RESUMO
Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.
Assuntos
Proteínas de Transporte/genética , Atrofia Muscular Espinal/genética , Mutação de Sentido Incorreto , Adulto , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Transporte/metabolismo , Pré-Escolar , Sequência Conservada , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Genes Dominantes , Estudos de Associação Genética , Ligação Genética , Complexo de Golgi/metabolismo , Complexo de Golgi/patologia , Células HeLa , Humanos , Masculino , Proteínas Associadas aos Microtúbulos , Atrofia Muscular Espinal/congênito , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Linhagem , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
BACKGROUND: Negative myoclonus is characterized by a brief sudden loss of muscle activity, and can be caused by a variety of acquired factors and epilepsy syndromes. PHENOMENOLOGY SHOWN: We show a clear video example of a patient with an extensive negative myoclonus that was induced by ciprofloxacin. EDUCATIONAL VALUE: Several neurotoxic effects have been associated with the use of ciprofloxacin, but negative myoclonus has not been reported previously.