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

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

Multiminicore Myopathy

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

Centronuclear Myopathy

Congenital Fiber-type Disproportion

Myosin Storage Myopathy

Cap Myopathy

Zebra Body Myopathy

Distal Myopathy With No Rods

Core myopathies:

These are among the most common form of congenital myopathies and are further divided into central core and multiminicore myopathies. 

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.

Core-Rod Myopathy

Late-onset Nemaline Myopathy

Zebra body myopathy

Cap myopathy

Reducing body myopathy

Myofibrillar myopathy

Sarcotubular myopathy (allelic to LGMD 2H)

Trilaminar myopathy

Hyaline body myopathy (familial myopathy with loss of myofibrils, myosin storage myopathy)

Other Myosin storage disorders:

Tubular aggregate myopathy

Mitochondrial Myopathy

Clinical features and management of Mitochondrial disorders

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.

MNGIE: TYMP

Mitochondrial DNA depletion syndrome 

Kearns-Sayre syndrome (KSS):   

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.

Mitochondrial myopathy treatment regimen:

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: