G.P.56 Novel homozygous stop mutation in alphaB crystallin: Expanding the phenotype

Abstract

Mutations in the CRYAB gene, encoding alpha-B crystalline cause different phenotypes including myofibrillar myopathy, cardiomyopathy, isolated cataract and a multisystemic disorder. Even if genotype–phenotype association is still unclear, previously reported autosomal recessive mutations in the alphaB crystallin (CRYAB) has been associated with a fatal hypertonic infantile muscular dystrophy, in association with two different CRYAB stop mutations, p.S21AfsX24, p.S115PfsX14. Here we present two children from a non-consanguineous family, originally from Ghana, who were homozygous for a third CRYAB stop mutation, c.404C>A, p.Ser135X. The proband presented with respiratory distress one week after routine two month-old vaccinations and rapidly progressed into respiratory failure due to extreme general muscle rigidity. Serum CK was 772U/L. EMG unremarkable and GLRA1 testing for stiffbaby syndrome was negative. Myofibrillary myopathy was suspected and targeted gene sequence analysis of CRYAB returned positive. The parents elected to withdrawal support and a muscle biopsy was performed. An older sister had a similar presentation after routine two month-old vaccinations to a local hospital and died at 18months of age without a diagnosis. Myopathic features observed in the muscle biopsy using routine histochemistry and enzyme histochemistry were mild and nonspecific. However, small inclusion bodies were detected using antibodies against alphaB crystallin and myotilin. A second alphaB crystallin antibody (C-terminus epitope) failed to detect the inclusion bodies. This new case of recessive MFM expands the phenotype showing a fatal form of the disease with milder myopathic features on muscle biopsy than the two previously reported autosomal recessive fatal cases.