DNMT1-associated sensory neuropathy and cerebellar ataxia: A novel variant and review of genotype-phenotype correlation

• Published in: Journal of the peripheral nervous system Vol. 28; no. 3; pp. 508 - 512
• Main Authors: Menon, Poornima Jayadev, Bogdanova-Mihaylova, Petya, McDermott, Garret, Crowley, Paul, Killeen, Ronan P, Alexander, Michael D, O'Dowd, Sean, Murphy, Sinéad M
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2023
• Subjects: Ataxia; Atrophy; Brain injury; Cerebellar ataxia; Cerebellum; Cochlea; Cochlear implants; Cognitive ability; Deafness; DNA methyltransferase; DNMT1 protein; Emotional behavior; Genotypes; Hearing loss; Narcolepsy; Neurodegenerative diseases; Neuropathy; Phenotypes; Sleep disorders; hereditary sensory neuropathy Type 1; DNMT1; inherited neuropathies
• ISSN: 1085-9489; 1529-8027
• DOI: 10.1111/jns.12560

Hereditary sensory neuropathy (HSN) 1E is a neurodegenerative disorder caused by pathogenic variants in DNA methyltransferase 1 (DNMT1). It is characterised by sensorineural deafness, sensory neuropathy and cognitive decline. Variants in DNMT1 are also associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy. A 42-year-old man presented with imbalance, lancinating pain, numerous paucisymptomatic injuries, progressive deafness since his mid-20s, mild cognitive decline and apathy. Examination revealed abnormalities of eye movements, distal sensory loss to all modalities, areflexia without weakness and lower limb ataxia. MRI brain and FDG-PET scan demonstrated biparietal and cerebellar atrophy/hypometabolism. Whole exome sequencing detected a heterozygous likely pathogenic missense variant in DNMT1, c.1289G > A, p.Cys430Tyr. Cochlear implant was performed at 44 years for the bilateral high frequency sensorineural hearing loss with improvement in hearing and day-to-day function. We describe a novel variant in DNMT1 and confirm that an overlapping HSN1E-cerebellar phenotype can occur. Only one prior case of cochlear implant in HSN1E has been reported to date but this case adds to that literature, suggesting that cochlear implant can be successful in such patients. We further explore the clinical and radiological signature of the cognitive syndrome associated with this disorder.