KIF5A – SPG10-related Hereditary Spastic Paraplegia

Hereditary spastic paraplegia 10 (SPG10) is an autosomal dominant motor neuron disorder caused by mutations in the kinesin family member 5A (KIF5A) gene, resulting in progressive spastic paraparesis often accompanied by axonal peripheral neuropathy ([PMID:21107874]). The disorder typically manifests in adulthood with lower limb spasticity and variable additional features such as spinal cord atrophy and sensory involvement.

Clinical Validity

The association between KIF5A and SPG10 is classified as Strong based on identification of at least 5 unrelated probands across 4 families, demonstration of co-segregation in 3 pedigrees, and concordant functional data showing impaired kinesin motor activity ([PMID:21107874]; [PMID:22788249]; [PMID:18245137]).

Genetic Evidence

SPG10 is inherited in an autosomal dominant manner. Five missense variants in KIF5A have been reported in five probands, with segregation in Italian, French, and Taiwanese families. Variant spectrum comprises primarily motor-domain missense mutations such as c.608C>G (p.Ser203Cys) and c.580G>C (p.Ala194Pro), all disrupting conserved residues critical for microtubule interaction ([PMID:21107874]; [PMID:22788249]; [PMID:40518753]).

Functional / Experimental Evidence

In vitro motility assays of KIF5A mutants demonstrate reduced microtubule affinity and gliding velocity, consistent with haploinsufficiency and dominant-negative mechanisms. Laser-trapping studies reveal severely curtailed stepping of mutant homodimers and mixed heterodimers, leading to deficient synaptic cargo delivery ([PMID:18203753]).

Conflicting Evidence

No significant conflicting reports have been documented; all studies to date support pathogenicity of motor-domain missense variants in SPG10.

Integration & Conclusion

Collectively, genetic and functional data establish a strong causal link between heterozygous KIF5A motor-domain mutations and SPG10. The identification of founder and recurrent alleles, combined with robust co-segregation and mechanistic insights, underscores the clinical utility of KIF5A testing in patients with adult-onset spastic paraplegia with or without peripheral neuropathy. Key Take-home: KIF5A motor-domain sequencing should be prioritized in autosomal dominant HSP presenting with spastic paraparesis and axonal neuropathy.

References

• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology • 2011 • A novel mutation in KIF5A gene causing hereditary spastic paraplegia with axonal neuropathy. PMID:21107874
• European journal of neurology • 2013 • Novel SPG10 mutation associated with dysautonomia, spinal cord atrophy, and skin biopsy abnormality. PMID:22788249
• Journal of neurology, neurosurgery, and psychiatry • 2008 • SPG10 is a rare cause of spastic paraplegia in European families. PMID:18245137
• Human molecular genetics • 2008 • Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. PMID:18203753

Evidence Based Scoring (AI generated)