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Creutzfeldt–Jakob disease with homozygous M232R mutation: A case report
Journal of the Neurological Sciences 352 (2015) 108–109
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Creutzfeldt–Jakob disease with homozygous M232R mutation: A case report Keywords: Creutzfeldt–Jakob disease Homozygous mutation M232R Polymorphism Prion protein gene Substitution
1. Introduction Creutzfeldt–Jakob disease (CJD) is a fatal neurodegenerative disease characterized by accumulation of an abnormal isoform of prion protein. More than 30 polymorphisms and mutations of the prion protein gene (PRNP) are involved in the development of genetic CJD [1]. A substitution from methionine to arginine at the PRNP codon 232 (M232R) is the fourth most frequent mutation in Japanese genetic prion disease (approximately 15%) [2]. However, the pathogenic roles of M232R substitution for CJD have been controversial [3], and all reported CJD patients with M232R mutation carry the heterozygous substitution [2]. Here, we describe the first CJD patient with homozygous M232R mutation, and our observations suggest pathogenicity of the mutation for CJD. 2. Case report A 50-year-old Japanese woman visited our outpatient clinic after a 2-month history of rapidly progressive dementia, and gait disturbance. She became bedridden, akinetic and mute in the following month. She had no past medical or family history, and no records of overseas traveling. Upon neurological examination, myoclonus was observed in her four extremities. 14-3-3 protein (2690 μg/ml, normal range
b500 μg/ml), total-tau protein (12,690 pg, normal range b1300 pg/ml) and neuron-specific enolase levels (42.7 ng/ml, normal range b12 ng/ml) were elevated in cerebrospinal fluid. Brain MRI demonstrated hyperintensity on diffusion-weighted imaging and fluid-attenuated inversion recovery, and hypointensity on apparent diffusion coefficient map in the bilateral cerebral cortex and the striatum (Fig. 1A–C). Typical periodic sharp-wave complexes were observed in EEG. She was clinically diagnosed with CJD. Genetic analysis of PRNP revealed a homozygous substitution from ATG (methionine) to AGG (arginine) at codon 232, a homozygous methionine at codon 129, and a homozygous glutamate at codon 219. She died of pneumonia 7 months after the onset of the disease. Autopsy could not be obtained. There are two clinical phenotypes; rapid- and slow-type, among heterozygous M232R CJD patients [4]. Our patient could be classified as rapid-type. Additionally, the onset age of our patient (50-year-old) was earlier and the disease duration (7 months) was shorter than CJD patients with heterozygous M232R mutation [4,5] (Table 1). 3. Discussion We described the first CJD patient with homozygous M232R mutation. Although postmortem examination could not be performed, the clinical features indicated the diagnosis of probable CJD [6] and definite CJD according to the MRI criteria [7]. The pathogenic roles of the M232R mutation for CJD have been controversial since not all patients with the heterozygous mutation develop CJD [3]. Indeed, Koide et al. reported an autopsy case of Lewy body dementia with the heterozygous M232R mutation [8]. However, etiological studies have shown that the heterozygous M232R mutation is identified significantly more in patients with CJD than the general Japanese population [2,9]. In addition, homozygous M232R mutation has not been found in patients with CJD and in the general Japanese population [2,9]. Thus, our patient is the firstly demonstrated case with homozygous M232R mutation. Previous evidence indicates that the heterozygous M232R mutation has a propensity for CJD development [2,4]. Firstly, the fact that a patient with the
Fig. 1. Brain MRI showing hyperintensity on diffusion weighted image (A) and fluid-attenuated inversion recovery (B), hypointensity on apparent diffusion coefficient map (C) in the bilateral cortex, the caudate and the putamen.
http://dx.doi.org/10.1016/j.jns.2015.03.017 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Letter to the Editor
109
Table 1 Clinical characteristics of the present case with homozygous M232R mutations and previously reported CJD with heterozygous M232R mutation (rapid- and slow-type). Present case Age at onset (year-old) Sex Family history Initial symptoms
50 Female None Progressive dementia Gait disturbance
From onset to akinetic mutism (month) From onset to death (month) Codon 129
3 7 Met/Met
Codon 219
Glu/Glu
Rapid-type (N = 17) [4,5]
Slow-type (N = 7) [4,5]
65.4 ± 5.2 [4] 9; male, 8; female None 9; progressive dementia 2; visual symptoms 2; cerebellar ataxia 2; involuntary movement 2; others 3.1 ± 1.5 [4] 16.2 ± 7.9 [5] 16; Met/Met 1; not available 15; Glu/Glu 1; Glu/Lys 1; not available
59.0 ± 12.8 [4] 4; male, 3; female None 4; progressive dementia 2; psychiatric symptoms 1; dressing apraxia
20.6 ± 4.4 [4] 21 ± 15.1 [5] 7; Met/Met 7; Glu/Glu
homozygous mutations developed probable CJD suggests that the mutation may exhibit a pathogenic relevance to CJD. Secondly, in the homozygous M232R patient, the onset was earlier and the clinical progression was more rapid, compared with CJD patients with the heterozygous M232R mutation [4,5]. Thus, the homozygous mutation possibly accelerates disease onset or progression. Taken together, this case report supports the hypothesis that the M232R mutation may be pathogenic for CJD.
Tomoya Kon⁎ Yasuo Miki Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan ⁎Corresponding author at: 2-1-1 Higashi-Tsukurimichi, Aomori 0308553, Japan. Tel.: +81 17 726 8111; fax: +81 17 726 8325. E-mail address: [email protected] (T. Kon).
Conflict of interest
Akira Arai Yukihisa Funamizu Tatsuya Ueno Rie Haga Haruo Nishijima Chieko Suzuki Jin-ichi Nunomura Masayuki Baba Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan
The authors declare that they have no conflicts of interest. References [1] Mead S. Prion disease genetics. Eur J Hum Genet 2006;14:273–81. [2] Nozaki I, Hamaguchi T, Sanjo N, Noguchi-Shinohara M, Sakai K, Nakamura Y, et al. Prospective 10-year surveillance of human prion diseases in Japan. Brain 2010;133: 3043–57. [3] Beck J, Collinge J, Mead S. Prion protein gene M232R variation is probably an uncommon polymorphism rather than a pathogenic mutation. Brain 2012;135: e209 [author reply e10]. [4] Shiga Y, Satoh K, Kitamoto T, Kanno S, Nakashima I, Sato S, et al. Two different clinical phenotypes of Creutzfeldt–Jakob disease with a M232R substitution. J Neurol 2007; 254:1509–17. [5] Iwasaki Y, Yokoi F, Tatsumi S, Mimuro M, Iwai K, Kitamoto T, et al. An autopsied case of Creutzfeldt–Jakob disease with mutation in the prion protein gene codon 232 and type 1 + 2 prion protein. Neuropathology 2013;33:568–75. [6] Masters CL, Harris JO, Gajdusek DC, Gibbs Jr CJ, Bernoulli C, Asher DM. Creutzfeldt– Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 1979;5:177–88. [7] Vitali P, Maccagnano E, Caverzasi E, Henry RG, Haman A, Torres-Chae C, et al. Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias. Neurology 2011;76:1711–9. [8] Koide T, Ohtake H, Nakajima T, Furukawa H, Sakai K, Kamei H, et al. A patient with dementia with Lewy bodies and codon 232 mutation of PRNP. Neurology 2002;59: 1619–21. [9] Hoque MZ, Kitamoto T, Furukawa H, Muramoto T, Tateishi J. Mutation in the prion protein gene at codon 232 in Japanese patients with Creutzfeldt–Jakob disease: a clinicopathological, immunohistochemical and transmission study. Acta Neuropathol 1996;92:441–6.
Yoshinobu Oyama Department of Neurology, Aomori Hospital, Aomori, Japan Yusei Shiga Aoba Neurosurgical Clinic, Sendai, Japan Tetsuyuki Kitamoto Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan Masahiko Tomiyama Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan 31 December 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Creutzfeldt–Jakob disease with homozygous M232R mutation: A case report Keywords: Creutzfeldt–Jakob disease Homozygous mutation M232R Polymorphism Prion protein gene Substitution
1. Introduction Creutzfeldt–Jakob disease (CJD) is a fatal neurodegenerative disease characterized by accumulation of an abnormal isoform of prion protein. More than 30 polymorphisms and mutations of the prion protein gene (PRNP) are involved in the development of genetic CJD [1]. A substitution from methionine to arginine at the PRNP codon 232 (M232R) is the fourth most frequent mutation in Japanese genetic prion disease (approximately 15%) [2]. However, the pathogenic roles of M232R substitution for CJD have been controversial [3], and all reported CJD patients with M232R mutation carry the heterozygous substitution [2]. Here, we describe the first CJD patient with homozygous M232R mutation, and our observations suggest pathogenicity of the mutation for CJD. 2. Case report A 50-year-old Japanese woman visited our outpatient clinic after a 2-month history of rapidly progressive dementia, and gait disturbance. She became bedridden, akinetic and mute in the following month. She had no past medical or family history, and no records of overseas traveling. Upon neurological examination, myoclonus was observed in her four extremities. 14-3-3 protein (2690 μg/ml, normal range
b500 μg/ml), total-tau protein (12,690 pg, normal range b1300 pg/ml) and neuron-specific enolase levels (42.7 ng/ml, normal range b12 ng/ml) were elevated in cerebrospinal fluid. Brain MRI demonstrated hyperintensity on diffusion-weighted imaging and fluid-attenuated inversion recovery, and hypointensity on apparent diffusion coefficient map in the bilateral cerebral cortex and the striatum (Fig. 1A–C). Typical periodic sharp-wave complexes were observed in EEG. She was clinically diagnosed with CJD. Genetic analysis of PRNP revealed a homozygous substitution from ATG (methionine) to AGG (arginine) at codon 232, a homozygous methionine at codon 129, and a homozygous glutamate at codon 219. She died of pneumonia 7 months after the onset of the disease. Autopsy could not be obtained. There are two clinical phenotypes; rapid- and slow-type, among heterozygous M232R CJD patients [4]. Our patient could be classified as rapid-type. Additionally, the onset age of our patient (50-year-old) was earlier and the disease duration (7 months) was shorter than CJD patients with heterozygous M232R mutation [4,5] (Table 1). 3. Discussion We described the first CJD patient with homozygous M232R mutation. Although postmortem examination could not be performed, the clinical features indicated the diagnosis of probable CJD [6] and definite CJD according to the MRI criteria [7]. The pathogenic roles of the M232R mutation for CJD have been controversial since not all patients with the heterozygous mutation develop CJD [3]. Indeed, Koide et al. reported an autopsy case of Lewy body dementia with the heterozygous M232R mutation [8]. However, etiological studies have shown that the heterozygous M232R mutation is identified significantly more in patients with CJD than the general Japanese population [2,9]. In addition, homozygous M232R mutation has not been found in patients with CJD and in the general Japanese population [2,9]. Thus, our patient is the firstly demonstrated case with homozygous M232R mutation. Previous evidence indicates that the heterozygous M232R mutation has a propensity for CJD development [2,4]. Firstly, the fact that a patient with the
Fig. 1. Brain MRI showing hyperintensity on diffusion weighted image (A) and fluid-attenuated inversion recovery (B), hypointensity on apparent diffusion coefficient map (C) in the bilateral cortex, the caudate and the putamen.
http://dx.doi.org/10.1016/j.jns.2015.03.017 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Letter to the Editor
109
Table 1 Clinical characteristics of the present case with homozygous M232R mutations and previously reported CJD with heterozygous M232R mutation (rapid- and slow-type). Present case Age at onset (year-old) Sex Family history Initial symptoms
50 Female None Progressive dementia Gait disturbance
From onset to akinetic mutism (month) From onset to death (month) Codon 129
3 7 Met/Met
Codon 219
Glu/Glu
Rapid-type (N = 17) [4,5]
Slow-type (N = 7) [4,5]
65.4 ± 5.2 [4] 9; male, 8; female None 9; progressive dementia 2; visual symptoms 2; cerebellar ataxia 2; involuntary movement 2; others 3.1 ± 1.5 [4] 16.2 ± 7.9 [5] 16; Met/Met 1; not available 15; Glu/Glu 1; Glu/Lys 1; not available
59.0 ± 12.8 [4] 4; male, 3; female None 4; progressive dementia 2; psychiatric symptoms 1; dressing apraxia
20.6 ± 4.4 [4] 21 ± 15.1 [5] 7; Met/Met 7; Glu/Glu
homozygous mutations developed probable CJD suggests that the mutation may exhibit a pathogenic relevance to CJD. Secondly, in the homozygous M232R patient, the onset was earlier and the clinical progression was more rapid, compared with CJD patients with the heterozygous M232R mutation [4,5]. Thus, the homozygous mutation possibly accelerates disease onset or progression. Taken together, this case report supports the hypothesis that the M232R mutation may be pathogenic for CJD.
Tomoya Kon⁎ Yasuo Miki Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan ⁎Corresponding author at: 2-1-1 Higashi-Tsukurimichi, Aomori 0308553, Japan. Tel.: +81 17 726 8111; fax: +81 17 726 8325. E-mail address: [email protected] (T. Kon).
Conflict of interest
Akira Arai Yukihisa Funamizu Tatsuya Ueno Rie Haga Haruo Nishijima Chieko Suzuki Jin-ichi Nunomura Masayuki Baba Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan
The authors declare that they have no conflicts of interest. References [1] Mead S. Prion disease genetics. Eur J Hum Genet 2006;14:273–81. [2] Nozaki I, Hamaguchi T, Sanjo N, Noguchi-Shinohara M, Sakai K, Nakamura Y, et al. Prospective 10-year surveillance of human prion diseases in Japan. Brain 2010;133: 3043–57. [3] Beck J, Collinge J, Mead S. Prion protein gene M232R variation is probably an uncommon polymorphism rather than a pathogenic mutation. Brain 2012;135: e209 [author reply e10]. [4] Shiga Y, Satoh K, Kitamoto T, Kanno S, Nakashima I, Sato S, et al. Two different clinical phenotypes of Creutzfeldt–Jakob disease with a M232R substitution. J Neurol 2007; 254:1509–17. [5] Iwasaki Y, Yokoi F, Tatsumi S, Mimuro M, Iwai K, Kitamoto T, et al. An autopsied case of Creutzfeldt–Jakob disease with mutation in the prion protein gene codon 232 and type 1 + 2 prion protein. Neuropathology 2013;33:568–75. [6] Masters CL, Harris JO, Gajdusek DC, Gibbs Jr CJ, Bernoulli C, Asher DM. Creutzfeldt– Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 1979;5:177–88. [7] Vitali P, Maccagnano E, Caverzasi E, Henry RG, Haman A, Torres-Chae C, et al. Diffusion-weighted MRI hyperintensity patterns differentiate CJD from other rapid dementias. Neurology 2011;76:1711–9. [8] Koide T, Ohtake H, Nakajima T, Furukawa H, Sakai K, Kamei H, et al. A patient with dementia with Lewy bodies and codon 232 mutation of PRNP. Neurology 2002;59: 1619–21. [9] Hoque MZ, Kitamoto T, Furukawa H, Muramoto T, Tateishi J. Mutation in the prion protein gene at codon 232 in Japanese patients with Creutzfeldt–Jakob disease: a clinicopathological, immunohistochemical and transmission study. Acta Neuropathol 1996;92:441–6.
Yoshinobu Oyama Department of Neurology, Aomori Hospital, Aomori, Japan Yusei Shiga Aoba Neurosurgical Clinic, Sendai, Japan Tetsuyuki Kitamoto Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Japan Masahiko Tomiyama Department of Neurology, Aomori Prefectural Central Hospital, Aomori, Japan 31 December 2014