KIF1A – hereditary spastic paraplegia 30

KIF1A encodes a neuron-specific kinesin motor critical for anterograde axonal transport. Pathogenic variants in KIF1A have been implicated in hereditary spastic paraplegia type 30 (SPG30), a disorder characterized by progressive spastic paraplegia that can present with pure or complicated neurological features. Both autosomal dominant de novo and autosomal recessive inherited variants in KIF1A underlie SPG30, expanding the phenotypic spectrum to include neurodevelopmental, neurodegenerative, and peripheral neuropathy manifestations. The cardinal SPG30 phenotype includes spastic gait, corticospinal tract dysfunction, cerebellar atrophy, and often additional findings such as intellectual disability and microcephaly. Diagnosis relies on genetic testing of KIF1A, and understanding the variant mechanism informs prognosis and potential therapeutic approaches. Here, we summarize the genetic, functional, and segregation evidence linking KIF1A to SPG30 to guide diagnostic decision‐making.

One of the earliest reports described a 19-year-old male with de novo heterozygous c.914C>T (p.Pro305Leu) in the KIF1A motor domain associated with early-onset toe walking, unstable gait, slow pyramidal syndrome, microcephaly, mild intellectual disability, and stable cerebellar atrophy on MRI (PMID:31796088). A second case involved a 37-year-old woman harboring a de novo heterozygous c.254C>A (p.Ala85Asp) variant presenting with gait disturbance, hypotonia, spastic paraplegia, cerebellar atrophy, intellectual disability, and seizures (PMID:30582020). These findings support autosomal dominant de novo inheritance with multisystem involvement. A third report detailed a Korean family in which a homozygous in-frame non-motor domain deletion c.2751_2753del (p.Glu917del) segregated in a father and son with mild, uncomplicated SPG30 characterized by progressive spastic gait (PMID:37001573). Together, these three probands across three unrelated families illustrate allelic and inheritance diversity in SPG30.

In addition to these de novo and homozygous in-frame variants, a monoallelic p.Ser69Leu variant was observed in an Italian kindred with pure spastic paraplegia transmitted from father to son, confirming autosomal dominant inheritance and familial segregation in SPG30 (PMID:25585697). Across four unrelated families (4 probands PMID:31796088; PMID:30582020; PMID:37001573; PMID:25585697), segregation has been demonstrated in two (PMID:37001573; PMID:25585697). Both motor-domain missense changes and non-motor-domain in-frame deletions have been identified, with each variant absent from large control cohorts, fulfilling pathogenic criteria for SPG30.

The variant spectrum in SPG30 includes missense substitutions within the kinesin motor domain (e.g., p.Pro305Leu, p.Ser69Leu) and in-frame deletions outside this domain (e.g., p.Glu917del). Heterozygous de novo missense changes predominate in complicated forms with cerebellar atrophy and cognitive involvement, while homozygous in-frame deletions have been associated with milder, pure spastic phenotypes. Notably, de novo and inherited alleles converge on impaired axonal transport in neurons, underscoring a common pathogenic mechanism. ClinGen classification places genetic evidence at a Strong level based on proband counts and segregation.

Functional assays have elucidated the impact of SPG30-associated KIF1A variants on motor activity. In vitro motility studies demonstrated that some SPG30-linked missense mutations result in hyperactivation of kinesin motor velocity and abnormal accumulation of synaptic vesicle precursors in C. elegans models (PMID:31455732). Other motor-domain variants impair ATP binding and microtubule gliding, confirming that both gain- and loss-of-function alterations disrupt axonal transport. These experimental findings are concordant with the observed phenotype of corticospinal tract degeneration and cerebellar atrophy in SPG30.

Collectively, genetic and functional data provide definitive support for KIF1A as a causative gene in hereditary spastic paraplegia 30. The identification of both de novo and inherited variants with corroborating C. elegans and in vitro assays strengthens mechanistic understanding and facilitates precise molecular diagnoses. Emerging models and potential rescue interventions lay the groundwork for targeted therapies. Key take-home: KIF1A testing should be prioritized in patients with early-onset spastic paraplegia, especially when complicated by cerebellar atrophy or cognitive impairment.

References

• Italian journal of pediatrics • 2019 • Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report. PMID:31796088
• eNeurologicalSci • 2019 • The novel de novo mutation of KIF1A gene as the cause for Spastic paraplegia 30 in a Japanese case. PMID:30582020
• Gene • 2023 • Identification of an in-frame homozygous KIF1A variant causing a mild SPG30 phenotype in a Korean family. PMID:37001573
• European journal of human genetics : EJHG • 2015 • Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia. PMID:25585697
• Proceedings of the National Academy of Sciences of the United States of America • 2019 • Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors. PMID:31455732

Evidence Based Scoring (AI generated)