A novel DNMT1 mutation associated with early onset hereditary sensory and autonomic neuropathy, cataplexy, cerebellar atrophy, scleroderma, endocrinopathy, and common variable immune deficiency.
DNA methyltransferase 1 (DNMT1) is an enzyme which has a role in methylation of DNA, gene regulation, and chromatin stability. Missense mutations in the DNMT1 gene have been previously associated with two neurological syndromes: hereditary sensory and autonomic neuropathy type 1 with dementia and deafness (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). We report a case showing overlap of both of these syndromes plus associated clinical features of common variable immune deficiency, scleroderma, and endocrinopathy that could also be mutation associated. Our patient was found to be heterozygous for a previously unreported frameshift mutation, c.1635_1637delCAA p.(Asn545del) in the DNMT1 gene exon 20. This case displays both the first frameshift mutation described in the literature which is associated with a phenotype with a high degree of overlap between HSAN1E and ADCA-DN and early age of onset (c. 8 years). Our case is also of interest as the patient displays a number of new non-neurological features, which could also be DNMT1 mutation related.
Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK.
Robin
R
Fox
Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK.
John
J
Ealing
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, UK.
Helen
H
Murphy
Department of Neurology, Dunedin Public Hospital, Dunedin, New Zealand.
David P
DP
Gow
Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK.
David
D
Gosal
D001921:Brain / Q000000981:diagnostic imaging; D002385:Cataplexy / Q000150:complications / Q000235:genetics*; D017074:Common Variable Immunodeficiency / Q000150:complications / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics*; D004252:DNA Mutational Analysis; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000150:complications / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D009290:Narcolepsy / Q000150:complications / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D055815:Young Adult
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human
autosomal dominant cerebellar atrophy; cataplexy; cerebellar atrophy; deafness and narcolepsy (ADCA-DN); genetics; hereditary sensory and autonomic neuropathy