P.15.11 Megaconial congenital muscular dystrophy in two children with mutations in the CHKB Gene

Abstract

Congenital Muscular Dystrophy (CMD) is a clinically and genetically heterogenous group of muscle disorders. Mutations in the gene encoding the beta subunit of choline kinase (CHKB) are associated with a recently described form of CMD characterised by the presence of large and abnormal mitochondria in muscle fibres. Choline kinase is a key enzyme in the synthesis of phosphatidyl choline and phosphatidylethanolamine, two phospholipids that are essential components of biological membranes. We present two children, 9 and 5 years old, with congenital hypotonia, joint hyperlaxity,proximal weakness and cognitive impairment without microcephaly or brain structural changes. Autonomous ambulation started at 2 and 3 years respectively Both patients showed mildly elevated creatine kinase levels (250–400 UI/L). Muscle pathology of both patients was similar showing dystrophic changes, oxidative enzymes staining defects and very large mitochondria distributed at the periphery of the fibre. Electron microscopy performed in one patient confirmed the presence of large mitochondrial with structurally abnormal cristae and inclusions. One patient was homozygous for a frameshift mutation (p.Gln198fs, exon 5) whereas the other patient was heterozygous for a mutation in intron 3 (c.447 + 2t > c) and a missense mutation in exon 9 (p.Arg344Gln). These mutations have not been reported before. This form of CMD must be taken into account in the differential diagnosis of children presenting in the first year of life with muscle weakness, elevated creatine kinase levels and mental retardation and with a characteristic muscle biopsy which shows dystrophic changes in combination with mitochondrial abnormalities.