Nishimura et al. (2004) described a Caucasian Brazilian family in which 26 members spanning 3 generations presented with clinical and neurologic signs compatible with the diagnosis of ALS with slow progression. The disorder affected both sexes equally, with ... Nishimura et al. (2004) described a Caucasian Brazilian family in which 26 members spanning 3 generations presented with clinical and neurologic signs compatible with the diagnosis of ALS with slow progression. The disorder affected both sexes equally, with no evidence of clinical anticipation. Clinical onset occurred between ages 31 and 45 years, and the cause of death was respiratory failure. Twelve family members were examined. All patients had lower motor neuron symptoms, and 5 also had bulbar involvement. Chen et al. (2010) reported a 73-year-old man with ALS8, who was not of Brazilian descent. He presented with wasting of the small muscles of the hands. He also had fasciculations of the leg, and later developed speech and swallowing difficulties. The diagnosis was confirmed by nerve conduction studies. The patient had a brother with ALS who died within 4 months of diagnosis from pneumonia, but DNA was not available for testing.
Nishimura et al. (2004) found that the autosomal dominant slowly progressive disorder in the large Brazilian family described by Nishimura et al. (2004), characterized by fasciculations, cramps, and postural tremor, was caused by a P56S mutation in the ... Nishimura et al. (2004) found that the autosomal dominant slowly progressive disorder in the large Brazilian family described by Nishimura et al. (2004), characterized by fasciculations, cramps, and postural tremor, was caused by a P56S mutation in the VAPB gene (605704.0001). Subsequently, the same mutation was identified in patients from 6 additional kindreds in which, however, patients demonstrated different clinical courses, such as ALS8, late-onset spinal muscular atrophy (182980), and typical severe ALS with rapid progression. Although it was not possible to link all these families genealogically, haplotype analysis suggested founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have a function in membrane transport. The data suggested that clinically variable motor neuron diseases may be caused by a dysfunction in intracellular membrane trafficking. Landers et al. (2008) identified the P56S mutation in affected members of a Brazilian family with ALS. The mean age at onset was between 45 and 55 years with survival varying from 5 to 18 years. Mutations in the VAPB gene were not identified in 79 other ALS families. Landers et al. (2008) concluded that VAPB mutations are not a common cause of ALS. Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162 French probands with familial ALS. The patient was of Japanese descent, representing the first non-Brazilian reported to carry this mutation. Three other family members had motor neuron disease, suggesting autosomal dominant inheritance. The patient had long disease duration with onset in the legs during the sixth decade. Millecamps et al. (2010) suggested that the finding of the P56S mutation in a Japanese patient may reflect the Portuguese trading connection with the Far East and Brazil in the mid-16th century. In 1 of 107 non-Brazilian probands with ALS, Chen et al. (2010) identified a heterozygous mutation in the VAPB gene (T46I; 605704.0002). In vitro functional expression studies in COS-7 and neuronal cells showed that the T46I mutation formed intracellular protein aggregates and ubiquitin aggregates, ultimately resulting in cell death. Chen et al. (2010) also postulated that disturbances in lipid metabolism may play a role in the pathogenesis of ALS.