ALS2 – Juvenile Amyotrophic Lateral Sclerosis Type 2

ALS2 encodes the 184 kDa protein alsin, containing multiple guanine nucleotide exchange factor (GEF) domains, and is located on chromosome 2q33. Juvenile amyotrophic lateral sclerosis type 2 (ALS2; MONDO:0008780) is a rare autosomal recessive motor neuron disease characterized by early-onset upper motor neuron degeneration and spasticity (Gene Symbol; Disease Name). The association between biallelic ALS2 variants and juvenile ALS2 was first established by mapping recessive familial cases to chromosome 2q33, identifying frameshift and nonsense mutations predicted to abolish protein function (PMID:11586298). Subsequent reports have expanded the variant spectrum to include missense substitutions and splice-site changes across diverse populations.

Genetic studies in two consanguineous Pakistani families described 11 affected individuals with infantile ascending hereditary spastic paraplegia, a phenotype overlapping juvenile ALS2. Targeted sequencing revealed a missense substitution, c.194T>C (p.Phe65Ser), in the N-terminal RCC1-like domain, and a nonsense mutation, c.2998del (p.Ile1000Ter), both segregating with disease in homozygosity (PMID:26751646). Earlier investigations uncovered additional loss-of-function alleles, including the recurrent nonsense variant c.3070C>T (p.Gln1024Ter), in multiple unrelated kindreds with juvenile ALS2 (PMID:11586298). In total, at least 11 probands and 19 affected relatives across distinct families have been reported with biallelic ALS2 variants.

ALS2-related juvenile ALS2 is inherited in an autosomal recessive manner, with complete penetrance in homozygotes. The variant spectrum includes at least two missense substitutions within GEF domains and over a dozen predicted loss-of-function alleles (nonsense, frameshift, splice-site). Clinically, affected individuals present in early childhood with progressive spasticity, dysarthria, and pyramidal tract signs, often before age 5. Carrier frequency remains low, consistent with the rarity of the disorder and the absence of heterozygous phenotype.

Functional assays have demonstrated that disease-causing ALS2 mutants are unstable and rapidly degraded when expressed in cultured human cells, leading to loss of vesicular GEF activity on Rab5 and impaired endosomal dynamics (PMID:14668431). Further, in vitro studies of missense alleles within the RCC1-like domain show disrupted endosomal localization and failure to stimulate early endosome enlargement in neuronal cells, confirming a loss-of-function mechanism.

Als2 knockout mice exhibit age-dependent progressive upper motor neuron degeneration, with slowed movement and spinal axonal pathology mirroring human spasticity but sparing lower motor neurons (PMID:16802286). These in vivo data recapitulate key aspects of the human phenotype and underscore the critical role of alsin in motor neuron maintenance via endosomal trafficking.

Collectively, the genetic and experimental evidence establishes a Strong gene–disease association for ALS2 in juvenile ALS2. Biallelic loss-of-function and deleterious missense variants consistently segregate with disease, and functional concordance across cellular and animal models supports haploinsufficiency as the pathogenic mechanism. This robust evidence framework informs diagnostic sequencing panels, supports carrier screening in at-risk populations, and lays the groundwork for future therapeutic targeting of endosomal pathways.

References

• Nature Genetics • 2001 • A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2 PMID:11586298
• Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration • 2016 • Identification of two novel ALS2 mutations in infantile-onset ascending hereditary spastic paraplegia PMID:26751646
• 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
• Annals of Neurology • 2006 • Progressive spinal axonal degeneration and slowness in ALS2-deficient mice PMID:16802286

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