SPART – Hereditary Spastic Paraplegia

SPART (HGNC:18514) has been implicated in a form of hereditary spastic paraplegia (MONDO:0019064) that presents with features including progressive lower‐limb spasticity and muscle weakness. Multiple independent case reports provide evidence for an autosomal recessive inheritance pattern, with patients exhibiting clinical signs such as spastic paraparesis and dysarthria (PMID:27539578).

In one study, whole exome sequencing in a child with Troyer syndrome—a variant of hereditary spastic paraplegia—revealed the homozygous variant c.988A>G (p.Met330Val) in SPART, which was associated with almost complete loss of spartin protein in skeletal muscle and mitochondrial cytochrome c oxidase deficiency (PMID:27539578). This finding underscores the genetic evidence linking SPART mutations with the disease.

Further supporting the genetic basis of this association, segregation analysis in an extended consanguineous family demonstrated that the mutation co‐segregated with the clinical phenotype in approximately five affected individuals (PMID:32661208). The recurrence of SPART variants in independent families reinforces a strong genetic association with hereditary spastic paraplegia.

Functional studies have provided complementary evidence; in cellular and animal models, mutant spartin exhibits defective mitochondrial localization and reduced complex I activity. These functional impairments are consistent with a loss‐of‐function mechanism that contributes to the pathogenesis of the disorder (PMID:16945107; PMID:31314595).

Integrating the clinical, genetic, and experimental data, the association between SPART and hereditary spastic paraplegia is robust. The convergence of case reports, segregation data, and functional assays supports a strong ClinGen gene–disease association, which is critical for diagnostic decision‑making and may facilitate targeted genetic testing and therapeutic development.

Key Take‑home: The combined genetic and functional evidence establishes that SPART mutations lead to mitochondrial dysfunction and a clinical phenotype of hereditary spastic paraplegia, offering valuable insights for clinical diagnosis and patient management.

References

• JIMD reports • 2017 • Novel Homozygous Missense Mutation in SPG20 Gene Results in Troyer Syndrome Associated with Mitochondrial Cytochrome c Oxidase Deficiency PMID:27539578
• Journal of genetics • 2020 • A novel missense mutation (c.1006C>T) of SPG20 gene associated with Troyer syndrome PMID:32661208
• Journal of neurochemistry • 2006 • The hereditary spastic paraplegia protein spartin localises to mitochondria PMID:16945107
• FASEB journal • 2019 • A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism PMID:31314595

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