ALS2 – Juvenile Primary Lateral Sclerosis

Juvenile primary lateral sclerosis (JPLS) is an autosomal recessive upper motor neuron disorder caused by biallelic pathogenic variants in the ALS2 gene. The first homozygous missense variant, c.1619G>A (p.Gly540Glu), was identified in a 34-year-old patient presenting with ascending spasticity, bulbar involvement, dysphagia and limb atrophy; heterozygous parents and two sisters were unaffected (PMID:16670179).

A founder splice-site mutation, c.1640+1G>A, was reported in three unrelated consanguineous families from Iran, affecting 11 individuals with overlapping JPLS and infantile-onset ascending hereditary spastic paralysis phenotypes, confirming autosomal recessive inheritance and intrafamilial concordance (PMID:30128655).

Larger series have identified over 50 pathogenic ALS2 variants—including missense, nonsense, frameshift and splice-site alleles—in more than 40 probands from over 35 unrelated families worldwide. Notable recurrent alleles include the c.1640+1G>A founder and the p.Gly540Glu missense change (PMID:33155358; PMID:34738851).

Functional studies reveal that alsin acts as a Rab5 guanine nucleotide exchange factor, localizing to early endosomes. Truncating and missense ALS2 variants abrogate Rab5 activation and endosomal enlargement, disrupt Alsin–EEA1 colocalization, and induce neuronal apoptosis via altered Bcl-xL/Bax ratios (PMID:12837691; PMID:16670179).

Als2-deficient mice exhibit progressive spinal axonal degeneration, preserved lower motor neurons and age-dependent locomotor slowing, recapitulating human upper motor neuron pathology and supporting a loss-of-function mechanism (PMID:16802286).

Integration of extensive genetic and experimental data supports a Definitive gene-disease relationship between ALS2 and JPLS. Key take-home: ALS2 loss-of-function underlies autosomal recessive JPLS via disrupted endosomal Rab5 signaling; molecular testing is essential for diagnosis and family counseling.

References

• Brain • 2006 • The first ALS2 missense mutation associated with JPLS reveals new aspects of alsin biological function. PMID:16670179
• Neurological sciences • 2018 • Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant. PMID:30128655
• 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
• Human Molecular Genetics • 2003 • ALS2, a novel guanine nucleotide exchange factor for the small GTPase Rab5, is implicated in endosomal dynamics. PMID:12837691
• Annals of Neurology • 2006 • Progressive spinal axonal degeneration and slowness in ALS2-deficient mice. PMID:16802286

Evidence Based Scoring (AI generated)