Megaconial congenital muscular dystrophy (MCMD) is a rare autosomal recessive myopathy caused by biallelic pathogenic variants in the CHKB gene. It is characterized by early-onset hypotonia, motor delay, and proximal muscle weakness, frequently overlapping with neurodevelopmental syndromes. Identification relies on the demonstration of enlarged, structurally abnormal mitochondria on muscle biopsy in correlation with molecular findings.

A 3-year-old female with global developmental delay with predominant motor involvement and delayed ambulation underwent clinical, biochemical, radiological, histopathological, and molecular evaluation. Serum creatine phosphokinase, MRI brain, echocardiography, and next-generation sequencing were performed, followed by parental segregation analysis and confirmatory muscle biopsy with ultrastructural assessment.

 A detailed neurological examination revealed axial hypertonia, appendicular hypotonia, mild proximal weakness, and normal deep tendon reflexes without facial dysmorphism or seizures. Serum CPK was elevated; although MRI brain and cardiac studies were normal. Genetic analysis identified a novel homozygous CHKB variant (ENST00000406938.3, c.1060G>C; p.Gly354Arg) classified as a variant of uncertain significance, with both parents heterozygous carriers. Muscle biopsy showed endomysial and perimysial fibrosis, central nuclei, and abnormal fibers on NADH-TR staining. Electron microscopy demonstrated markedly enlarged mitochondria with irregular cristae, confirming megaconial change. Supportive physiotherapy and early developmental interventions yielded modest motor improvement over six months.

CHKB-associated MCMD is extremely rare condition with a classic recognizable electron microscopic finding representing a diagnostically challenging mitochondrial myopathy that may clinically mimic developmental delay syndromes. Integration of histopathological and molecular findings is critical for accurate diagnosis, genetic counseling, and early institution of supportive care.