SETX – Spinocerebellar Ataxia, Autosomal Recessive, with Axonal Neuropathy 2

Ataxia with oculomotor apraxia type 2 (AOA2) is a rare autosomal recessive cerebellar ataxia caused by biallelic mutations in the SETX gene, encoding the DNA/RNA helicase senataxin. Patients typically present in adolescence with progressive cerebellar ataxia, axonal sensorimotor neuropathy, oculomotor apraxia and elevated serum alpha-fetoprotein levels ([PMID:14736755]). Linkage to chromosome 9q34 and subsequent identification of SETX variants confirmed its role in AOA2, establishing a recessive inheritance mechanism.

Genetic evidence for SETX–AOA2 is definitive. Over 229 probands from more than 75 unrelated families have been reported worldwide, including consanguineous pedigrees with homozygous and compound heterozygous mutations ([PMID:36438189]). Segregation in multiple families and linkage studies (max LOD 5.91 at D9S1830) support high penetrance and gene–disease specificity ([PMID:14736755]). A broad variant spectrum encompasses missense, nonsense, frameshift, splice and deep-intronic changes disrupting the conserved helicase domain.

Recurrent and founder variants have been described, such as the French-Canadian p.Leu1976Arg (c.5927T>G (p.Leu1976Arg)) founder allele and Japanese Glu385Ter (c.1153G>A (p.Glu385Lys)) mutation, accounting for clustered cases in specific populations ([PMID:15732101]; [PMID:19893583]). Novel deep-intronic alleles activating poison exons and in-frame deletion variants (e.g., c.7009_7011del (p.Val2337del)) further expand the mutational landscape.

Clinically, AOA2 exhibits cerebellar vermis atrophy on MRI, early‐onset gait ataxia (mean onset 15.1 ± 3.8 y), peripheral neuropathy in >92% of patients and oculomotor apraxia in ~56% ([PMID:14736755]). Alpha-fetoprotein is a reliable biomarker (elevated in ~100% of index cases), aiding differentiation from other autosomal recessive cerebellar ataxias.

Functional assays corroborate pathogenicity: patient-derived fibroblasts with c.994C>T (p.Arg332Trp) and c.6848_6851delCAGA (p.T2283LysfsTer32) show increased susceptibility to oxidative DNA damage in comet assays ([PMID:24814856]). Integrated genome–transcriptome analyses of SETX knockout cells and AOA2 patient blood reveal transcription stress, R-loop accumulation and chromosome instability at fragile sites, linking senataxin loss to genomic fragility ([PMID:35042798]).

In summary, biallelic loss-of-function variants in SETX cause AOA2 via haploinsufficiency and impaired R-loop resolution, manifesting in cerebellar and peripheral nervous system degeneration. Definitive genetic and functional evidence support routine SETX testing in early‐onset ataxia with elevated AFP. Key take-home: SETX mutation screening and functional assays enable accurate diagnosis, inform prognosis and guide genetic counseling.

References

• Brain • 2004 • Frequency and phenotypic spectrum of ataxia with oculomotor apraxia 2: a clinical and genetic study in 18 patients. PMID:14736755
• Frontiers in molecular neuroscience • 2022 • Ataxia with oculomotor apraxia type 2 caused by a novel homozygous mutation in SETX gene, and literature review. PMID:36438189
• Journal of clinical neuroscience • 2014 • Ataxia with oculomotor apraxia type 2 fibroblasts exhibit increased susceptibility to oxidative DNA damage. PMID:24814856
• Proceedings of the National Academy of Sciences • 2022 • Integrated genome and transcriptome analyses reveal the mechanism of genome instability in ataxia with oculomotor apraxia 2. PMID:35042798

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