ALS2 – juvenile amyotrophic lateral sclerosis

Biallelic variants in ALS2 underlie autosomal recessive juvenile amyotrophic lateral sclerosis (MONDO:0017593). Patients typically present in infancy or early childhood with progressive upper motor neuron degeneration leading to spasticity, dysphagia, and muscle weakness.

In a cohort of seven unrelated families (11 patients) with early‐onset motor neuron disease—clinically classified as infantile ascending hereditary spastic paralysis or juvenile primary lateral sclerosis—next‐generation sequencing identified five novel homozygous ALS2 variants including c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (PMID:33155358). A larger Brazilian case series reviewed 35 non-related families harboring mostly loss‐of‐function variants dispersed across ALS2, confirming allelic heterogeneity and interfamilial phenotypic diversity (PMID:34738851). Overall, over 23 distinct pathogenic ALS2 variants have been reported in ≥50 probands with juvenile amyotrophic lateral sclerosis or overlapping phenotypes.

The variant spectrum includes nonsense (e.g., c.1044C>G (p.Tyr348Ter)), frameshift (e.g., c.275_276delAT (p.Tyr92CysfsTer11)), splice-site (c.1471+1G>A), and missense changes (e.g., c.470G>A (p.Cys157Tyr)) within the RCC1-like, DH/PH, and VPS9 domains (PMID:16718699). Recurrent founder alleles such as c.1640+1G>A have been described in consanguineous pedigrees, with multi‐family segregation supporting pathogenicity (PMID:30128655).

Functional assays demonstrate that disease‐causing mutants destabilize ALS2 protein, abolishing its Rab5 guanine nucleotide exchange factor activity and perturbing endosomal dynamics in neuronal and non‐neuronal cells (PMID:14668431; PMID:12837691). Alsin-deficient mice exhibit progressive spinal axonal degeneration and upper motor neuron dysfunction recapitulating key clinical features (PMID:16802286).

One study reported that ALS2 loss did not modify the SOD1(G93A) ALS phenotype, indicating gene-specific pathogenic pathways (PMID:16973244). No robust conflicting evidence disputes the ALS2–JALS link.

Integration of genetic and experimental data supports a mechanism of loss of function via protein instability, GEF inactivation, and disrupted endosomal trafficking. The breadth of pathogenic alleles, consistent AR inheritance, segregation in multiple consanguineous families, and concordant functional models satisfy ClinGen criteria for a Strong gene–disease relationship.

Key Take-home: ALS2 genetic testing enables diagnosis of autosomal recessive juvenile ALS, informing prognosis and carrier screening.

References

• American Journal of Medical Genetics Part A • 2021 • Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations PMID:33155358
• Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration • 2022 • The expanding clinical and genetic spectrum of alsin-related disorders: the first cohort of Brazilian patients PMID:34738851
• Annals of Neurology • 2006 • Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis PMID:16718699
• Proceedings of the National Academy of Sciences USA • 2003 • Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease PMID:14668431
• Annals of Neurology • 2006 • Progressive spinal axonal degeneration and slowness in ALS2-deficient mice PMID:16802286
• Neurobiology of Aging • 2007 • Deficiency in the ALS2 gene does not affect the motor neuron degeneration in SOD1(G93A) transgenic mice PMID:16973244

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