Sleep Medicine 15 (2014) 582–585
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
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 Keivan Kaveh Moghadam a, Fabio Pizza a,b, Caterina Tonon c, Raffaele Lodi c, Valerio Carelli a,b, Francesca Poli a,b, Christian Franceschini d, Piero Barboni e, Marco Seri f, Simona Ferrari f, Chiara La Morgia a,b, Claudia Testa c, Ferdinando Cornelio g, Rocco Liguori a,b, Juliane Winkelmann h,i, Ling Lin i, Emmanuel Mignot i, Giuseppe Plazzi a,b,⇑ a
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy Functional MR Unit, DIBINEM Alma Mater Studiorum, University of Bologna, Bologna, Italy d Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy e Studio Oculistico d’Azeglio, Bologna, Italy f Medical Genetics Unit, Policlinico Sant’Orsola-Malpighi, DIMEC Alma Mater Studiorum, University of Bologna, Bologna, Italy g IRCCS, Istituto Nazionale Neurologico C. Besta, Milan, Italy h Institute of Human Genetics and Department of Neurology, Technische Universitat Munchen, Munich, Germany i Center for Sleep Sciences and Medicine, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA b c
a r t i c l e
i n f o
Article history: Received 9 July 2013 Received in revised form 19 September 2013 Accepted 22 September 2013 Available online 12 February 2014 Keywords: ADCA-DN DNMT1 Narcolepsy MSLT MR spectroscopy Genetic Neurodegeneration
a b s t r a c t 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. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) syndrome (OMIM 604121) is a neurodegenerative disease first reported in a Swedish family [1], recognized worldwide in only five further pedigrees [2,3]. The disease is transmitted as an autosomal dominant trait and is characterized ⇑ Corresponding author. Address: Ospedale Bellaria Pad, G1-via Altura 3, 40139 Bologna, Italy. Tel.: +39 0514966926; fax: +39 0514966098. E-mail address: [email protected] (G. Plazzi). http://dx.doi.org/10.1016/j.sleep.2013.09.028 1389-9457/Ó 2014 Elsevier B.V. All rights reserved.
mainly by cerebellar syndrome, hearing loss, and narcolepsy with cataplexy (NC) symptoms, namely excessive daytime sleepiness with sleep-onset rapid eye movement periods (SOREMPs) (i.e., rapid eye movement sleep occurring within 15 min from sleep onset), cataplexy, hypnagogic hallucinations, sleep paralysis, and nocturnal sleep disruption. Patients also may develop optic atrophy, psychiatric features, dementia, extrapyramidal, pyramidal and dysautonomic signs, polyneuropathy, diabetes mellitus, cardiomyopathy, lower limbs lymphedema, and epilepsy [1–4]. The disease has been recently associated with pathogenic mutations affecting exon 21 of the
583
K.K. Moghadam et al. / Sleep Medicine 15 (2014) 582–585
novo mutation at the exon 21 of the DNMT1 gene (Fig. 1). Both subjects underwent presymptomatic genetic counseling according to the Italian guidelines and genetic testing through molecular analysis for the identification of the causative mutation using Sanger sequencing of exon 21 of the DNMT1 gene, HLA typing, 48 h continuous video-polysomnography (vPSG) (24 h for adaptation and 24 h for diagnostic purposes), followed by multiple sleep latency test (MSLT), audiometry, dilated fundus eye examination, retinal optical coherence tomography scan, pattern visual evoked potentials, and conventional brain MRI with proton MR spectroscopy (1H-MRS) studies. The study was approved by local institutional review board and all subjects signed a written informed consent. 3. Results
Fig. 1. Autosomal dominant cerebellar ataxia, deafness, and narcolepsy kindred tree. Age at the time of the study is reported next to each symbol in years. The black symbol indicates the affected individual (proband) and split symbols indicate asymptomatic carriers.
DNA (cytosine-5-)-methyltransferase gene, DNMT1, located on chromosome 19 [2]. Age at onset can be variable, but the full-blown clinical picture usually develops in the fourth or fifth decades of life, with NC and deafness as the presenting symptoms [1–3]. We performed genetic studies, neurophysiologic assessments, and advanced brain magnetic resonance imaging (MRI) scans in two young asymptomatic daughters of a recently reported Italian patient with ADCA-DN [2]. 2. Methods Clinical assessment was performed in two asymptomatic young daughters (III-1 and III-2) of a patient with ADCA-DN due to a de
The two subjects were 28 and 23 years of age, respectively. (III-1 and III-2). Their father (II-1) was a 57-year-old man with NC progressively complicated by a wider involvement of the central and peripheral nervous system since the age of 42 years (Table 1). Given the clinical overlap with previously described cases and the detection of the pathogenic DNMT1 gene mutation [2], ADCA-DN was diagnosed. None of the other family members are clinically affected (Fig. 1); however, DNA sequencing in both daughters revealed the same mutation on exon 21 of the DNMT1 gene–p.Ala570Val (RefSeq NM_001130823.1: c.1709G.A). Both III-1 and III-2 subjects did not report any sleep or neurologic symptoms, but they did report the presence of polycystic ovary syndrome. Neurological, ophthalmological and audiometric examinations revealed no abnormalities. The HLA DQB106:02 allele, typically associated with NC, was absent in both daughters. Ad libitum 48-h continuous vPSG showed a long-lasting sleep episode (up to 275 and 243 min, respectively) during the daytime, with a SOREMP in III-2, a nocturnal SOREMP in III-1, and periodic
Table 1 Clinical and instrumental data. II-1
III-1
III-2
Age at time of study (y)
57
28
23
Clinical data (onset age) Gender Excessive daytime sleepiness Cataplexy Hypnagogic hallucinations Sleep paralysis RBD Hearing loss Cerebellar ataxia Optic atrophy Lower limbs edema Sensory neuropathy Depression Pyramidal signs Extrapyramidal signs Dysautonomic signs
M 42 42 No No 49 43 46 55 45 47 48 53 56 52
W No No No No No No No No No No No No No No
W No No No No No No No No No No No No No No
p.Ala570Val 16 Negative 123
p.Ala570Val 4 Negative na
p.Ala570Val 7 Negative na
539 Bilateral sensorineural deafness Abnormal (both eyes) Abnormal (both eyes)
na Normal Normal Normal
na Normal Normal Normal
Objective tests DNMT1 gene mutation Epworth sleepiness scale (cutoff score of
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Original Article
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 Keivan Kaveh Moghadam a, Fabio Pizza a,b, Caterina Tonon c, Raffaele Lodi c, Valerio Carelli a,b, Francesca Poli a,b, Christian Franceschini d, Piero Barboni e, Marco Seri f, Simona Ferrari f, Chiara La Morgia a,b, Claudia Testa c, Ferdinando Cornelio g, Rocco Liguori a,b, Juliane Winkelmann h,i, Ling Lin i, Emmanuel Mignot i, Giuseppe Plazzi a,b,⇑ a
DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy Functional MR Unit, DIBINEM Alma Mater Studiorum, University of Bologna, Bologna, Italy d Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy e Studio Oculistico d’Azeglio, Bologna, Italy f Medical Genetics Unit, Policlinico Sant’Orsola-Malpighi, DIMEC Alma Mater Studiorum, University of Bologna, Bologna, Italy g IRCCS, Istituto Nazionale Neurologico C. Besta, Milan, Italy h Institute of Human Genetics and Department of Neurology, Technische Universitat Munchen, Munich, Germany i Center for Sleep Sciences and Medicine, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, CA, USA b c
a r t i c l e
i n f o
Article history: Received 9 July 2013 Received in revised form 19 September 2013 Accepted 22 September 2013 Available online 12 February 2014 Keywords: ADCA-DN DNMT1 Narcolepsy MSLT MR spectroscopy Genetic Neurodegeneration
a b s t r a c t 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. Ó 2014 Elsevier B.V. All rights reserved.
1. Introduction Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) syndrome (OMIM 604121) is a neurodegenerative disease first reported in a Swedish family [1], recognized worldwide in only five further pedigrees [2,3]. The disease is transmitted as an autosomal dominant trait and is characterized ⇑ Corresponding author. Address: Ospedale Bellaria Pad, G1-via Altura 3, 40139 Bologna, Italy. Tel.: +39 0514966926; fax: +39 0514966098. E-mail address: [email protected] (G. Plazzi). http://dx.doi.org/10.1016/j.sleep.2013.09.028 1389-9457/Ó 2014 Elsevier B.V. All rights reserved.
mainly by cerebellar syndrome, hearing loss, and narcolepsy with cataplexy (NC) symptoms, namely excessive daytime sleepiness with sleep-onset rapid eye movement periods (SOREMPs) (i.e., rapid eye movement sleep occurring within 15 min from sleep onset), cataplexy, hypnagogic hallucinations, sleep paralysis, and nocturnal sleep disruption. Patients also may develop optic atrophy, psychiatric features, dementia, extrapyramidal, pyramidal and dysautonomic signs, polyneuropathy, diabetes mellitus, cardiomyopathy, lower limbs lymphedema, and epilepsy [1–4]. The disease has been recently associated with pathogenic mutations affecting exon 21 of the
583
K.K. Moghadam et al. / Sleep Medicine 15 (2014) 582–585
novo mutation at the exon 21 of the DNMT1 gene (Fig. 1). Both subjects underwent presymptomatic genetic counseling according to the Italian guidelines and genetic testing through molecular analysis for the identification of the causative mutation using Sanger sequencing of exon 21 of the DNMT1 gene, HLA typing, 48 h continuous video-polysomnography (vPSG) (24 h for adaptation and 24 h for diagnostic purposes), followed by multiple sleep latency test (MSLT), audiometry, dilated fundus eye examination, retinal optical coherence tomography scan, pattern visual evoked potentials, and conventional brain MRI with proton MR spectroscopy (1H-MRS) studies. The study was approved by local institutional review board and all subjects signed a written informed consent. 3. Results
Fig. 1. Autosomal dominant cerebellar ataxia, deafness, and narcolepsy kindred tree. Age at the time of the study is reported next to each symbol in years. The black symbol indicates the affected individual (proband) and split symbols indicate asymptomatic carriers.
DNA (cytosine-5-)-methyltransferase gene, DNMT1, located on chromosome 19 [2]. Age at onset can be variable, but the full-blown clinical picture usually develops in the fourth or fifth decades of life, with NC and deafness as the presenting symptoms [1–3]. We performed genetic studies, neurophysiologic assessments, and advanced brain magnetic resonance imaging (MRI) scans in two young asymptomatic daughters of a recently reported Italian patient with ADCA-DN [2]. 2. Methods Clinical assessment was performed in two asymptomatic young daughters (III-1 and III-2) of a patient with ADCA-DN due to a de
The two subjects were 28 and 23 years of age, respectively. (III-1 and III-2). Their father (II-1) was a 57-year-old man with NC progressively complicated by a wider involvement of the central and peripheral nervous system since the age of 42 years (Table 1). Given the clinical overlap with previously described cases and the detection of the pathogenic DNMT1 gene mutation [2], ADCA-DN was diagnosed. None of the other family members are clinically affected (Fig. 1); however, DNA sequencing in both daughters revealed the same mutation on exon 21 of the DNMT1 gene–p.Ala570Val (RefSeq NM_001130823.1: c.1709G.A). Both III-1 and III-2 subjects did not report any sleep or neurologic symptoms, but they did report the presence of polycystic ovary syndrome. Neurological, ophthalmological and audiometric examinations revealed no abnormalities. The HLA DQB106:02 allele, typically associated with NC, was absent in both daughters. Ad libitum 48-h continuous vPSG showed a long-lasting sleep episode (up to 275 and 243 min, respectively) during the daytime, with a SOREMP in III-2, a nocturnal SOREMP in III-1, and periodic
Table 1 Clinical and instrumental data. II-1
III-1
III-2
Age at time of study (y)
57
28
23
Clinical data (onset age) Gender Excessive daytime sleepiness Cataplexy Hypnagogic hallucinations Sleep paralysis RBD Hearing loss Cerebellar ataxia Optic atrophy Lower limbs edema Sensory neuropathy Depression Pyramidal signs Extrapyramidal signs Dysautonomic signs
M 42 42 No No 49 43 46 55 45 47 48 53 56 52
W No No No No No No No No No No No No No No
W No No No No No No No No No No No No No No
p.Ala570Val 16 Negative 123
p.Ala570Val 4 Negative na
p.Ala570Val 7 Negative na
539 Bilateral sensorineural deafness Abnormal (both eyes) Abnormal (both eyes)
na Normal Normal Normal
na Normal Normal Normal
Objective tests DNMT1 gene mutation Epworth sleepiness scale (cutoff score of
