is not known.
Treatment: There is no specific medical treatment.
Reducing body myopathy
Reducing body myopathy is a rare disorder that has varied clinical presentation. It can present in infancy with severe generalized weakness, hypotonia, and joint contractures. Ptosis may be present. There is an increased mortality due to associated ventilatory muscle weakness. Some affected individuals develop muscle weakness later in childhood or adulthood. The proximal or distal muscles may be preferentially affected, and involvement can be asymmetric, particularly in the arms. The course can vary from mild stable weakness to progressive deterioration of strength, leading to death. Some affected patients develop contractures of the major joints, scoliosis, and rigidity of the spine.
Serum CK levels are usually normal to mildly elevated. NCS are normal. EMG demonstrated myopathic features.
Muscle biopsy: The characteristic features on muscle biopsies are "reducing bodies," named because of the unique ability to reduce nitroblue tetrazolium with mediated by menadione. These reducing body stain purple with modified GTS and pink on H&E stain and are devoid of oxidative enzyme staining. Immunohistochemistry reveals increased desmin at the periphery of some reducing bodies, but alpha-beta-crystallin, alpha-actinin, titin, and nebulin immunostains are normal. There is usually type I fiber predominance as seen in most other congenital myopathies, but the reducing bodies are evident in both fiber types. On EM, reducing bodies appear to be composed of electron dense granules and 12-17 nm tubulo-filaments.
Molecular genetics and pathogenesis: It is caused by mutations in the four and a half LIM gene (FHL1), located on Xq26.3 that encodes for four and a half LIM. Rarely mutations with desmin (DES) have been reported. The histopathology resembles MFM.
Treatment: No specific treatment is available.
Myofibrillar myopathy
It is genetically heterogeneous group of disorders, which are now considered to be forms of muscular dystrophy as opposed to congenital myopathies.
Sarcotubular myopathy (allelic to LGMD 2H)
Clinical features: Patients present with exertional myalgias or proximal muscle weakness in infancy or adult life. Scapular winging, calf hypertrophy, foot drop, and mild facial weakness may be appreciated. MSR are usually diminished.
Serum CK levels range from norma to 20 fold elevated. EMG may be normal or may reveal myopathic features.
Muscle biopsy may reveal increase in internal nuclei, muscle fiber splitting, and many fibers (mostly type 2) with small vacuoles. These vacuoles, which abut T-tubules, appear to be membrane bound, and are empty or contain a small amount of amorphous debris on EM. The vacuoles immunostain for sarcoplasmic reticulum-associated ATPase.
TRIM32 gene mutations encoding the tripartite-motif containing protein 32. This protein is though to play a critical role in recognition of other protein(s) targeted to be ubiquitinated by this ligase enzyme.
There is no specific medical treatment.
Trilaminar myopathy
Clinical features: A single case report of an infant with rigidity of its trunk and limbs, decreased spontaneous movements, weak suck and swallowing, and numerous joint contractures has been reported with this disorder. Sensation appeared normal and MSR were intact. By 10 months of age, the infant had some head control, but was still unable to sit. Subsequently, the patient was able to ambulate, albeit with difficulty.
Serum CK was markedly elevated at birth (~ 10 times normal). EMG and NCS are normal.
Muscle biopsy demonstrated variability in fiber size. The unique feature was that ~25% of fibers were hypertrophic and had three concentric zones that displayed a differential staining pattern. The inner and outer zones stained intensely with GTS and NADH stains, while the inverse pattern was seen on ATPase staining. On EM, the innermost zone demonstrated myofibrillar disarray and densely packed mitochondria, glycogen granules, and myofilaments. The intermediate zone revealed Z-band streaming. The outer zone was composed of disorganized myofibrils, mitochondria, lipid droplets, and vesicles.
No pathogenic gene mutation is identified.
No specific treatment is available.
Hyaline body myopathy (familial myopathy with loss of myofibrils, myosin storage myopathy)
Clinical features: Rare congenital myopathy presenting in infancy to as late as the 5th decade of life with limb-girdle or scapuloperoneal pattern of weakness. Muscle strength is stable or only slowly deteriorates and is nonprogressive. Rarely patients have cardiomyopathy. MSR are preserved. Variability in severity within families is seen.
Serum CK is normal or mildly elevated. EMG studies are normal or may show myopathic pattern. TTE reveals DCM with reduced LVEF.
Muscle biopsy: Subsarcolemmal "hyaline" bodies that stain pale green on modified GTS and pale pink on H&E stains. They occur in type 1 fibers, which are hypotrophic. The hyaline bodies do not stain with oxidative enzymes or PAS, but demonstrate intense ATPase activity. Angulated neurogenic fibers and fiber-type grouping may also be appreciated. Immunostaining demonstrates strong reactivity for slow myosin heavy chain (MyHC) in some but not all hyaline bodies. The hyaline bodies are nonreactive for alpha-beta-crystallin, ubiquitin, tropomyosin, actins, desmin, and components of sarcolemma. On EM, the hyaline bodies appear to be composed of granulofilamentous debris often with fragments of sarcomeres and surrounded by a zone of sarcomeric disorganization.
Molecular genetics and pathogenesis: Missense mutations in the MYH7 gene that encodes for slow/beta-cardiac MyHC cause most cases of AD hyaline body myopathy. Mutation in this gene is also associated with a familial form of CM and Laing-type distal myopathy/dystrophy. CM is not reported in cases of hyaline body myopathy. MyHC7 encodes the major protein isoform seen in type 1 muscle fiber and cardiac muscle. It appears that normal MyHC is essential for the assembly of thick filaments in skeletal muscle.
Treatment: No specific medical treatment is available.
Other Myosin storage disorders:
An autosomal dominant myopathy characterized by mild weakness and myalgia with onset in childhood or early adult life has been linked to mutations in the MYH2 gene, which encodes for MyHC IIa. MyHC IIa isoform of MyHCs is expressed in type 2 A muscle fibers. Some patients present with congenital arthrogryposis, ophthalmoplegia, mild proximal weakness beginning in adulthood. As muscle biopsies may demonstrate rimmed vacuoles and tubulofilamentous inclusions, this disorder has been called hereditary inclusion body myopathy type III.
Tubular aggregate myopathy
Tubular aggregate are a nonspecific histological abnormality, which may be found in muscle biopsies of patients with hereditary periodic paralysis, hyperthyroidism, congenital myasthenia (slow channel syndrome), hypoxia, and some toxic myopathies. Also found in patients with no symptoms or signs of a myopathy.
There are at least 3 clinical syndromes in which the primary pathologic feature is tubular aggregates on muscle biopsy.
Individuals affected may have slow progressive limb girdle weakness beginning in childhood or early adulthood. There is a form that resemble congenital myasthenia, which presents with slowly progressive muscle weakness from infancy.
Patient's demonstrate fatigable weakness, which improves with anti-acetylcholinesterase medications.
A subgroup comprises patients with generalized myalgia, which are worse with exertion.
Muscle tone, bulk, and strength are normal as is the rest of the physical examination.
In addition, there is a rare tubular aggregate myopathy associated with immunodeficiency and such a sub-type also is associated with miosis.
Laboratory features:
CK is normal or mildly increased.
Electrodiagnostic features:
Routine motor and sensory NCS are normal.
Patients with the myasthenic syndrome demonstrated decremental response on repetitive stimulation, which improves with pyridostigmine.
EMG can be normal or can demonstrate myopathic motor unit potentials and fibrillation potentials.
Patient with a muscle pain syndrome typically have completely normal electrodiagnostic findings.
Muscle biopsy: Tubular aggregates stain basophilic on H&E stain) and red on Modified GTS. These react intensely to NADH-TR both small to SDH. Tubular aggregates are located in subsarcolemmal position and are present only in type 2 muscle fibers in the syndromes associated with periodic paralysis and muscle pain but are seen in both type 1 and 2 muscle fiber types in the limb-girdle syndrome. On EM, the aggregates are composed of bundles of tubules 60-80 nm in diameter, which course in various directions with respect to the long axis of muscle fibers.
Molecular genetics and pathogenesis: Mutations in the genes that encode for stromal interaction molecules 1, STIM1, cause a dominantly inherited tubular aggregate myopathy associated with immunodeficiency. STIM1 regulates calcium in the endoplasmic reticulum. Mutations in the genes that encodes for oral-1, ORA1, are also associated with an autosomal dominant tubular aggregate myopathy associated with immunodeficiency along with miosis. Some forms of congenital myasthenia can easily be mistaken for a congenital myopathy. This is especially so if one does not appreciate fatigability or decrement with RNS, are associated with tubular aggregates. These include mutations in the genes that encode for DPAGT1 and GFPT1.
Treatment: Patients with congenital myasthenic syndrome may benefit from pyridostigmine. Individuals with muscle pain syndrome may improve with dantrolene or tricyclic antidepressants.
Mitochondrial Myopathy
Clinical features and management of Mitochondrial disorders
Ocular symptoms: External ophthalmoplegia, ptosis, optic atrophy, pigmentary retinopathy, cataracts
CNS: Encephalolpathy, stroke-like episodes, seizures, myoclonus, ataxia, psychosis, and migraines.
Migraine, encephalopathy, stroke-like episodes (MELAS)
EEG
MRI
Avoid valproate
Peripheral neuropathy: axonal, sensory neuronopathy, ganglionopathy, SNHL, autonomic dysfx,
Musculoskeletal: skeletal myopathy: ocular > axial/proximal > distal > respiratory
PFT, sleep study, CK, CoQ10 levels, EMG
Cardiac: CM, conduction def,
ECG, TTE, Holter
Endocrine: DM, hypothyroidism, hypoparathyroidism, gonadal failure, GH def
HbA1C, TSH, T3, T4, PTH, Ca, GH, GHRH-arginine test, LH, FSH,
Renal tubular defects
Dysphagia due to esophageal dysmotility, constipation/diarrhea, hepatic failure
Short stature,
Spontaneous abortions.
PEO: In patients with progressive external ophthalmoplegia, the most commonly found abnormality is a defect that predisposes to multiple mtDNA deletions in three nuclear genes ANT1 (adenine nucleotide translocator-1), TWINKLE (an adenine nucleotide dependent mtDNA helicase), and POLG.
Progressive external ophthalmoplegia is a combination of progressive ptosis and symmetrical external ophthalmoplegia, and it is a common manifestation of mitochondrial disease.
Usually, there is no diplopia or strabismus, or at most only transient diplopia, so that the disorder can exist for a long time before it brings the patient to a physician.
In clinical practice, nearly all cases of PEO are due to mtDMA deletions, but, in rare cases, the condition can be simulated by a genetically determined muscular dystrophy, including oculopharyngeal dystrophy and a type in which PEO is linked to facioscapulohumeral dystrophy.
The first warning sign of PEO is typically progressive, bilateral ptosis with notably different clinical characteristics from myasthenic ptosis. Once begun, PEO progresses relentlessly, impairing conjugate eye movements until the eyes are motionless.
There is, considerable overlap of symptoms and signs among PEO, KSS, MELAS, and MERRF but there is general agreement that cases of PEO, KSS, and mitochondrial myopathy should be considered separately. Their shared feature is the histological abnormality of the muscle mitochondria, which results in ragged red fibers, named for the subsarcolemmal and intermyofibrillar collections of membranous (mitochondrial) material in type 1 muscle fibers visualized by the modified Gomori trichrome stain in sections of frozen muscle.
MNGIE: TYMP
Mitochondrial DNA depletion syndrome
Kearns-Sayre syndrome (KSS):
Diagnosis: Kearns Sayre Syndrome is an extensive multisystem failure (best described as a mitochondrial cytopathy). It includes the following:
PEO
Atypical pigmentary retinal degeneration
Heart block and cardiomegaly requiring a pacemaker
Elevated CSF protein
Sensory-neural hearing loss
Ataxia with cerebellar atrophy
Dysphagia due to pharyngeal dystrophy corrected by cricopharyngeal myotomy
Blindness
Proximal myopathy
The skeletal muscle biopsy shows ragged red fibers and a 3.8 kilobase mtDNA deletion.
Clinical manifestations of mitochondrial disease:
Neurological: External ophthalmoplegia, myopathy, fatiguability, cerebellar ataxia, pigmentary retinopathy, epilepsy, myoclonus, sensorineural deafness, peripheral neuropathy, dementia, stroke, episodic nausea and vomiting, dystonia, basal ganglia calcification.
Non-neurological: Short stature, cardiac conduction, cardiomyopathy, cataracts, lactic acidosis, diabetes mellitus, hypoparathyroidism, renal tubular defects, pancytopenia, intestinal pseudoobstruction, and multiple lipomas.
MNGIE: Myopathy, external ophthalmoplegia, Neuropathy, Gastro-Intestinal and Encephalopathy syndrome.
This disorder is caused by mutations of the thymidine phosphorylase (TYMP) gene (previously known as ECGF1) encoding thymidine phosphorylase, which is critical for degradation of thymidine. This leads to multiple mitochondrial DNA deletions and marked elevation of plasma thymidine, which may be toxic. There is some indication that allogenic stem cell transplantation may be able to correct the metabolic abnormalities and arrest disease progression.
MNGIE, is a rare autosomal recessive mitochondrial disorder. Patients have marked cachexia, profound gastrointestinal symptoms of various types, ptosis, ophthalmoparesis, sensory or sensorimotor neuropathy, variable myopathy, and other findings, such as hearing loss and white matter magnetic resonance imaging changes without notable cognitive decline.
Plasma thymidine levels greater than 3 umol/L and deoxyuridine levels greater than 5 umol/L can be sufficient to confirm the diagnosis of mitochondrial neurogastrointestinal encephalopathy.
Mitochondrial myopathy treatment regimen:
Careful and progressive exercise; no exercise during illness
Avoid fasting
Cocktail regimen:
Coenzyme Q10 (CoQ) or idebenone 5 - 15 mg/kg/day + alpha-lipoic acid 5 - 15 mg/kg/day + vitamin E 5 - 15 IU/kg/day + creatine monohydrate - 0.1 g/kg/day
LevoCARNitine (Carnitor), only if levels are low; start at 330 mg PO tid and retest.
Vitamin C 100 mg PO daily
Niacin 100 mg PO daily
Ribflavin 50 mg PO daily
Thiamine 100 mg PO daily
Genetic testing strategy
The panel should include congenital myopathies associated with cardiomyopathy which are:
Titin, ACTA1, SPEG, LMOD3, GAA, FHL1
Dystrophies like: DMD, LMNA (lamin A/C), EDMD
Then, if you don't get a hit, they will move the sample to whole exome for you.
Genotype and Phenotype correlations:
Selenoprotein (SEPN1) mutation: congenital muscular dystrophy with rigid spine syndrome, multi/minicore, some cases of MFM.
TRIM32: sarcotubular myopathy, LGMD2H
Central cores: RYR1, selenoprotein N1 (SEPN1), alpha-actin 1 (ACTA1), titin (TTN). coiled-coiled domain containing gene (CCD78)
MYH7 (myosin heavy chain 7 gene): eccentric cores and multi/minicores.
Cores and nemaline rods: NEB, KBTBD13.
Phenotypes associated with RYR1:
Central core, multi/minicore, core-rod myopathies.
Exertional myalgia with rhabdomyolysis in the absence of baseline weakness.
King-Denborough syndrome is a rare disorder characterized by susceptibility to malignant hyperthermia, delayed motor development, short stature, cryptorchidism, skeletal abnormalities, and variable dysmorphic features that in some cases have been associated with RYR1 mutations.
Late onset axial myopathy presenting as bent-spine syndrome (camptocormia) or neck extensor myopathy have been found to have RYR1 mutations. CKs are normal or slightly elevated. EMG may be normal in extremities and demonstrate fibrillation potentials and positive sharp waves only in axial/paraspinal muscles. Muscle biopsies of weak muscle - upper trapezius or paraspinal muscles may demonstrate cores, multiminicores, or moth-eaten fibers.