title: Narcolepsy is a common phenotype in HSAN IE and ADCA-DN.
abstract: We report on the extensive phenotypic characterization of five Italian patients from four unrelated families carrying dominant heterozygous DNMT1 mutations linked to two distinct autosomal dominant diseases: hereditary sensory and autonomic neuropathy with dementia and hearing loss type IE (HSAN IE) and autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). Patients underwent genetic analysis of DNMT1 gene, neurophysiological tests investigating sleep, auditory functions and peripheral nervous system, ophthalmological studies including optical coherence tomography, lymphoscintigraphy, brain magnetic resonance and nuclear imaging, cerebrospinal fluid hypocretin-1, total tau, phosphorylated tau, amyloid-β1-42 and 14-3-3 proteins measurement, skin, muscular and sural nerve biopsies. Exome and direct sequencing studies disclosed two different point mutations affecting exon 21 of DNMT1 gene in patients with ADCA-DN, a novel heterozygous point mutation in exon 20 in two affected HSAN IE siblings, and a trinucleotide deletion in exon 20 in the latter patient with HSAN IE. Phenotypic characterization pinpoints that ADCA-DN and HSAN IE represent two discrete clinical entities belonging to the same disease spectrum, with variable degree of overlap. Remarkably, narcolepsy with or without cataplexy with low/intermediate or normal cerebrospinal fluid hypocretin-1 is present in both diseases. The human leukocyte antigen DQB1*06:02 was absent in all patients. Other common symptoms and features observed in our cases, involving the central and peripheral nervous system, include deafness, optic neuropathy-previously not reported in HSAN IE-large and small fibres polyneuropathy and lower limbs oedema. Overall, the two syndromes share more characteristics than previously recognized and narcolepsy is common to both. HSAN IE and ADCA-DN are two extreme phenotypic manifestations of a DNMT1 methylopathy.
authors.affiliation: 1 Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: Keivan Kaveh
authors.initials: KK
authors.lastname: Moghadam
authors.affiliation: 1 Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy 2 IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, Bologna, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pizza
authors.affiliation: 1 Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy 2 IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: La Morgia
authors.affiliation: 3 Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Franceschini
authors.affiliation: 4 MR Functional Unit, DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Tonon
authors.affiliation: 4 MR Functional Unit, DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lodi
authors.affiliation: 5 Studio Oculistico d'Azeglio, Bologna, Italy 6 Istituto Scientifico San Raffaele, Milano, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.affiliation: 7 Medical Genetics Unit, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: 7 Medical Genetics Unit, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: 1 Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy 2 IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, Bologna, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.affiliation: 2 IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, Bologna, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Donadio
authors.affiliation: 1 Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy 2 IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Parchi
authors.affiliation: 8 Fondazione IRCCS Istituto Nazionale Neurologico Carlo Besta, Milan, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Cornelio
authors.affiliation: 9 NEUROFARBA Department, Neuroscience Section, University of Florence, Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Inzitari
authors.affiliation: 10 Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mignarri
authors.affiliation: 11 Department of Neuroscience, Santa Maria Hospital, Terni, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Capocchi
authors.affiliation: 10 Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Dotti
authors.affiliation: 12 Institute of Human Genetics and Department of Neurology, Technische Universitat Munchen, Munich, Germany13 Centre for Sleep Sciences and Medicine, Department of Psychiatry and Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.affiliation: 13 Centre for Sleep Sciences and Medicine, Department of Psychiatry and Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: 13 Centre for Sleep Sciences and Medicine, Department of Psychiatry and Department of Genetics, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
authors.affiliation: 1 Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy 2 IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, Bologna, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.affiliation: 1 Department of Biomedical and Neuromotor Sciences (DIBINEM), Alma Mater Studiorum, University of Bologna, Bologna, Italy 2 IRCCS Istituto delle Scienze Neurologiche di Bologna, AUSL di Bologna, Bologna, Italy giuseppe.plazzi@unibo.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Plazzi
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics; D000328:Adult; D003638:Deafness / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009290:Narcolepsy / Q000175:diagnosis / Q000235:genetics*; D009849:Olivopontocerebellar Atrophies / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D048948:14-3-3 Proteins
keywords: ADCA-DN; DNMT1; HSAN IE; cataplexy; narcolepsy; neurodegeneration