Genetics of ALS

Several gene/loci associated with ALS have been identified (Table I).

1. SOD1 Gene

Approximately 5-10% of ALS cases are familial, and in almost all cases inheritance exhibits an autosomal-dominant pattern. Approximately 15-20% ofpatients with autosomal-dominant FALS have missense point mutations in the gene that encodes cytosolic Cu/Zn SOD1 (Table I), the enzyme that catalyzes the conversion of • O2 to O2 and H2O2. To date, > 70 different mutations have been identified in the SOD1 gene. There is clear evidence of allelic heterogeneity, with phenotypes associated with different mutations sometimes showing differences; for example, cases of A4V SOD1 FALS have limited involvement of the corticospinal tract, whereas other SOD1 mutations are associated with a more classic ALS syndrome.

2. Other Genes/Loci Relevant to ALS

A variety of chromosomal loci have been linked to autosomal-dominant, autosomal-recessive, and X-linked-dominant forms of ALS. Notably, investigators have described a large family with autosomal-dominant juvenile ALS (JALS) linked to a locus at the 9q34 region. Manifested by the presence of slowly progressive distal atrophy, weakness, and corticospinal signs, these cases show a marked loss of spinal motor neurons and less pronounced degeneration of the corticospinal tracts. The peripheral nerves and dorsal and ventral roots show prominent axonal and

Table I

Genes and Chromosomal Loci Associated with Different Classes of Motor Neuron Disease

Table I

Genes and Chromosomal Loci Associated with Different Classes of Motor Neuron Disease

Motor neuron disease

Genes/chromosomal loci

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