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    Drugs & Diseases>Neurology

    Congenital Myopathies

    Updated: Oct 18, 2024
    • Author: Matthew Harmelink, MD; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA  more...
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    Overview

    Background

    Congenital myopathies are a set of genetic diseases that predominantly affect the muscles. The first report of a congenital myopathy was of a patient with central core disease (CCD) in 1956. Since then, the classification of congenital myopathy has been evolving from a primary pathologic diagnosis to one with a genetic basis. There are more than 40 types of congenital myopathy with more than 30 identified causative genes. [1]

    The typical features of congenital myopathy include early-onset muscle weakness, often associated with features of low muscle bulk and tone. While these features are typically found in neonates and infants, children or even adults can present with milder forms of congenital myopathy. In certain cases, patients can have normal strength and tone but be at risk of rhabdomyolysis and/or malignant hyperthermia. Due to the early weakness, dysmorphic features such as contractures, a high arched palate, and facial dysmorphisms can be seen.

    The classification of congenital myopathies has evolved to no longer be a pure pathologic diagnosis but rather relying more on genetic data. However, the genotype-to-phenotype correlation is variable on the gene level and more accurate when described by a specific mutation. Given this, the taxonomy of congenital myopathies can be somewhat confusing. Diagnosis should be a combination of genetic, phenotypic, and, if needed to confirm, pathologic, electrodiagnostic, and serum features.

    The skeletal muscle involvement can also result in secondary breathing and swallowing difficulties. However, non-skeletal muscle features can manifest based upon the specific disease. 

    Additionally confounding is that, more recently, genes known to cause congenital myopathy have now also been described to cause a dystrophic process such as seen in congenital muscular dystrophies. However, the traditional pathologic subdivision of congenital myopathy does give some guidance in regards to genotype and prognostication and cannot be disregarded. As such, the congenital myopathies can be divided into six pathologic categories. [2, 3]

    • nemaline myopathy (subtypes: rod, core-rod, cap and zebra body myopathy);
    • core myopathy (subtypes: central core and multiminicore myopathy);
    • centronuclear myopathy (subtypes: myotubular myopathy and autosomal centronuclear myopathy);
    • congenital fiber-type disproportion myopathy;
    • myosin storage myopathy; and
    • nonspecific myopathic changes
    Next: Pathophysiology

    Pathophysiology

    The gene affected in each type of congenital myopathy predicts the presentation of disease features. However, amongst each gene there are variations in presentation based upon the specific change. Occasionally, these result in phenotypic overlap between genes as well as genes causing congenital myopathy to occasionally have phenotypes more consistent with congenital muscular dystrophies, limb-girdle muscular dystrophies, or even possible neuropathic or neuromuscular junction diseases. 

    Additionally, each gene may have other tissue expression, which can result in nonmuscle symptoms.

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    Next: Pathophysiology

    Epidemiology

    Frequency

    The true incidence of congenital myopathies is unknown, as no large population-based studies have been conducted. However, there are a varied number of stuidies that demonstrate a relative incidence of the diseases. Of hypotonic infants due to neurologic causes, approximately 60%–80% were from a central cause and 12%–34% were from a peripheral cause. [4, 5]  In the children with a peripheral cause of hypotonia, less than 50% of the cases were due to congenital myopathy. [4, 5]

    The frequency of symptom onset was in the neonatal period in 76% of cases in one cohort study. [6]

    Sex

    Any sex bias is dictated by the underlying genetic mutation. Given most diseases are autosomal, the most common form of variance is in the form of CNM1, which causes x-linked myotubular myopathy.

    Age

    The classic age of presentation is in the neonatal period, but milder forms can present at any age. 

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    Next: Pathophysiology

    Prognosis

    The prognosis for congenital myopathies varies broadly. In the most severe cases newborns and infants may die, while milder mutations result only in mild weakness and some effects on activities of daily living (ADLs).

    Given the wide spectrum of disease, the largest cause of morbidity and mortality is related to muscle function loss resulting in respiratory and/or feeding failure.

    According to a study by Colombo et al, at birth, neonates with congenital myopathy required respiratory support and nasogastric feeding in 30.4% and 25.2% of cases, respectively. Of note, in the study cohort, 12% of patients died within the first year, whereas 74.1% achieved independent ambulation with 62.9% being late walkers. [6]

    Phenotype can vary greatly even in a single gene or pathologic classification. As such, consideration for the specific etiology is needed. Additionally, many infants/neonates with congenital myopathy can make improvements in the first few years of life. This makes early decisions regarding long-term goals of care, such as use of supportive care, difficult.  

    However, after this initial gain, a small group can decline. The Colombo et al. cohort demonstrated this in the 9% of patients who were ambulatory but lost the ability. [6]  While this can be from the primary pathologic process, this may also be related to a relative weakness in the context of a growing child with disproportionate needs for strength as compared to what their muscles can produce and may not be objective worsening weakness.

    Other morbidities include extra-muscular features or risks. Most noticeably is the risk for malignant hyperthermia. While this is best described in a subset of patients with RYR1 mutations, there are other myopathic and dystrophic genes that can also be causative. There are also nonmyopathic phenotypes of these genes that can have nonweak presentations.

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    Next: Pathophysiology

    Patient Education

    Genetic counseling is often helpful to assist patients with family-planning decisions. However, definitive prenatal diagnosis is only possible if a disease-causing mutation has been identified. Genetic counseling is especially important for families of patients with central core disease to avoid unexpected cases of malignant hyperthermia in asymptomatic relatives.

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