SPG11 – juvenile amyotrophic lateral sclerosis

SPG11 encodes spatacsin, a large protein required for neuronal maintenance. Biallelic loss‐of‐function variants in SPG11 are established causes of autosomal recessive hereditary spastic paraplegia with thin corpus callosum (ARHSP‐TCC). Juvenile amyotrophic lateral sclerosis (JALS, [MONDO:0017593]) shares motor neuron features with ARHSP, and SPG11 mutations have emerged as a genetic etiology in JALS cohorts.

Exome sequencing of 8 unrelated probands identified biallelic SPG11 variants presenting with both ARHSP and JALS features ([PMID:32383541]). All patients exhibited thin corpus callosum on MRI and motor neuronopathy on electrodiagnosis. Two novel variants were described, and a recurrent frameshift variant p.Glu1026ArgfsTer4 was found in 6 Iranian probands, suggesting a founder allele. No additional segregation beyond probands was reported.

The spectrum of SPG11 variants includes nonsense, frameshift, splice‐site, and large rearrangements. Functional LoF alleles such as c.4846C>T (p.Gln1616Ter) underscore critical spatacsin roles in neurodevelopment.

Morpholino knockdown of zebrafish spg11 recapitulates CNS defects, with disrupted neuronal differentiation and axon pathway formation ([PMID:20390432]). In patient‐derived cells, SPG11 mutations impair autophagic lysosome reformation, showing milder autophagy defects compared to SPG15 but confirming a LoF mechanism ([PMID:30081747]).

No studies have refuted the association of SPG11 and JALS or assigned distinct phenotypes to SPG11‐mutant JALS cohorts. Data across independent patients and model systems consistently support a unified AR‐LoF mechanism.

Integration of genetic, imaging, neurophysiological, and functional data places SPG11–JALS in a Moderate clinical validity category. SPG11 molecular testing should be included in diagnostic panels for juvenile ALS presentations, especially when thin corpus callosum is present.

Key Take-home: AR‐LoF SPG11 variants cause a combined ARHSP/JALS phenotype, and spatacsin testing is clinically actionable in juvenile motor neuron disease.

References

• Molecular genetics & genomic medicine • 2020 • Description of combined ARHSP/JALS phenotype in some patients with SPG11 mutations. PMID:32383541
• Neurogenetics • 2010 • Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish. PMID:20390432
• Autophagy • 2019 • ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis. PMID:30081747

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