Ataxia - adult onset

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, 4:27 p.m. | Last Modified: 1 Sep 2020, 4:27 p.m.

Panel Version: 0.4091

Publications

• 31984424

Green List (high evidence)

- Missense in exon 20 have been reported in patients with HSAN1E (hereditary sensory and autonomic neuropathy with dementia and hearing loss)

- Missense in exon 21 in patients with ADCA-DN (autosomal dominant cerebellar ataxia deafness and narcolepsy)

Created: 28 Feb 2020, 1:53 a.m. | Last Modified: 28 Feb 2020, 1:53 a.m.

Panel Version: 0.1473

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant, 604121; Neuropathy, hereditary sensory, type IE, 614116

Publications

• PMID: 22328086
• 21532572

Green List (high evidence)

2 different variants reported in 4 families with hereditary sensory neuropathy with dementia and hearing loss (PMID: 21532572)

3 different missense variants reported in 4 families with (PMID: 22328086)

Missense in exon 20 have been reported in patients with HSAN1E (hereditary sensory and autonomic neuropathy with dementia and hearing loss) (Klein 2011), whereas missense in exon 21 in patients with ADCA-DN (autosomal dominant cerebellar ataxia deafness and narcolepsy) (Winkelmann 2012)

Created: 27 Feb 2020, 12:13 a.m. | Last Modified: 27 Feb 2020, 12:13 a.m.

Panel Version: 0.15

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

Phenotypes
Neuropathy, hereditary sensory, type IE (MIM#614116); Cerebellar ataxia, deafness, and narcolepsy, autosomal dominant (MIM#604121)

Publications

• PMID: 21532572