Spastic ataxia: genes and variants

Genes linked to Spastic ataxia

• SETX: Helicase senataxin

  It resolves RNA-DNA hybrids and supports transcription termination, RNA processing, and genome stability, particularly in long-lived neurons. Different pathogenic mechanisms cause ataxia with oculomotor apraxia type 2 or juvenile amyotrophic lateral sclerosis type 4.

  2 disease-causing and 1 uncertain variants in SETX are linked to Spastic ataxia.

• STXBP1: Syntaxin-binding protein 1

  It controls SNARE-complex assembly and synaptic-vesicle fusion, making it essential for rapid neurotransmitter release. Haploinsufficiency causes STXBP1-related neurodevelopmental disorder with developmental impairment, epilepsy, movement abnormalities, and intellectual disability.

  2 disease-causing and 1 uncertain variants in STXBP1 are linked to Spastic ataxia.

• SPG7: Mitochondrial inner membrane m-AAA protease component paraplegin

  It participates in mitochondrial inner-membrane protein quality control and respiratory homeostasis as part of the m-AAA protease machinery. Biallelic pathogenic variants cause SPG7-related disease, commonly presenting with spastic ataxia, optic neuropathy, or progressive gait impairment.

  1 disease-causing and 1 uncertain variants in SPG7 are linked to Spastic ataxia.

• DNMT1: DNA (cytosine-5)-methyltransferase 1

  It copies existing DNA methylation patterns during replication and also contributes to chromatin regulation and neuronal maintenance. Dominant pathogenic variants can cause hereditary sensory neuropathy with dementia and hearing loss or a cerebellar ataxia-deafness-narcolepsy syndrome.

  1 disease-causing and 1 uncertain variants in DNMT1 are linked to Spastic ataxia.

• TUBB3: Tubulin beta-3 chain

  It forms neuronal microtubules required for axon growth, guidance, and intracellular transport. Heterozygous pathogenic variants can cause congenital fibrosis of the extraocular muscles type 3 and broader tubulinopathy phenotypes with brain and cranial-nerve abnormalities.

  1 disease-causing and 0 uncertain variants in TUBB3 are linked to Spastic ataxia.

Weakly linked (only a few uncertain records): LYST, CACNA1A, ERCC4, FAT2, KCNMA1, SCN2A, SCN8A and SPAST.

Known disease-causing variants in Spastic ataxia

Same protein, different disease

• Early-infantile DEE is also caused by STXBP1 variants; they fall mostly in different places as the Spastic ataxia variants (45 disease-causing).
• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 is also caused by SETX variants; they fall mostly in different places as the Spastic ataxia variants (17 disease-causing).
• Amyotrophic lateral sclerosis is also caused by SETX variants; they fall mostly in different places as the Spastic ataxia variants (6 disease-causing).
• Hereditary spastic paraplegia is also caused by SPG7 variants; they fall mostly in different places as the Spastic ataxia variants (26 disease-causing).
• Autosomal dominant cerebellar ataxia, deafness and narcolepsy is also caused by DNMT1 variants; they fall mostly in different places as the Spastic ataxia variants (5 disease-causing).
• Hereditary sensory neuropathy-deafness-dementia syndrome is also caused by DNMT1 variants; they fall mostly in different places as the Spastic ataxia variants (3 disease-causing).
• Complex cortical dysplasia with other brain malformations 7 is also caused by TUBB3 variants; they fall mostly in different places as the Spastic ataxia variants (23 disease-causing).
• Fibrosis of extraocular muscles, congenital, 3A, with or without extraocular involvement is also caused by TUBB3 variants; they fall mostly in different places as the Spastic ataxia variants (6 disease-causing).
• TUBB3-related tubulinopathy is also caused by TUBB3 variants; they fall mostly in different places as the Spastic ataxia variants (5 disease-causing).

Diseases related to Spastic ataxia

• Hereditary spastic paraplegia, also linked to SETX and SPG7
• Early-infantile DEE, also linked to STXBP1
• Amyotrophic lateral sclerosis, also linked to SETX
• Complex cortical dysplasia with other brain malformations 7, also linked to TUBB3
• Ovarian cancer, also linked to TUBB3
• Acute myeloid leukemia, also linked to DNMT1
• Epilepsy, also linked to STXBP1
• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, also linked to SETX
• Non-small cell lung carcinoma, also linked to TUBB3
• Hereditary pancreatitis, also linked to SPG7
• Male infertility with azoospermia or oligozoospermia due to single gene mutation, also linked to TUBB3
• Mitochondrial disease, also linked to SPG7

Frequently asked questions

Which genes are linked to Spastic ataxia?

In CATVariant, Spastic ataxia is linked to 5 analyzed proteins: SETX (Helicase senataxin), STXBP1 (Syntaxin-binding protein 1), SPG7 (Mitochondrial inner membrane m-AAA protease component paraplegin), DNMT1 (DNA (cytosine-5)-methyltransferase 1) and TUBB3 (Tubulin beta-3 chain).

How many genetic variants are linked to Spastic ataxia?

23 variants: 7 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 13 are of uncertain significance or have conflicting reports.

Which uncertain variants in Spastic ataxia look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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