SPG11 – hereditary spastic paraplegia 11

Hereditary spastic paraplegia type 11 (HSP11) is an autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in the SPG11 gene, which encodes the spatacsin protein. Patients typically present in adolescence with progressive spastic paraplegia, cerebellar ataxia, thinning of the corpus callosum, and cognitive impairment. Corpus callosum thinning correlates with clinical severity and may progress over time ([PMID:21779300]).

Genetic studies across diverse populations have identified over 181 SPG11 variants in more than 339 affected individuals, including frameshift, nonsense, splice-site, and missense mutations. Segregation of biallelic SPG11 variants has been demonstrated in multiple consanguineous and non-consanguineous families, with 18 additional affected relatives reported in linkage studies of Italian cohorts ([PMID:14745065], [PMID:33581793]). Compound heterozygous and homozygous loss-of-function alleles are most common, and no clear genotype–phenotype correlation has emerged.

The variant spectrum encompasses 70% frameshift and nonsense mutations, 15% splice-site variants, and rare missense alleles. Recurrent founder deletions mediated by Alu elements and complex rearrangements account for ~19% of pathogenic alleles. A representative pathogenic variant is c.733_734del (p.Met245ValfsTer2), which causes a premature termination and has been observed in patients with blended PWS-SPG11 phenotypes ([PMID:36524102]).

Functional studies support a loss-of-function mechanism. Morpholino knockdown of the zebrafish spg11 ortholog recapitulates CNS developmental defects and axon pathfinding abnormalities, confirming spatacsin’s role in neuronal differentiation ([PMID:20390432]). Cellular assays reveal that SPG11 loss disrupts autophagic lysosomal reformation without affecting autophagosome–endosome fusion, implicating defective autophagy as a key pathogenic process ([PMID:30081747]).

There is no substantial conflicting evidence disputing the SPG11–HSP11 association; all genetic and experimental data converge on spatacsin deficiency causing the characteristic spastic paraplegia and thin corpus callosum phenotype.

Taken together, the SPG11–hereditary spastic paraplegia 11 association is definitive, with robust genetic segregation, a broad variant spectrum, and concordant functional data. SPG11 testing should be incorporated into diagnostic panels for early-onset spastic paraplegia, especially when MRI shows corpus callosum thinning.

References

• Journal of clinical neurology (Seoul, Korea) • 2011 • Thinning of the corpus callosum and cerebellar atrophy is correlated with phenotypic severity in a family with spastic paraplegia type 11. PMID:21779300
• Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia • 2021 • Hereditary spastic paraplegia type 11: Clinicogenetic lessons from 339 patients. PMID:33581793
• 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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