ALS2 – Infantile-onset Ascending Hereditary Spastic Paralysis

Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare, early-onset autosomal recessive motor neuron disease caused by biallelic pathogenic variants in ALS2. Affected individuals develop spastic paraparesis in the first two years of life, with rapid ascending involvement of upper limbs, bulbar muscles, and severe scoliosis leading to tetraplegia and dysarthria.

Genetic evidence derives from multiple cohorts: 16 patients from 11 families (PMID:12601111), 11 affected individuals from three Iranian families with a founder splice-site variant c.1640+1G>A (PMID:30128655), two Chinese siblings homozygous for c.1815G>T (p.Lys605Asn) (PMID:38297306), and 46 patients from 23 Egyptian families with 16 distinct ALS2 variants (PMID:37055917), plus a singleton case with c.3836+1G>T (PMID:24144828). Segregation of variants was demonstrated in 11 individuals in the Iranian pedigrees (PMID:30128655) and in two siblings (PMID:38297306).

The variant spectrum includes canonical splice-site (c.3836+1G>T), missense (c.1815G>T (p.Lys605Asn); c.485C>T (p.Thr162Ile); c.470G>A (p.Cys157Tyr)), nonsense, and frameshift alleles spanning the RCC1-like, DH/PH, and VPS9 domains of the 184-kDa alsin protein. The recurrent c.1640+1G>A splice variant in consanguineous Middle Eastern families suggests a founder effect.

Functional studies show that pathogenic ALS2 variants lead to loss of Rab5 GEF activity, endosomal trafficking defects, and decreased protein stability. Disease-causing mutants and truncated isoforms are rapidly degraded in patient cells, and in vitro assays reveal impaired oligomerization and endosomal localization (PMID:14668431; PMID:12837691).

Als2-null mice display progressive upper motor neuron degeneration, lateral spinal axonal loss, and spastic motor deficits without lower motor neuron involvement, recapitulating human IAHSP pathology (PMID:16802286).

Although ALS2 mutations account for IAHSP in many families, the syndrome is genetically heterogeneous; some IAHSP cases lack ALS2 variants, indicating additional loci (PMID:12601111). Nonetheless, concordant clinical, genetic, and experimental data support a definitive gene-disease relationship.

Key Take-home: Biallelic loss-of-function variants in ALS2 cause autosomal recessive IAHSP, providing a strong molecular diagnostic target and guiding genetic counseling and preventative screening.

References

• European journal of paediatric neurology • 2014 • Infantile-onset ascending hereditary spastic paralysis: a case report and brief literature review. PMID:24144828
• Neurology • 2003 • Infantile ascending hereditary spastic paralysis (IAHSP): clinical features in 11 families. PMID:12601111
• Neurological sciences • 2018 • Clinical presentation and natural history of infantile-onset ascending spastic paralysis from three families with an ALS2 founder variant. PMID:30128655
• BMC medical genomics • 2024 • Clinical features and molecular genetic investigation of infantile-onset ascending hereditary spastic paralysis (IAHSP) in two Chinese siblings caused by a novel splice site ALS2 variation. PMID:38297306
• Clinical genetics • 2023 • Clinical and molecular spectrum of a large Egyptian cohort with ALS2-related disorders of infantile-onset of clinical continuum IAHSP/JPLS. PMID:37055917
• Proceedings of the National Academy of Sciences of the United States of America • 2003 • Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease. PMID:14668431
• 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)