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Congenital Myopathies: An Overview

Gayatri Nerakh1, Megha Uppin2, Prajnya Ranganath1
1Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
2Department of Pathology, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
Correspondence to: Dr Prajnya Ranganath      Email: prajnyaranganath@gmail.com

1 Abstract

Congenital myopathies (CM) are a clinically and genetically heterogeneous group of disorders affecting the skeletal muscles. Hypotonia, hyporeflexia and muscle weakness are common clinical presentations but the severity can be very variable ranging from the severe form with death in early infancy to the milder form with survival until adulthood. Most types have typical histopathological features which help in characterization, but molecular genetic testing helps in more definitive etiological diagnosis. An overview of the classification, clinical presentations, histopathological features and management of congenital myopathies is presented here.

2 Introduction

Congenital myopathies (CM) are heterogeneous with respect to their clinical presentations, pathologic features and molecular genetic bases. CMs have been traditionally classified on the basis of clinical features and muscle biopsy findings. However, with advances in genetic testing, it has been identified that these myopathies are associated with specific genes and now the approach to the diagnosis of CMs is slowly shifting from a “phenotype down” approach to “genotype up” one (North, 2011). The International Standard of Care Committee for Congenital Myopathies has outlined certain key features common to all congenital myopathies and the specific features of different genetic subtypes (North et al. & International Standard of Care Committee for Congenital Myopathies, 2014).

3 Pathophysiology

Studies on cell lines, patient tissues and animal models have helped to understand the pathophysiology underlying CMs. The main mechanisms identified to be associated with CMs include defects in excitation–contraction coupling, defects in thin–thick filament assembly and interactions, mitochondrial dysfunction, and imbalance in protein synthesis or degradation (Jungbluth et al., 2018; De Winter et al., 2017; Ravenscroft et al., 2015). However, the precise pathophysiological basis for many of the CMs remains obscure.

4 Classification

Congenital myopathies are traditionally classified based on the predominant pathologic feature observed under light and electron microscopy as listed in Table 1 (North et al. & International Standard of Care Committee for Congenital Myopathies, 2014).

 Table  1: Classification of congenital myopathies based on muscle histopathology.

Structured abnormalities on muscle biopsy

1. With protein accumulation

i. Nemaline myopathy

ii. Cap disease

iii. Myosin storage (hyaline body) myopathy

iv. Reducing (zebra) body myopathy

v. Intranuclear rod myopathy

vi. Actin myopathy

2. With cores

i. Central core disease

ii. Multiminicore disease

iii. Core-rod myopathy

3. With central nuclei

i. Myotubular myopathy

ii. Centronuclear myopathy

Non-structured abnormalities on muscle biopsy

4. With fiber size variation

i. Congenital fiber type disproportion

5 Molecular Genetic Basis

The genetics of congenital myopathies with respect to the histopathological types is complex. One histopathologic type of CM can be caused by mutation(s) in any one of multiple different genes (genetic heterogeneity) and mutations in the same gene can lead to different types of CMs. Moreover, there can be significant intrafamilial and interfamilial variability in severity even for the same gene mutation (North, 2011; North et al. & International Standard of Care Committee for Congenital Myopathies, 2014). Genotype and phenotype correlations of congenital myopathies are hindered by the clinical variability of the phenotype but certain specific features may point to the involvement of a particular gene. Table 2 lists the various genes known to be associated with CMs and their patterns of inheritance.

 Table  2: Genes associated with congenital myopathies.

Nemaline myopathy


Pattern of


NEB (Nebulin)


ACTA1 (Alpha skeletal muscle actin)


TPM3 (Alpha tropomyosin)


TPM2 (Beta tropomyosin)


TNNT1 (Troponin)


KLHL40 (Kelch-like family 40)


KLHL41 (Kelch-like family 41)


KBTBD13 (Kelch Repeat- and BTB/POZ domain-containing protein)


LMOD3 (Leiomodin 3)


CFL2 (Cofilin 2)


Central core and Multi mini core myopathy

RYR1 (Ryanodine receptor)


TTN (Titin)


Centronuclear myopathy

MYM1 (Myotubularin)


DNM2 (Dynamin)


BIN1 (Bridging integrator)


CCDC78 (Coiled-coil domain containing protein 78)


SPEG (Striated muscle preferentially expressed protein)


ZAK (Leucine zipper and sterile alpha motif containing kinase)


RYR1 (Ryanodine receptor)


Congenital fiber type disproportion

TPM3 (Alpha tropomyosin)


SELENON (Selenoprotein N)


ACTA1 (Alpha skeletal muscle actin)


AR – Autosomal recessive; AD – Autosomal dominant; XL – X-linked

6 Clinical Manifestations

Common clinical presentations of CMs include hypotonia, hyporeflexia and muscle weakness which can overlap with other neuromuscular disorders including congenital muscular dystrophies, spinal muscular atrophy, congenital myasthenic syndromes, congenital myotonic dystrophy and metabolic myopathies. Certain features of diagnostic importance include facial weakness associated with ptosis/ophthalmoplegia, bulbar and respiratory weakness and orthopedic complications like pectus carinatum and kyphoscoliosis. The severity may range from profound weakness in neonates with death in early infancy to mild weakness and survival to adulthood (North, 2011). Most of the congenital myopathies have generalized or proximal muscle weakness. Some have prominent axial or respiratory muscle weakness or weakness of ankle dorsiflexion. Cardiac involvement is unusual in congenital myopathies except in patients with variants in genes encoding titin (TTN) and myosin heavy chain 7 (MYH7). Table 3 lists some of the clinical features which are specific to certain types of congenital myopathies and can help in narrowing down the possible genetic diagnoses.

 Table  3: Clinical clues to the etiological diagnosis of congenital myopathies.

Clinical feature

Type of congenital myopathy

Genes involved

Neonatal onset

  • Nemaline myopathy
  • Core myopathy
  • Centronuclear myopathy

  • RYR1
  • MTM1

Mild course with survival into adulthood

  • Central core myopathy
  • Centronuclear myopathy

  • SEPN1
  • MTM1, DNM2


  • Centronuclear myopathy (X-linked myotubular myopathy -severe neonatal form)

  • MTM1

Facial involvement

  • Nemaline myopathy
  • Centronuclear myopathy

  • MTM1, DNM2, RYR1


  • Central core myopathy
  • Multi mini core myopathy
  • Centronuclear myopathy

  • RYR1/SEPN1
  • SEPN1/RYR1
  • MTM1, DNM2, RYR1


  • Centronuclear myopathy
  • Central core myopathy
  • Multi mini core myopathy

  • MTM1, DNM2, RYR1
  • RYR1

Neck muscle weakness

  • Nemaline myopathy

  • ACTA1

Severe respiratory involvement at birth

  • Nemaline myopathy
  • Core myopathy
  • Centronuclear myopathy

  • TPM3, TNNT1, KLHL40, LMOD3
  • RYR1
  • MTM1


  • Nemaline myopathy
  • Core myopathies (Central core and Multi minicore)

  • TPM2, ACTA1
  • MYH7, TTN

Predominant axial hypotonia

  • Core myopathy

  • RYR1

Joint contractures

  • Nemaline myopathy
  • Central core myopathy
  • Centronuclear myopathy

  • TPM2, TNNT1, KLHL40,
  • RYR1
  • MTM1, RYR1


  • Nemaline myopathy
  • Core myopathy

  • NEB
  • RYR1, SEPN1

Foot drop/pes cavus

  • Nemaline myopathy
  • Multi mini core myopathy
  • Centronuclear myopathy

  • NEB, TPM3, TPM2
  • MYH7
  • DNM2

Malignant hyperthermia

  • Central core myopathy
  • Multi minicore myopathy
  • Centronuclear myopathy

  • RYR1
  • RYR1
  • RYR1

7 Clinical Approach

A systematic clinical approach helps in appropriate assessment and management of the patient and in accurate interpretation of the results of molecular genetic tests.

7.1 History/ Clinical examination

History of decreased fetal movements, early neonatal death due to respiratory insufficiency, floppiness and failure to thrive due to feeding difficulty during infancy, motor developmental delay, difficulty in walking and a waddling gait, and difficulty in climbing stairs and getting up from a sitting or squatting position, with or without history of similar features in other family members, suggest the possibility of a congenital myopathy. Clinical examination findings include myopathic facies, hypotonia, diminished deep tendon reflexes, reduction in muscle power more significantly in the axial and proximal limb muscles, and joint laxity. There is significant overlap between the clinical features of CMs with other genetic neuromuscular disorders. Clinical features of tongue fasciculations, facial dysmorphism other than myopathic faces, rapid progression and extreme joint laxity may be pointers for an alternative diagnosis.

7.2 Differential diagnosis

The following conditions can have significant phenotypic overlap with CMs and should be considered as possible differential diagnoses.

a. During infancy: Spinal muscular atrophy (SMA) type 1, congenital muscular dystrophies (CMD), congenital myotonic dystrophy, congenital myasthenic syndromes (CMS), metabolic myopathies, Prader–Willi syndrome and congenital hypomyelinating neuropathy can have overlapping phenotypic features. Table 4 lists the features that help to differentiate these conditions from congenital myopathies.

 Table  4: Differential diagnoses for congenital myopathies presenting with significant floppiness during infancy.


Differentiating features

Spinal muscular atrophy type 1

Sparing of facial muscles, tongue fasciculations, normal/raised serum CPK, denervation pattern in ENMG

Congenital muscular dystrophy

Sparing of facial muscles, calf muscle hypertrophy (dystroglycanopathies), distal joint laxity (collagen VI associated), raised serum CPK, dystrophic changes in muscle biopsy, neuronal migration defects (dystroglycanopathies) and T2-white matter hyperintensity (merosin deficiency) in MRI brain

Congenital myotonic dystrophy

Myotonia in the mother, evidence of myotonia in EMG

Congenital myasthenic syndrome

Ptosis and ophthalmoplegia, single-fiber EMG/RNS showing specific pattern of myasthenia with absence of acetyl choline receptor antibodies

Metabolic myopathies

Central nervous system involvement, raised serum or CSF lactate, ragged red fibers on muscle biopsy - mitochondrial cytopathy

Elevated ammonia, metabolic acidosis, abnormal plasma amino acid and urine organic acid screen - inborn errors of small molecule metabolism

Hepatomegaly with hypertrophic cardiomyopathy - Pompe disease

Prader-Willi syndrome

Feeding difficulty with failure to thrive, marked hypotonia with normal ENMG

Congenital hypomyelinating neuropathy

Slowing of nerve conduction velocity in NCS and denervation pattern in ENMG

Serum CPK – serum creatine phosphokinase; EMG – Electromyography; ENMG – Electroneuromyography; RNS – Repetitive nerve stimulation study; NCS – Nerve conduction study; CSF – cerebrospinal fluid

b. During childhood and in adults: Limb-girdle muscular dystrophies, SMA types 3 and 4, myotonic dystrophy, hereditary motor sensory neuropathy (HMSN) and acquired causes including autoimmune and inflammatory myopathies can mimic the milder forms of congenital myopathy which have survival until adulthood. Table 5 lists the features that help to differentiate these conditions from congenital myopathies.

 Table  5: Differential diagnoses for milder forms of congenital myopathies.


Differentiating features

Limb-girdle muscular dystrophies

Facial muscle sparing, calf muscle hypertrophy, cardiac involvement, progressive symptoms, elevated serum CPK

Spinal muscular atrophy types 3 and 4

Facial muscle sparing, normal to slightly raised serum CPK, denervation pattern in ENMG

Myotonic dystrophy

Grip myotonia and percussion myotonia, evidence of myotonia in EMG

Hereditary motor and sensory neuropathy

Facial muscle sparing, predominant distal muscle weakness, NCS suggestive of demyelinating or axonal neuropathy

Acquired: Inflammatory Disorders/ Autoimmune disorders

Muscle pain, other systemic features of autoimmune conditions including arthritis and rashes, presence of inflammatory markers, response to immunosuppressive therapy

Serum CPK – serum creatine phosphokinase; EMG – Electromyography; ENMG – Electroneuromyography; NCS – Nerve conduction study

7.3 Laboratory evaluation

The following laboratory evaluation is done in patients presenting with a CM phenotype:

Serum CPK: is usually within normal limits or is only mildly elevated in CMs.
Electromyography (EMG): shows myopathic changes or may be normal.
Nerve conduction study (NCS): is usually normal but low-amplitude motor responses may be seen if there is marked loss of muscle bulk.


 Figure 1: A neonate with the severe congenital-onset form of nemaline myopathy with respiratory insufficiency since birth and multiple congenital joint contractures.

7.4 Muscle biopsy

Most congenital myopathies can be diagnosed using muscle biopsy followed by light microscopy and electron microscopy, unlike cases of muscular dystrophies where immunohistochemical studies are needed. Electron microscopy helps in histopathological diagnosis of subtypes of congenital myopathies. However, with the availability of next generation sequencing in recent years and the consequent ease of molecular diagnosis and accurate characterization, many clinicians prefer to defer muscle biopsy due to its invasive nature. But muscle biopsy can help to corroborate the diagnosis in cases where molecular genetic testing identifies novel variants or variants of unknown significance and also helps in characterization when genetic evaluation does not yield the diagnosis.

The typical histopathology findings in different types of CMs are as follows:

a. Nemaline myopathy: The biopsy shows characteristic nemaline rods (‘nema’ in Greek=thread) on modified Gomori’s trichrome stain (MGT) (Figure 2). These appear as red colored rods in clusters at the centre or periphery of the fibers and are seen in all fiber types. At later stages of disease, the biopsy can reveal changes of chronicity like fatty infiltration, fibrosis and fiber splitting. On electron microscopy (EM) rods have a lattice structure similar to the Z-line and can show continuity with the Z-line.


 Figure 2: Muscle biopsy with modified Gomori trichrome (MGT) staining (100X) showing presence of red colored nemaline rods in the periphery as well as in the centre of the fibers in nemaline myopathy.

b. Core myopathy: The core myopathies are characterized by presence of central cores on staining with the oxidative stains succinic dehydrogenase (SDH), nicotinamide adenine dinucleotide (NADH) and cytochrome oxidase (COX) (Figure 3A). These are areas of absent oxidative enzyme stain on muscle biopsy that reflect the absence of mitochondria. These cores run along the longitudinal axis of the muscle fiber and may be central, peripheral, more than one per fiber and of variable size (Dubowitz et al., 2013). On electron microscopy, these cores may be structured (without any disruption of the intrinsic sarcomeric structure) or unstructured (with disruption of sarcomeric structure) with absence of mitochondria in the cores. Unlike central cores, minicores are identified as multiple focal areas devoid of oxidative enzyme activity which appears only as uneven stain on transverse section (Figures 3B&C).

 Figure 3: Muscle biopsy showing features of Core myopathy. A. Central area of absence of oxidative staining on NADH representing central cores (100X); B. & C. Multiple areas of absence of oxidative enzyme activity on NADH representing minicores.

c. Centronuclear myopathy: The characteristic feature is the presence of internalized and central nuclei (Figures 4 A & B). The biopsy in X-linked myotubular myopathy reveals fiber atrophy with many fibers showing centralized nuclei resembling myotubes; these are seen on longitudinal section as a row of nuclei. The central nuclei have reduced ATPase reaction and increased periodic acid-Schiff (PAS) and oxidative enzyme staining surrounded by a clear halo (Romero & Bitoun, 2011). Electron microscopy shows central nuclei with aggregates of mitochondria.

 Figure 4: Muscle biopsy with hematoxylin and eosin (H&E) staining showing features of centronuclear myopathy. A. Transverse section of muscle biopsy showing central nuclei (40X); B. Central nuclei are seen arranged in rows (40X).

d. Congenital fibre type disproportion: Patients of CFTD associated with known genetic abnormalities show type 1 fibers that are generally at least 40% to over 80% smaller than type 2 fibers (Figures 5 A & B).

It is important to emphasize that each of these structured and non-structured abnormalities described on biopsy can be seen in various other disorders including muscle degeneration, aging, metabolic changes, muscular dystrophies and even exercise induced changes. Therefore, it is essential that these changes are interpreted in the light of complete clinical examination and genetic results for a definite diagnosis of congenital myopathy.

 Figure 5: Muscle biopsy showing features of Congenital fibre type disproportion. A. Transverse section of muscle biopsy showing atrophic fibers (H&E 40X). B. Atrophic type I fibers seen with ATPase staining (40X).

7.5 Muscle imaging

Magnetic resonance imaging (MRI) of muscles can help to differentiate between different forms of congenital myopathies based on the pattern of selective muscle involvement. Imaging also helps in identifying the exact site from where the muscle biopsy has to be taken and has been used along with muscle biopsy to prioritize gene testing in the pre-NGS era.

7.6 Molecular genetic testing

Molecular genetic testing is now the preferred modality for confirmation of the clinical diagnosis of congenital myopathy and for exact characterization of the subtype, and is being used as the first line confirmatory test in place of muscle biopsy in many centres. Apart from accurate diagnosis for the proband, identification of the exact genetic etiology helps in accurate assessment of the risk of recurrence in other family members, in presymptomatic screening and carrier testing of other at-risk family members and in prenatal genetic testing to prevent recurrence in the family.

Availability of next generation sequencing (NGS) has significantly reduced the cost and time for molecular genetic testing for CMs. NGS has also vastly improved the mutation detection rate and helped in identification of many novel genes and gene variants related to CMs (Gonorazky et al., 2018). NGS-based congenital myopathy-associated multigene sequencing panel or Focused exome sequencing panel can be used as the first-tier test and if no significant variants are found, Whole exome sequencing and/or Whole genome sequencing can be done further. RNA sequencing (RNA-seq) is likely to result in improved diagnostic yield for congenital myopathies in unsolved cases (Ravenscroft et al., 2018).

8 Management

There are no definite curative therapies available at present for any of the congenital myopathies. Multidisciplinary management involving Neurology, Pulmonology, Gastroenterology, Clinical Genetics, Orthopedics and Physiotherapy is required for optimum care of affected individuals (Wang CH, et al). In the less severe cases, as the disorder is nonprogressive, good supportive care and physical therapy to maintain mobility and reduce joint contractures, and aggressive treatment of respiratory problems can help achieve a satisfactory outcome and better life expectancy. Management includes supportive and symptomatic care in the form of:

9 Genetic Counseling

Following accurate diagnosis of the affected individual, appropriate genetic counseling can be provided to the patient and the family about the nature of the disorder, natural course and prognosis, available management options and the surveillance/ monitoring plan. Based on the identified underlying genetic etiology, the exact pattern of inheritance i.e. autosomal dominant, autosomal recessive or X-linked can be clearly ascertained and the risk of recurrence in subsequent pregnancies in the family can be determined. Prenatal diagnosis can be offered for at-risk pregnancies through targeted mutation analysis after identifying the exact pathogenic variant(s) in the affected proband and/ or carrier parents. Variable expressivity (ranging from mild to severe) even amongst affected members of the same family for certain autosomal dominant congenital myopathies such as RYR1 gene-associated central core disease can make counseling, especially about the prognosis and postnatal outcome, difficult.

10 Recent Advances

Certain therapeutic modalities for congenital myopathies are being investigated. Tyrosine has been reported as a beneficial supplement for nemaline myopathy mainly for sialorrhea (Ryan et al., 2008). N-acetylcysteine is being tried as an antioxidant therapy for RYR1-related congenital myopathies (Dowling et al., 2012). Pyridostigmine, an acetylcholinesterase inhibitor, has been reported in some studies to show significant clinical improvement in centronuclear myopathy. A single intravenous dose of AAV8 hMTM1 for X-linked myotubular myopathy is under Phase I/II clinical trials (ASPIRO trial, ClinicalTrials.gov).

11 Conclusion

Congenital myopathies are an important group of genetic neuromuscular disorders. Precise genetic diagnosis has important implications for disease management, monitoring for potential complications, avoidance of anesthetic complications, for genetic counseling and screening of other family members, and for prenatal diagnosis of subsequent pregnancies in the family to prevent recurrence.


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