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Abstract: Cap myopathy is a congenital myopathy with cap-like structures under the sarcolemma. Mutations in TPM2 and TPM3 genes have been reported in cap myopathy so far. We report a newborn boy with persistent profound weakness who required gastro-jejunal tube feeding, tracheostomy and life-long ventilation until he died at 5years of age. Muscle biopsy at 5weeks of age was uninformative. Repeat biopsy at 4.5years revealed subsarcolemmally located caps that were immunopositive for alpha-actinin, actin and to some extent, desmin. EM confirmed loosely arranged thin filaments and paucity of thick filaments. Molecular analysis of ACTA1 gene identified a novel de novo Met47Val mutation. In addition to a new ACTA1 gene mutation, our case emphasizes the genetic heterogeneity of cap myopathy and its association with ACTA1 gene as well as the importance of repeat muscle biopsy in patients with undiagnosed muscle weakness. [Copyright &y& Elsevier]

Abstract: We describe an 11-year-old boy with dystrophinopathy who presented with a history of progressive proximal muscle weakness and elevated serum creatine kinase levels at age 6. Sequence analysis of the dystrophin (DMD) gene did not identify a mutation in the coding regions but revealed a nucleotide substitution in intron 26 (c.3603+3A>T). Since computer algorithms did not conclusively indicate that this sequence variant inactivated the splice site, we analyzed the DMD mRNA from a muscle biopsy of the patient to determine its functional significance. PCR and sequence analysis of the cDNA demonstrated that the mutation reduced the efficiency of the donor splice site and caused activation of a cryptic donor site 113bp downstream. Activation of the cryptic donor site led to inclusion of 116bp of intronic sequence containing a stop codon producing a truncated dystrophin protein. Residual wild-type splicing was also detected, which would explain the milder Becker rather than Duchenne phenotype in this patient. We highlight the importance of mRNA analysis for determination of pathogenicity in patients with ambiguous sequence variants in the DMD gene. [Copyright &y& Elsevier]

Abstract: We report a new fibroblast and lymphoblast based protein O-mannosyl β-1,2-N-acetylglucosaminyltransferase 1 enzymatic assay, which allows rapid and accurate diagnosis of carriers and patients with muscle–eye–brain type of congenital muscular dystrophy. Seven patients with genetically confirmed muscle–eye–brain disease were assayed for protein O-mannosyl β-1,2-N-acetylglucosaminyltransferase 1 enzyme activity. In three patients and their heterozygous parents, the assays were done on EBV-transformed lymphoblasts, in another three patients they were done on cultured fibroblasts and in the last patient on both fibroblasts and lymphoblasts. Cultured fibroblasts and lymphoblasts from the muscle–eye–brain patients showed a highly significant decrease in protein O-mannosyl β-1,2-N-acetylglucosaminyltransferase 1 activity relative to controls. The residual protein O-mannosyl β-1,2-N-acetylglucosaminyltransferase 1 level in fibroblasts (average 0.11nmoles/h per mg) was about 13% of normal controls. The ratio of protein O-mannosyl β-1,2-N-acetylglucosaminyltransferase 1 activity to the activity of a glycosyltransferase control (N-acetylglucosaminyltransferase 1; GnT1) in fibroblasts was on average 0.006 in muscle–eye–brain patients and 0.045 in controls. The average residual protein O-mannosyl β-1,2-N-acetylglucosaminyltransferase 1 level in lymphoblasts was 15% of normal controls. The average ratio of protein O-mannosyl β-1,2-N-acetylglucosaminyltransferase 1/GnT1 activity was 0.007 in muscle–eye–brain patients, 0.026 in heterozygous carriers and 0.046 in normal controls. Assay of protein O-mannosyl β-1,2-N-acetylglucosaminyltransferase 1 activity in fibroblasts and lymphoblasts from muscle–eye–brain carriers and patients provides a rapid and relatively simple diagnostic test for this disease and could be used as a screening test in carriers and patients with complex congenital muscular dystrophy. [Copyright &y& Elsevier]