Keivan Kaveh Moghadam1, Fabio Pizza2, Caterina Tonon3, Raffaele Lodi3, Valerio Carelli2, Francesca Poli2, Christian Franceschini4, Piero Barboni5, Marco Seri6, Simona Ferrari6, Chiara La Morgia2, Claudia Testa3, Ferdinando Cornelio7, Rocco Liguori2, Juliane Winkelmann8, Ling Lin9, Emmanuel Mignot9, Giuseppe Plazzi10. 1. DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy. 2. DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. 3. Functional MR Unit, DIBINEM Alma Mater Studiorum, University of Bologna, Bologna, Italy. 4. Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. 5. Studio Oculistico d'Azeglio, Bologna, Italy. 6. Medical Genetics Unit, Policlinico Sant'Orsola-Malpighi, DIMEC Alma Mater Studiorum, University of Bologna, Bologna, Italy. 7. IRCCS, Istituto Nazionale Neurologico C. Besta, Milan, Italy. 8. 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. 9. Center for Sleep Sciences and Medicine, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA. 10. DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy. Electronic address: giuseppe.plazzi@unibo.it.
Abstract
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.
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.