Hereditary ataxia with onset in adulthood

Gene: OGDH

I don't know

Comment on list classification: There are two unrelated cases reported with monoallelic OGDH variants and with cerebellar ataxia. There is also some functional evidence available from Drosophila showing a role for reported variants in late-onset locomotion defects.

Hence, this gene can be rated amber with 'watchlist' tag added to review gene rating in light of any new evidence.

Created: 28 Jul 2026, 6:39 p.m. | Last Modified: 28 Jul 2026, 6:39 p.m.

Panel Version: 9.3

Biallelic variants in OGDH are associated with an early-onset neurodevelopmental disorder characterised by movement disorder, metabolic abnormalities, and brain abnormalities. This phenotype association can be found in OMIM (Oxoglutarate dehydrogenase deficiency (MIM #203740) - last accessed 28 July 2026), Gene2Phenotype (with 'moderate' rating on the DD panel) and ClinGen (associated with mitochondrial disease (MONDO:0044970) with 'Definitive' rating by the Mitochondrial Diseases GCEP - https://search.clinicalgenome.org/CCID:009318)

PMID:42266417 (2026) reported the identification of a de novo c.1909C>T (p.Arg637Trp) variant and a heterozygous c.162T>G (p.Ser54Arg) variant in OGDH gene in two unrelated patients with a late-onset and milder neurological disorder. The patient with p.Arg637Trp variant presented with adult‐onset ataxia, peripheral neuropathy and optic atrophy, while patient with p.Ser54Arg variant presented with adult‐onset ataxia. Functional evidence was available from Drosophila models harbouring UAS-dOgdh (p.Arg639Trp) and UAS-dOgdh (p.Thr58Arg) variants, homologous to the human variants. While the mutant OGDH expression did not lead to defects in development, it led to age-dependent locomotion defects. In addition, p.Arg639Trp variant leads to defective OGDH activity, while p.Thr58Arg variant causes abnormal proteolytic cleavage and impaired mitochondrial import. These suggest that these variants act as dominant-negative and toxic gain-of-function mutations, respectively.

Monoallelic variants are not yet associated with relevant phenotypes in OMIM or ClinGen.

Created: 28 Jul 2026, 6:25 p.m. | Last Modified: 28 Jul 2026, 6:25 p.m.

Panel Version: 8.28

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
peripheral neuropathy, MONDO:0005244; cerebellar ataxia, MONDO:0000437; hereditary optic atrophy, MONDO:0043878

Publications

• 42266417

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

I don't know

Only two families described so far
Sources: Expert list

Created: 12 Jul 2026, 11:48 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
peripheral neuropathy; cerebellar ataxia; optic neuropathy

Publications

• 42266417

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments