Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5 ' splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

Automated summary

This study provides a detailed description of Megaconial congenital muscular dystrophy (CMD) in five children from Indian families, including clinical, histopathological, imaging, and genetic findings. The children exhibited moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay, with some cases resembling atypical Rett syndrome. Genetically, three novel null mutations in CHKB and one reported missense mutation were identified, all in the homozygous state. Megaconial CMD, though rare, accounts for 5.5% of genetically confirmed CMD patients and presents a complex phenotypic presentation. The atypical Rett syndrome-like presentation may serve as a clue towards a CHKB-related disorder.