SPG21 – Hereditary Spastic Paraplegia

SPG21 (HGNC:20373) has been implicated in hereditary spastic paraplegia (MONDO_0019064) through various lines of genetic and functional evidence. Several independent studies have documented cases with classical features of HSP, including spasticity, ataxia, and cognitive impairment (PMID:35111129). These reports, spanning different populations, provide robust support for the gene–disease association.

The overall clinical validity for SPG21 in HSP is classified as Strong based on evidence from at least 5 probands in 3 unrelated families (PMID:35111129) and segregation analysis demonstrating 19 additional affected relatives (PMID:22554690). Detailed phenotypic assessments further confirm the presence of spasticity (HP_0001257), cognitive impairment (HP_0100543), and ataxia (HP_0001251), along with neuroimaging findings such as global brain atrophy (HP_0002283) in affected individuals.

Genetic evidence supports an autosomal recessive mode of inheritance for this condition. Critical variant types include truncating and frameshift mutations. For instance, the truncating variant c.118C>T (p.Arg40Ter) has been identified in affected patients, marking a clear pathogenic hit that disrupts protein function. This variant, alongside others, underscores a consistent loss‑of‑function mechanism in SPG21-related HSP (PMID:35111129).

Functional studies further bolster the biological plausibility of SPG21’s role in HSP. In vitro assays and animal models demonstrate that loss of SPG21 function leads to impaired maintenance of the corticospinal tract and other neuronal pathways, aligning well with the complex neurological presentation observed in patients (PMID:22554690). These studies, although moderate in experimental evidence, provide important mechanistic insights that complement the genetic data.

It is noteworthy that while one study reported wild‑type sequencing in select cases (PMID:16138254), the cumulative data from multiple independent cohorts and familial segregation studies strongly support a pathogenic role for SPG21 in HSP. Integration of genetic and functional findings has thus firmly established this gene–disease association.

In conclusion, the robust convergence of genetic evidence—including multiple pathogenic alleles and clear segregation patterns—with supportive functional data makes SPG21 a critical gene in the diagnostic workup for hereditary spastic paraplegia. Key take‑home: The strong link between SPG21 and HSP offers high clinical utility for patient diagnosis, management, and future therapeutic strategies.

References

• Neuropediatrics • 2005 • Complicated hereditary spastic paraplegia with thin corpus callosum and childhood onset PMID:16138254
• Journal of human genetics • 2014 • Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses PMID:24451228
• Journal of the neurological sciences • 2012 • Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance PMID:22554690
• Frontiers in neurology • 2021 • Mast Syndrome Outside the Amish Community: SPG21 in Europe PMID:35111129

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