Of 6 Japanese individuals from consanguineous marriages who had ALS, Maruyama et al. (2010) identified 3 with mutations in the OPTN gene. Two were sibs. One member of the sib pair developed muscle weakness of her left arm ... Of 6 Japanese individuals from consanguineous marriages who had ALS, Maruyama et al. (2010) identified 3 with mutations in the OPTN gene. Two were sibs. One member of the sib pair developed muscle weakness of her left arm at 33 years of age that progressed to dysphagia requiring endotracheal intubation. She was bedridden by age 34 and died at age 57. Her brother also had onset with left arm weakness at 36 years of age and 1 year later developed dysphagia, dysarthria, and tongue fasciculations. He likewise required endotracheal intubation, was bedridden by age 37, and died at the age of 55. The third patient from a consanguineous family developed dysarthria at 52 years of age and had muscle weakness of her left upper and lower extremities starting at 54 years of age. Her deep tendon reflex was exaggerated, but there was no pathologic reflex. She was still breathing independently at 60 years of age. These 3 individuals were homozygous for mutation in OPTN; 4 other heterozygous individuals identified in a separate analysis had onset in their 50s with slow progression. All individuals with mutations of OPTN showed onset from 30 to 60 years of age. Most of them showed a relatively slow progression and long duration before respiratory failure, although the clinical phenotypes were not homogeneous.
Among 8 Japanese patients with ALS, Maruyama et al. (2010) identified homozygosity for 2 null mutations in the OPTN gene, one a deletion of exon 5 (602432.0005) in 2 sibs and the other a nonsense mutation (Q398X; 602432.0006) ... Among 8 Japanese patients with ALS, Maruyama et al. (2010) identified homozygosity for 2 null mutations in the OPTN gene, one a deletion of exon 5 (602432.0005) in 2 sibs and the other a nonsense mutation (Q398X; 602432.0006) in 2 individuals thought to be unrelated but who shared a haplotype for a 0.9-Mb region containing the OPTN gene. The authors also identified heterozygosity for a missense mutation (E478G; 602432.0007) within the OPTN ubiquitin-binding domain in 4 individuals from 2 families. The pedigree of one of these families suggested that the disorder is an autosomal dominant trait with incomplete penetrance. Although these 2 families were not known to be related, all affected individuals shared their haplotype for 2.3 Mb on chromosome 10 around the OPTN gene. Neither the Q398X nor the E478G mutations were observed in 781 healthy Japanese volunteers or in over 6,800 (including 1,728 Japanese) individuals in glaucoma studies, in which the entire coding region of the gene was investigated. Collectively, the mutation was absent over a total of 5,000 Japanese chromosomes. The deletion mutation was also absent in 200 Japanese, and not reported in the over 6,800 glaucoma individuals.