RESUMO
OBJECTIVE: Immunocharacterization of congenital muscular dystrophy (CMD) to determine the frequency of various subtypes in a large Indian Cohort. MATERIALS AND METHODS: This retrospective (2014-2017) study was carried on muscle biopsies of clinically suspected cases of CMD with histological evidence of dystrophy/myopathic features. Immunohistochemistry (IHC) to antibodies against laminin (α2, α5,ß1,γ1), Collagen-VI (A1,2,3), and Western blot (WB) for α-dystroglycan and POMT1 was performed. RESULTS: The study included 57 cases, of which 15 cases (26.3%) had mean age at presentation of 3.5 years, M: F = 1.5:1, elevated creatinine kinase (CK) (mean 1657 U/L), global developmental delay, multiple contractures, abnormal facies, white matter hyperintensities and showed laminin-α2 deficiency (Merosin deficient CMD). In addition, secondary reduction in laminin-ß1, over-expression of laminin-α5, and preserved laminin-γ1 was noted. Ullrich CMD constituted 11/57 cases (19.2%) with mean age at presentation of 5.3 years, M: F = 1.2:1 and normal CK. They presented with proximal muscle weakness, soft velvety palms and soles, contractures, and joint hyperextensibility. Collagen-VI (A1,2,3) showed either complete (n = 3) or sarcolemmal specific (n = 8) loss of staining. Out of the remaining 31 cases, WB for α-dystroglycan was performed in 17 cases which showed deficiency in seven (12.3%). Three of these in addition revealed secondary partial loss of laminin-α2. WB for POMT1 showed deficiency in a single case clinically diagnosed Walker-Warburg syndrome, who presented with seizures and classical features of pachygyria, lissencephaly, and cerebellar cyst on MRI. Twenty-four cases (42.2%) remained uncharacterized and need genetic evaluation. CONCLUSION: The study helped in characterizing 57.8% of the proband. Immunotyping helps to direct mutational analysis for targeted genes and offers a potential route for prenatal diagnosis.
RESUMO
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.