Polysomnographic and neurometabolic features may mark preclinical autosomal dominant cerebellar ataxia, deafness, and narcolepsy due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.
OBJECTIVE
We aimed to report the clinical picture of two asymptomatic daughters of a patient with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.


METHODS
Clinical assessment based on history, neurologic examination, sleep recordings, neurophysiologic neuroimaging, and genetic tests was performed.


RESULTS
History and neurologic examination in both subjects were unremarkable. Genetic analysis disclosed in both the paternally-inherited heterozygous point mutation in the DNMT1 gene. Sleep recordings found sleep-onset rapid eye movement periods (SOREMPs) and proton magnetic resonance spectroscopy (MRS) revealed increased cerebellar myoinositol (mI) in both subjects. Auditory and ophthalmologic investigations as well as structural brain magnetic resonance imaging (MRI) scans revealed no abnormalities.


CONCLUSIONS
The two asymptomatic carriers of the heterozygous DNMT1 mutation for ADCA-DN, a late-onset neurodegenerative disease, presented with SOREMPs associated with an increase of mI in the brain, a marker of glial cell activity and density characteristic of early stages of neurodegenerative diseases. Therefore, SOREMPs may precede the clinical picture of ADCA-DN as an early polysomnographic marker of central nervous system involvement detected by MRS.
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Keivan Kaveh
KK
Moghadam
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.
Fabio
F
Pizza
Functional MR Unit, DIBINEM Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Caterina
C
Tonon
Functional MR Unit, DIBINEM Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Raffaele
R
Lodi
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.
Valerio
V
Carelli
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.
Francesca
F
Poli
Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
Christian
C
Franceschini
Studio Oculistico d'Azeglio, Bologna, Italy.
Piero
P
Barboni
Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, DIMEC Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Marco
M
Seri
Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, DIMEC Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Simona
S
Ferrari
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.
Chiara
C
La Morgia
Functional MR Unit, DIBINEM Alma Mater Studiorum, University of Bologna, Bologna, Italy.
Claudia
C
Testa
IRCCS, Istituto Nazionale Neurologico C. Besta, Milan, Italy.
Ferdinando
F
Cornelio
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy.
Rocco
R
Liguori
Institute of Human Genetics and Department of Neurology, Technische Universitat Munchen, Munich, Germany; Center for Sleep Sciences and Medicine, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA.
Juliane
J
Winkelmann
Center for Sleep Sciences and Medicine, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA.
Ling
L
Lin
Center for Sleep Sciences and Medicine, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA.
Emmanuel
E
Mignot
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. Electronic address: giuseppe.plazzi@unibo.it.
Giuseppe
G
Plazzi
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058070:Asymptomatic Diseases; D001921:Brain / Q000473:pathology; D002524:Cerebellar Ataxia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D002531:Cerebellum / Q000737:chemistry; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D003638:Deafness / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007294:Inositol / Q000032:analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009290:Narcolepsy / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D059906:Neuroimaging; D010375:Pedigree; D017286:Polysomnography; D066244:Proton Magnetic Resonance Spectroscopy; D012890:Sleep / Q000235:genetics / Q000502:physiology; D055815:Young Adult
D007294:Inositol; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human
ADCA-DN; DNMT1; Genetic; MR spectroscopy; MSLT; Narcolepsy; Neurodegeneration