DNMT1 – Autosomal Dominant Cerebellar Ataxia, Deafness and Narcolepsy

Clinical Validity (Strong): DNMT1 mutations have been identified as causative for ADCA-DN in multiple unrelated families, including 1 de novo proband (PMID:23904686) and 5 Italian patients from four families (PMID:24727570), with co-segregation in a mother–daughter pair (PMID:31957642).

Genetic Evidence

Autosomal dominant inheritance is confirmed by de novo and familial segregation. A Brazilian patient presented with c.1786T>C (p.Cys596Arg) in exon 21 (PMID:23904686). Two asymptomatic daughters carried the same paternal mutation, preclinical for SOREMPs and MRS changes (PMID:24709307). A second family harbored c.1723G>A (p.Glu575Lys) segregating in mother and daughter (PMID:31957642). Multi-family analysis of 5 patients across four Italian pedigrees revealed additional exon 21 mutations and a broader variant spectrum (PMID:24727570). A kindred with c.1531T>C (p.Tyr511His) further delineates genotype–phenotype correlation (PMID:33433851).

Variant Spectrum

Reported variants cluster in exon 21 of DNMT1: missense changes including c.1786T>C (p.Cys596Arg), c.1723G>A (p.Glu575Lys), c.1531T>C (p.Tyr511His), c.1520C>T (p.Pro507Leu), c.1520C>G (p.Pro507Arg), and in-frame deletion c.1559AGA[1] (p.Lys521del). All alter the maintenance methyltransferase domain, consistent with dominant-negative or haploinsufficient mechanisms.

Functional Evidence

No disease-specific assays for ADCA-DN have been reported. While DNMT1’s role in maintenance methylation is established, direct functional studies of ADCA-DN variants remain lacking. Mechanistic inference is limited to predicted disruption of enzyme activity and recruitment to replication foci.

Integration & Clinical Utility

DNMT1 exon 21 missense variants cause a distinct neurodegenerative syndrome characterized by cerebellar ataxia, sensorineural hearing loss and narcolepsy. Genetic testing for DNMT1 should be considered in patients with progressive ataxia and early-onset sleep-wake disturbances, even if HLA-DQB1*06:02 is negative. Preclinical carriers may exhibit polysomnographic markers and MRS changes, offering opportunities for early diagnosis. Further functional studies are warranted to elucidate pathogenic mechanisms. Key take-home: DNMT1 testing enables definitive diagnosis of ADCA-DN, guiding surveillance for hearing loss and sleep disorders.

References

• Sleep • 2013 • A novel de novo exon 21 DNMT1 mutation causes cerebellar ataxia, deafness, and narcolepsy in a Brazilian patient. PMID:23904686
• Sleep medicine • 2014 • Polysomnographic and neurometabolic features may mark preclinical autosomal dominant cerebellar ataxia, deafness, and narcolepsy due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1. PMID:24709307
• Journal of clinical sleep medicine • 2020 • Cataplexy and ataxia: red flags for the diagnosis of DNA methyltransferase 1 mutation. PMID:31957642
• Brain • 2014 • Narcolepsy is a common phenotype in HSAN IE and ADCA-DN. PMID:24727570
• Journal of molecular neuroscience • 2021 • Cerebellar Ataxia as a Common Clinical Presentation Associated with DNMT1 p.Y511H and a Review of the Literature. PMID:33433851

Evidence Based Scoring (AI generated)