Autosomal Recessive Juvenile Amyotrophic Lateral Sclerosis: Molecular Pathogenesis of ALS2 and ALS5*
Introduction: While adult-onset dominant cases predominate in Western registries, autosomal recessive forms of familial ALS typically manifest during childhood or adolescence as juvenile-onset motor neuron diseases. Mapping these rare kindreds has highlighted crucial regulators of endosomal trafficking and axonal maintenance.
Molecular and Clinical Features of Recessive ALS:
ALS2 (Alsin / 2q33): Encodes alsin, a protein featuring three guanine-nucleotide exchange factor domains. Alternative splicing yields a short form (juvenile ALS) and a long form (juvenile primary lateral sclerosis). Onset occurs in early childhood (mean 6.5 years), characterized by severe spasticity, dysarthria, and retrograde degeneration of upper motor neurons.
ALS5 (15q15.1-q21.1): Juvenile-onset typical ALS presenting between ages 8 and 18, featuring both upper and lower motor neuron signs, tongue fasciculations, and slow progression.