Narcolepsy is a common phenotype in HSAN IE and ADCA-DN

Keivan Kaveh Moghadam, Fabio Pizza, Chiara La Morgia, Christian Franceschini, Caterina Tonon, Raffaele Lodi, Piero Barboni, Marco Seri, Simona Ferrari, Rocco Liguori, Vincenzo Donadio, Piero Parchi, Ferdinando Cornelio, Domenico Inzitari, Andrea Mignarri, Giuseppe Capocchi, Maria Teresa Dotti, Juliane Winkelmann, Ling Lin, Emmanuel MignotValerio Carelli, Giuseppe Plazzi

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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.

Original languageEnglish
Pages (from-to)1643-1655
Number of pages13
Issue number6
StatePublished - Jun 2014


  • DNMT1
  • cataplexy
  • narcolepsy
  • neurodegeneration


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