Abstract
Mutations of the lipid phosphatase FIG4 that regulates PI(3,5)P(2) are responsible for the recessive peripheral-nerve disorder CMT4J. We now describe nonsynonymous variants of FIG4 in 2% (9/473) of patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Heterozygosity for a deleterious allele of FIG4 appears to be a risk factor for ALS and PLS, extending the list of known ALS genes and increasing the clinical spectrum of FIG4-related diseases.
Highlights
SALS cases included individuals from National Institute of Neurological Disorders and Stroke panels NDPT025, NDPT026, and NDPT029, as well as 92 SALS patients from the Massachusetts General Hospital who had onset at 53 5 15 years, a disease duration of 4.8 5 4 years, and a male to female ratio of 2:1
The site of disease onset was 23% bulbar, 43% upper extremities, 28% lower extremities, and 7% multiple sites, The familial history (FALS) patients had onset at 55 5 15 years and disease duration of 3.4 5 3.2 years, with a male to female ratio of 1:1.3
The FALS patients were previously tested for mutations in SOD1; their site of disease onset was 27% bulbar, 31% upper extremities, 37% lower extremities, and 5% multiple sites
Summary
One family exhibited adult onset and primarily motor symptoms that resembled amyotrophic lateral sclerosis (ALS) (MIM 105400), except for reduced nerve-conduction velocity and segmental demyelination indicative of Schwann cell involvement.[5] Because mutation of FIG4 affects motorneuron function in humans and mice, we tested FIG4 as a candidate gene for ALS. To screen for pathogenic mutations in the coding sequence and splice sites, we amplified the 23 exons of FIG4 from 473 patient genomic-DNA samples.
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