CMD is a genetically heterogeneous umbrella encompassing dozens of distinct monogenic disorders, each caused by mutations in a different gene affecting a specific molecular pathway; no single gene or mechanism accounts for all cases. Known subtypes represented within the CMD spectrum include LAMA2-related CMD (congenital merosin-deficient muscular dystrophy 1A), CMD due to LMNA mutation, CMD due to integrin alpha-7 deficiency, collagen 6-related congenital muscular dystrophy (encompassing Ullrich CMD and Bethlem myopathy), the muscular dystrophy-dystroglycanopathy group (a family of disorders involving glycosylation of the dystroglycan protein), muscle-eye-brain disease, rigid spine syndrome, arthrogryposis due to muscular dystrophy, megaconial type CMD, and congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, among others. The implicated molecular pathways span extracellular matrix assembly, nuclear envelope integrity, protein glycosylation, and sarcomere organization, reflecting the breadth of cellular processes involved in muscle fiber maintenance. The inheritance pattern for the large majority of CMD subtypes is autosomal recessive, meaning two altered copies of the causative gene—one from each parent—are required for the condition to manifest. Because CMD is genetically heterogeneous, comprehensive genetic investigation is necessary to identify the specific subtype and its molecular basis in a given individual.

The diagnosis of CMD is established through the clinical recognition of early-onset muscle weakness and hypotonia, supported by laboratory, pathological, and genetic findings. Serum creatine kinase is elevated in many but not all subtypes; a normal level does not exclude the diagnosis. Muscle biopsy demonstrates dystrophic changes—such as fiber size variation, fibrosis, and necrosis—and immunostaining for specific structural proteins can suggest the affected pathway in certain forms. Brain imaging may be informative in subtypes with central nervous system involvement, such as muscle-eye-brain disease, where structural brain abnormalities may be present. Electrodiagnostic studies help distinguish CMD from conditions affecting the motor neuron or neuromuscular junction. Genetic panel testing or whole-exome sequencing provides definitive subtype identification in most cases. Because CMD encompasses a family of genetically distinct disorders, diagnosis proceeds through the integration of clinical, pathological, and molecular findings. No universal published diagnostic criteria exist for the umbrella CMD diagnosis; characterization proceeds through subtype-specific assessment.

No FDA-approved treatments exist specifically for congenital muscular dystrophy. Care follows the Standard of Care Guidelines for CMD and involves multidisciplinary supportive management aimed at optimizing function and minimizing complications across all organ systems affected. Supportive management draws on pediatric neurology, orthopedics, physical and occupational therapy, respiratory medicine, speech-language pathology, developmental pediatrics, cardiology, audiology, and clinical genetics, with the disciplines involved depending on the specific subtype and its clinical manifestations. Respiratory management is a central component in subtypes with progressive respiratory muscle weakness. Orthopedic care addresses contractures and scoliosis. Nutritional support and feeding assessment are relevant in individuals with significant hypotonia affecting swallowing. Three agents have received orphan drug designation for CMD and remain under active investigation: omigapil, an AAV-based gene therapy targeting the fukutin related protein (ssAAVMYO2.tMCK.FKRP) intended for FKRP-related subtypes, and insulin-like growth factor-1 (IGF-1). None of these designated agents has received FDA marketing approval for CMD.

Congenital muscular dystrophy is characterized by progressive muscle weakness and degeneration. The long-term clinical trajectory depends substantially on the specific genetic subtype and the organ systems involved. Some subtypes are associated with significant involvement of systems beyond skeletal muscle, including the central nervous system, eyes, and respiratory system—as reflected in subtype designations such as muscle-eye-brain disease and congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome—while others follow a more restricted course primarily confined to skeletal muscle. The pace of disease progression, functional decline, and development of respiratory or cardiac complications varies by subtype. Specific natural history data for the umbrella CMD diagnosis are not included in this packet; prognosis at the individual level is informed by genetic subtype identification and the evolving understanding of each subtype's natural history.

Active clinical research is under way across CMD subtypes. A natural history observational study in children aged 0 to 5 years with LAMA2-related CMD (NCT06503367) is currently recruiting at Nationwide Children's Hospital, with planned completion in 2028. This study aims to characterize the early natural history of one of the most common CMD subtypes. A study examining modifying factors in striated muscle laminopathies (NCT05394506) is recruiting in France through 2027, addressing LMNA-related and related laminopathy forms of CMD. The Swiss Registry for Neuromuscular Disorders (NCT05102916) is enrolling patients with CMD and related neuromuscular conditions in a long-term observational registry extending through 2071, providing a longitudinal data resource for natural history and outcomes research.