Hereditary ataxia with onset in adulthood

Gene: PNPT1

Green List (high evidence)

Comment on list classification: There are at least 4 unrelated families with adult-onset Spinocerebellar ataxia and heterozygous PNPT1 variants. While some carriers were very mildly affected or reported unaffected, there is good evidence of PNPT1 variants cosegregating with ataxia, supporting an autosomal dominant inheritance mode. Based on available evidence, this gene should be promoted to Green for Hereditary ataxia with onset in adulthood.

Created: 12 Dec 2025, 2:10 p.m. | Last Modified: 12 Dec 2025, 2:10 p.m.

Panel Version: 8.15

PMID: 35411967 Barbier et al., 2022
461–7 French index patient - congenital deafness, ataxia onset at 23yo with a Moderate (24/40) ataxia score - heterozygous for NM_033109.5:c.2091delA; p.Lys697AsnfsTer6 - inherited from an unaffected father.
Australian family A1 - 6 individuals with autosomal dominant progressive ataxia, 3 other individuals were heterozygous and mildly affected.
4 heterozygous candidate variants identified: MSH6 NM_000179.2:c.2633T>C; p.Val878Ala; STON1 NM_001198595.1:c.1231G>A; p.Glu411Lys; PSME4 NM_014614.2:c.3400G>A; p.Glu1134Lys, and PNPT1 NM_033109.5:c.2014-3C>G. The PNPT1 splice variant introduces a premature stop codon (p.Gln672SerfsTer6) - confirmed by RT-PCR. OXPHOS enzyme activities were normal,
Ataxia age of onset = 4 cases under 18 yrs old, 3 adult-onset cases (20-56yrs).

PMID: 39924761 Haddad et al., 2025
Reported two families with heterozygous PNPT1 variants with sensory ataxic neuropathy, including 3 adult-onset cases (20s-30s) - 2 of these cases had no neuropathy score, and 1 case (BII6) with CMT score of 15.
Affected members of Family 1 were heterozygous for NM_033109.5 PNPT1 c.2014‐3C>G; patients in Family 2 were heterozygous for PNPT1 NM_033109.5 c.2143C>T p.Arg715Ter - both variants segregated with disease.

PNPT1 is associated with AD Spinocerebellar ataxia 25 MIM:608703, AR Combined oxidative phosphorylation deficiency 13, MIM:614932, and AR Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration, MIM:614934 in OMIM (accessed 12th Dec 2025).

Created: 12 Dec 2025, 1:52 p.m. | Last Modified: 12 Dec 2025, 2:07 p.m.

Panel Version: 8.15

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Spinocerebellar ataxia 25, OMIM:608703

Publications

• 35411967
• 39924761

Green List (high evidence)

Already green on childhood ataxia panel, see https://panelapp.genomicsengland.co.uk/panels/477/gene/PNPT1/
The ataxia phenotype can manifest in adulthood, therefore suggest adding to this panel also.
Sources: NHS GMS

Created: 20 Nov 2025, 3:08 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted