TDP1 – Spinocerebellar Ataxia with Axonal Neuropathy Type 1

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is critical for resolving stalled topoisomerase I–DNA complexes. Biallelic pathogenic variants in TDP1 cause spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1; OMIM:607250), an ultrarare autosomal recessive neurodegenerative syndrome characterized by progressive cerebellar ataxia and peripheral axonal neuropathy.

The first causal link was established in a Saudi Arabian kindred by genome-wide linkage and positional cloning, identifying a homozygous NM_018319.4:c.1478A>G (p.His493Arg) variant disrupting a conserved active-site histidine and segregating with disease (PMID:12244316).

Independent replication in two unrelated Omani families (n = 4 affected) confirmed the same c.1478A>G (p.His493Arg) allele with shared haplotype and autosomal recessive transmission, substantiating a founder effect in the Middle East (PMID:31182267). More recently, whole-exome sequencing in a consanguineous Pakistani pedigree revealed a novel homozygous NM_018319.4:c.1432C>T (p.His478Tyr) variant, expanding both the genotypic and phenotypic spectra to include congenital onset SCAN1 (PMID:39576382).

Functional characterization shows that p.His493Arg reduces Tdp1 catalytic activity ~25-fold and traps a covalent Tdp1–DNA intermediate, leading to camptothecin hypersensitivity in patient cells and yeast rescue assays, consistent with a neomorphic loss-of-function mechanism (PMID:15920477). Mouse and cellular models replicate genome instability and neuronal vulnerability, aligning with human neurodegeneration.

Collectively, genetic segregation, recurrence of a founder variant, discovery of a novel allele, and concordant functional studies support a haploinsufficiency/neomorphic mechanism. Clinical features include cerebellar atrophy (HP:0001272), progressive cerebellar ataxia (HP:0002073), hypercholesterolemia (HP:0003124), elevated alpha-fetoprotein, and variable cognitive impairment.

References

• Nature Genetics • 2002 • Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy PMID:12244316
• Journal of Clinical Neuroscience • 2019 • Spinocerebellar ataxia with axonal neuropathy type 1 revisited PMID:31182267
• Molecular Biology Reports • 2024 • Report of a novel missense TDP1 variant in a Pakistani family affected with an extremely rare disorder congenital spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) PMID:39576382
• The EMBO Journal • 2005 • SCAN1 mutant Tdp1 accumulates the enzyme--DNA intermediate and causes camptothecin hypersensitivity PMID:15920477

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