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.

Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E

“…9 It has been suggested that these two adult-onset neurodegenerative disorders can be considered in the differential of each other as HSAN1E and ADCA-DN patients may share a similar set of phenotypes with varied severity and onset age. 10 More HSAN1E families have been recognized and a hot spot mutation at amino acid 495 was identified as Y495C mutation is the most common causal mutation found among HSAN1E patients. 8,11 The DNMT1 Y495C mutation leads to DNMT1 protein misfolding and decreased enzymatic activity.…”

Dna Methyltransferase 1 Mutations and Mitochondrial Pathology: Is Mtdna Methylated?

“…Two other HSN1E families has been described in 2014, presenting mutations in exon 20 of DNMT1 : one point mutation (p.Pro506Arg, NP_001124295.1) hitting the same amino acid position of another previously reported case (Klein et al, 2011), and a novel trinucleotide deletion (p.Lys521del, NP_001124295.1; Moghadam et al, 2014). The extensive characterization of the HSN1E patients in this latter study showed that subclinical symptoms usually characterizing ADCA-DN, such as NC (without cataplexy and with normal hypocretin-1 level in cerebrospinal fluid) and optic atrophy, may be present in patients affected by HSN1E, highlighting aphenotypic overlap between these two diseases (Moghadam et al, 2014). …”

“…Shortly after, another adult-onset neurodegenerative disease, ADCA-DN (OMIM 604121), has been associated to mutations in DNMT1 located in the same functional domain (Winkelmann et al, 2012). HSN1E and ADCA-DN have been initially considered as two distinct clinical entities, but more recently the evidence of overlapping clinical features, often subclinical, has emerged, strongly suggesting that they can be better considered as phenotypes belonging to the same neurodegenerative spectrum (Moghadam et al, 2014). …”

“…ADCA-DN is initially characterized by late-onset NC with or without cataplexy, complicated in later stages of the disease by sensorineural deafness, cerebellar ataxia, and dementia appear (Melberg et al, 1995). Mild polyneuropathy, optic atrophy, epilepsy, psychosis, diabetes mellitus, cardiomyopathy, and progressive cerebral, cerebellar, and brainstem atrophy may also be present (Melberg et al, 1999; Winkelmann et al, 2012; Moghadam et al, 2014). DNMT1 mutations in exon 21 have been found to cause ADCA-DN (Winkelmann et al, 2012), thus qualifying DNMT1 as the third mutant leading to genetically determined NC (Peyron et al, 2000; Hor et al, 2011).…”

Medical Management of Hereditary Optic Neuropathies

“…(2)] such as OPA1 “plus” syndrome (3), mitochondrial encephalomyopathy lactic acidosis and stroke-like syndrome (MELAS) (4), LHON/dystonia/MELAS/Leigh overlapping syndrome (5, 6), myoclonic epilepsy with ragged red fibers (MERRF) (7), POLG1-related syndrome (8), Friedreich ataxia (9), Charcot–Marie Tooth type 2A (10), Mohr–Tranebjerg syndrome (11), SPG7 syndrome (12), Wolfram syndrome (13), spinocerebellar ataxias (14), and DNMT1-related disorders (15). …”