Jonathan Baets, Xiaohui Duan, Yanhong Wu, Gordon Smith, William W. Seeley, Ine`s Mademan, Nicole M. McGrath, Noah C. Beadell, Julie Khoury, Maria-Victoria Botuyan, Georges Mer, Gregory A. Worrell, Kaori Hojo, Jessica DeLeon, Matilde Laura, Yo-Tsen Liu, Jan Senderek, Joachim Weis, Peter Van den Bergh, Shana L. Merrill, Mary M. Reilly, Henry Houlden, Murray Grossman, Steven S. Scherer, Peter De Jonghe, Peter J. Dyck, Christopher J. Klein
Brain 138:845-861, 2015. PMCID Journal- in process.
We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identiﬁed HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dom-inant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efﬁciency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average sur-vival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43–75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18–51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identiﬁed in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in ﬁve of six patients. Marked variability in cognitive deﬁcits was observed, but the majority of patients (89%) developed signiﬁcant cog-nitive deﬁcit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifest-ations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA main-tenance methyltransferase lead to selective central and peripheral neurodegeneration.