Submission Details

ALS2 was first reported in relation to motor neuron disease in 2001 (Hadano S, et al., 2001, PMID: 11586298). From GeneReviews, Pathogenic variants in ALS2 are responsible for a retrograde degeneration of the upper motor neurons of the pyramidal tracts, leading to phenotypes on a clinical continuum ranging from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile forms without lower motor neuron involvement (juvenile primary lateral sclerosis [JPLS]) or with lower motor neuron involvement (juvenile amyotrophic lateral sclerosis [JALS]), and as such have been lumped into a single disease entity for curation. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Thirteen variants have been curated in relation to motor neuron disease (including frameshift, nonsense, and splice variants as well as some missense), found in 12 probands in 5 publications (PMIDs: 11586298, 16240357, 23282280, 24562058, 33155358). Cosegregation of variants with disease was reported in at least 18 family members as well. Additional evidence is available in the literature but the maximum score for genetic evidence was reached. Experimentally, this gene-disease relationship is supported by its biochemical function; ALS2 encodes Alsin, which regulates actin-based neurite outgrowth (PMID: 16049005) as a prominent guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 (PMID: 12837691). The pathomechanism of ALS2 mutations is considered to be loss of function, and likely involves unlinking or disturbing the connections between ALS2 and Rab5, which reduces actin-based intracellular trafficking and glutamate signaling at synapses (Lai et al., 2009). The presence of both Rac1 and Rab5 GEF activities makes Alsin a unique dual exchange factor that may couple endocytosis (via Rab5 activation) to cytoskeletal modulation (via Rac1 activation). Several different lines of ALS2 knockout (ALS2–/–) mice have been generated by independent groups (PMIDs: 16107644, 16321985, 16769894, 16802286, 16675207, 17855450). The loss of alsin does not have a drastic effect on the survival or function of motor neurons in mice. However, subtle deficits observed in the behavior and pathology of these mice have aided in the understanding of the relationship between alsin and motor neuron dysfunction. In summary, there is definitive evidence to support the gene-disease relationship of autosomal recessive ALS2 related motor neuron disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.