Hereditary ataxia with onset in adulthood

Gene: DNMT1

Additional functional evidence: PMID: 31984424 - Maresca et al - studied the effects of different DNMT1 mutations in fibroblasts from four Autosomal Dominant Cerebellar Ataxia-Deafness and Narcolepsy (ADCA-DN) and two Hereditary Sensory Neuropathy with Dementia and Hearing loss (HSN-IE) patients who were unrelated. They found mitochondrial hyper-function that resulted in increased oxidative stress but no change in mitochondrial DNA CpG methylation. They demonstrated that DNMT1 is not localized within mitochondria, but it is associated to the mitochondrial outer membrane. AMPK and mTORC1, the two major sensors of cellular energy, were implicated in the pathogenic mechanism of the most severe DNMT1 mutations.

Created: 1 Sep 2020, 4:35 p.m. | Last Modified: 1 Sep 2020, 4:35 p.m.

Panel Version: 2.8

Publications

• 31984424

Green List (high evidence)

In Sheffield and Oxford panel. Overlap with sleep disorder panel. 18 DM in HGMD - 4 mention ataxia in phenotype and 1 mentions cerebellar atrophy.

Created: 27 Apr 2019, 7:39 p.m.

I don't know

Review and rating submitted by James Polke (Neurogenetics Laboratory, Institute of Neurology, London) on behalf of London North GLH for GMS Neurology specialist test group

Created: 27 Apr 2019, 8:55 p.m.

Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.

Created: 15 Apr 2019, 10:21 a.m.

Green List (high evidence)

Multiple reports in literature. Pathogenic variants appear to be limited to the targetting sequence domain, N-terminal end gives Neuropathy, C-terminal end gives ataxia and narcolepsy

Created: 15 Apr 2019, 10:06 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cerebellar ataxia, deafness and narcolepsy, 604121, Hereditary sensory neuropathy type IE, 614116

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

Variants in this GENE are reported as part of current diagnostic practice