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A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease
Parkinsonism and Related Disorders xxx (2016) 1e3
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Correspondence
A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease
Keywords: Parkinson's disease CHCHD2 Depression
Parkinson's disease (PD) is the second most common neurodegenerative disorder, following Alzheimer's disease. Robust genetic analyses have revealed pathogenic mutations in hereditary PD [1]. Recently, our group reported coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) mutations, located in 7p11.2 (OMIM#617710), detected from a large pedigree with autosomal dominant inheritance [2]. Following this, we identified three patients with PD with autosomal dominant inheritance (ADPD) in our Juntendo PD DNA bank. These patients were from Sado Island, which is a small island located in northern Japan with a population of approximately 58,000 (Fig. 1a). We then focused on patients with PD from Sado Island. Eventually, we identified three patients with ADPD and one patient with PD, sporadic form. We screened known pathogenic mutations related to PDdSNCA multiplication, LRRK2 (ex11, 21, 31, and 41), parkin (deletion, multiplication, and missense mutations), as well as CHCHD2 (missense mutations)dusing the Sanger method and MLPA® (Multiplex ligation-dependent probe amplification, MRC“MRC_Holland” is wong. Please change from it to “MRC-Holland”. Holland, Netherlands), and detected that the sporadic PD patient had a novel mutation, CHCHD2 c.23G > A, p.R8H. The other three patients did not show any pathogenic mutations on these screening tests. This study was approved by the ethical committee of the Juntendo University School of Medicine. All participants gave written informed consent. The patient noticed difficulty in writing, resting tremor, and started hesitating at the age of 38 years. She was diagnosed with PD at another hospital, and levodopa/benserazide 200 mg/day and trihexyphenidile were prescribed with good response. After experiencing good health for 15 years, the patient noticed a prominent wearing-off effect. At the age of 56, she frequently fell while walking, and she developed depression. Her symptoms exacerbated with several other medications. After her husband's death, she attempted suicide because of severe depression. She was then admitted to a hospital and treated by psychiatrists for six months. After discharge, her motor symptoms related to parkinsonism continued deteriorating. At the age of 57 years, she was the
admitted to our hospital after referral. The neurological examination did not show any cognitive decline. Her indices were 27/30 in the Mini-Mental State Examination and 17/18 in the frontal assessment battery. She had no hallucinations. Her depression scores indicated improvement: 8/63 in Beck's depression inventory and 8/68 in the Hamilton Rating Scale for Depression-17. She manifested rigidity and resting tremor in the left upper and lower extremities, small voice, masked face, scoliosis to the right side, and unsteady gait with small steps. Hoehn and Yahr staging showed that the stage was III (on) and IV (off). Unified Parkinson's disease rating scale part III was 33/56 (on). She had a good response to levodopa/carbidopa 900 mg, rotigotine 18 mg, and entacapone 300 mg/ day. Brain magnetic resonance imaging showed mild atrophic changes in parietal lobe bilaterally. Dopamine transporter imaging with [123I]-ioflupane showed a severe bilateral reduction in dopamine transporters. She also presented dysautonomia symptoms such as orthostatic hypotension, proven by head-up tilt test and constipation. We detected a novel mutation in CHCHD2, c.23G > A, p.R8H (Fig. 1b). This mutation was located in mitochondrial targeting sequence [2,3]. We confirmed conservation over species by NCBI homolo gene (Fig. 1c). We also confirmed genetic pathogenesis by using mutation taster, PolyPhen-2, and SIFT. These database indicated p.R8H as the disease causing gene and protein deterioration. A search on dbSNP, The human genetic variation database, and ExAc browser showed none of the variants of p.R8H. The uniform resource locator in each website described in supplementary material. A large family with CHCHD2 mutation, located in the northern area in Japan, closer to Sado Island was the first to be reported [2]. Most PD patients with CHCHD2 mutation manifested characteristic features of parkinsonism such as gait disturbance, no appearances of cognitive dysfunctions even after 10 years from disease onset, lesser autonomic dysfunction, and good response to levodopa. These findings are similar to the sporadic form of PD. Our patient also showed no cognitive dysfunction 19 years after disease onset, with good response for levodopa. One marked symptom was severe depression without hallucination or delusion, in addition to autonomic dysfunctions. CHCHD2 p.R8H seems to be one of the pathogenic genes in the gene data base. The inheritance pattern of CHCHD2 mutation may be incomplete or de novo. The rare exonic variants in CHCHD2 are more frequent in PD and Lewy body disease [3]. Although the prevalence of CHCHD2 is low, compared to other pathogenic mutations [4], CHCHD2 mutation also generates the common clinical symptoms similar to sporadic PD. Our findings will expand clinical spectrum of PD patients harboring CHCHD2 mutation.
http://dx.doi.org/10.1016/j.parkreldis.2016.10.018 1353-8020/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: A. Ikeda, et al.A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.10.018
Fig. 1. The map of Sado island, the results of direct sequencing in CHCHD2, and conservation of p.R8H. (a) A map of Japan and Sado Island. Sado Island is located at a latitude of 38 and longitude of 138 , and Tokyo city is located at a latitude of 35 and longitude of 139 . (b) The results of direct sequencing depict c.23G > A, p.R8H in CHCHD2. p.R8H positions are enclosed by the line. (c) Conservation of c.23G > A, p.R8H. Protein homologues were aligned using NCBI homolo gene (http://www.ncbi.nlm.nih.gov/pubmed/). GeneBank accession numbers: Homo sapiens, NP_057223.1; P. troglodytes, XP_001161277.1; M. mulatta, XP_001089512.1; C. lupus familiaris, XP_536830.2; B. taurus, NP_001029918.1; M. musculus, NP_485502.1; R. norvegicus, NP_001015019.1; G. gallus, NP_001006218.1; D. rerio, NP_957061.1; X. tropicalis, NP_001008432.1.
Please cite this article in press as: A. Ikeda, et al.A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.10.018
Correspondence / Parkinsonism and Related Disorders xxx (2016) 1e3
Disclosure The authors report no conflicts of interest relevant to the manuscript. Acknowledgements KN was supported by JSPS KAKENHI Grant Number 2586076 and 16K09678. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2016.10.018. References [1] A. Puschmann, Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations, Park. Relat. Disord. 19 (2013) 407e415. [2] M. Funayama, K. Ohe, T. Amo, N. Furuya, J. Yamaguchi, S. Saiki, et al., CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genomewide linkage and sequencing study, Lancet Neurol. 14 (2015) 274e282. [3] K. Ogaki, S. Koga, M.G. Heckman, F.C. Fiesel, M. Ando, C. Labbe, et al., Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders, Neurology 85 (2015) 2016e2025. [4] I.E. Jansen, J.M. Bras, S. Lesage, C. Schulte, J.R. Gibbs, M.A. Nalls, et al., CHCHD2 and Parkinson's disease, Lancet Neurol. 14 (2015) 678e679.
Aya Ikeda, Takashi Matsushima, Kensuke Daida, Sho Nakajima, Silvio Conedera, Yuanzhe Li Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
3
Hiroyo Yoshino Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan Genko Oyama Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Manabu Funayama Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan Kenya Nishioka Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Nobutaka Hattori* Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan *
Corresponding author. E-mail address: [email protected] (N. Hattori). 4 August 2016
Please cite this article in press as: A. Ikeda, et al.A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.10.018
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Correspondence
A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease
Keywords: Parkinson's disease CHCHD2 Depression
Parkinson's disease (PD) is the second most common neurodegenerative disorder, following Alzheimer's disease. Robust genetic analyses have revealed pathogenic mutations in hereditary PD [1]. Recently, our group reported coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) mutations, located in 7p11.2 (OMIM#617710), detected from a large pedigree with autosomal dominant inheritance [2]. Following this, we identified three patients with PD with autosomal dominant inheritance (ADPD) in our Juntendo PD DNA bank. These patients were from Sado Island, which is a small island located in northern Japan with a population of approximately 58,000 (Fig. 1a). We then focused on patients with PD from Sado Island. Eventually, we identified three patients with ADPD and one patient with PD, sporadic form. We screened known pathogenic mutations related to PDdSNCA multiplication, LRRK2 (ex11, 21, 31, and 41), parkin (deletion, multiplication, and missense mutations), as well as CHCHD2 (missense mutations)dusing the Sanger method and MLPA® (Multiplex ligation-dependent probe amplification, MRC“MRC_Holland” is wong. Please change from it to “MRC-Holland”. Holland, Netherlands), and detected that the sporadic PD patient had a novel mutation, CHCHD2 c.23G > A, p.R8H. The other three patients did not show any pathogenic mutations on these screening tests. This study was approved by the ethical committee of the Juntendo University School of Medicine. All participants gave written informed consent. The patient noticed difficulty in writing, resting tremor, and started hesitating at the age of 38 years. She was diagnosed with PD at another hospital, and levodopa/benserazide 200 mg/day and trihexyphenidile were prescribed with good response. After experiencing good health for 15 years, the patient noticed a prominent wearing-off effect. At the age of 56, she frequently fell while walking, and she developed depression. Her symptoms exacerbated with several other medications. After her husband's death, she attempted suicide because of severe depression. She was then admitted to a hospital and treated by psychiatrists for six months. After discharge, her motor symptoms related to parkinsonism continued deteriorating. At the age of 57 years, she was the
admitted to our hospital after referral. The neurological examination did not show any cognitive decline. Her indices were 27/30 in the Mini-Mental State Examination and 17/18 in the frontal assessment battery. She had no hallucinations. Her depression scores indicated improvement: 8/63 in Beck's depression inventory and 8/68 in the Hamilton Rating Scale for Depression-17. She manifested rigidity and resting tremor in the left upper and lower extremities, small voice, masked face, scoliosis to the right side, and unsteady gait with small steps. Hoehn and Yahr staging showed that the stage was III (on) and IV (off). Unified Parkinson's disease rating scale part III was 33/56 (on). She had a good response to levodopa/carbidopa 900 mg, rotigotine 18 mg, and entacapone 300 mg/ day. Brain magnetic resonance imaging showed mild atrophic changes in parietal lobe bilaterally. Dopamine transporter imaging with [123I]-ioflupane showed a severe bilateral reduction in dopamine transporters. She also presented dysautonomia symptoms such as orthostatic hypotension, proven by head-up tilt test and constipation. We detected a novel mutation in CHCHD2, c.23G > A, p.R8H (Fig. 1b). This mutation was located in mitochondrial targeting sequence [2,3]. We confirmed conservation over species by NCBI homolo gene (Fig. 1c). We also confirmed genetic pathogenesis by using mutation taster, PolyPhen-2, and SIFT. These database indicated p.R8H as the disease causing gene and protein deterioration. A search on dbSNP, The human genetic variation database, and ExAc browser showed none of the variants of p.R8H. The uniform resource locator in each website described in supplementary material. A large family with CHCHD2 mutation, located in the northern area in Japan, closer to Sado Island was the first to be reported [2]. Most PD patients with CHCHD2 mutation manifested characteristic features of parkinsonism such as gait disturbance, no appearances of cognitive dysfunctions even after 10 years from disease onset, lesser autonomic dysfunction, and good response to levodopa. These findings are similar to the sporadic form of PD. Our patient also showed no cognitive dysfunction 19 years after disease onset, with good response for levodopa. One marked symptom was severe depression without hallucination or delusion, in addition to autonomic dysfunctions. CHCHD2 p.R8H seems to be one of the pathogenic genes in the gene data base. The inheritance pattern of CHCHD2 mutation may be incomplete or de novo. The rare exonic variants in CHCHD2 are more frequent in PD and Lewy body disease [3]. Although the prevalence of CHCHD2 is low, compared to other pathogenic mutations [4], CHCHD2 mutation also generates the common clinical symptoms similar to sporadic PD. Our findings will expand clinical spectrum of PD patients harboring CHCHD2 mutation.
http://dx.doi.org/10.1016/j.parkreldis.2016.10.018 1353-8020/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: A. Ikeda, et al.A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.10.018
Fig. 1. The map of Sado island, the results of direct sequencing in CHCHD2, and conservation of p.R8H. (a) A map of Japan and Sado Island. Sado Island is located at a latitude of 38 and longitude of 138 , and Tokyo city is located at a latitude of 35 and longitude of 139 . (b) The results of direct sequencing depict c.23G > A, p.R8H in CHCHD2. p.R8H positions are enclosed by the line. (c) Conservation of c.23G > A, p.R8H. Protein homologues were aligned using NCBI homolo gene (http://www.ncbi.nlm.nih.gov/pubmed/). GeneBank accession numbers: Homo sapiens, NP_057223.1; P. troglodytes, XP_001161277.1; M. mulatta, XP_001089512.1; C. lupus familiaris, XP_536830.2; B. taurus, NP_001029918.1; M. musculus, NP_485502.1; R. norvegicus, NP_001015019.1; G. gallus, NP_001006218.1; D. rerio, NP_957061.1; X. tropicalis, NP_001008432.1.
Please cite this article in press as: A. Ikeda, et al.A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.10.018
Correspondence / Parkinsonism and Related Disorders xxx (2016) 1e3
Disclosure The authors report no conflicts of interest relevant to the manuscript. Acknowledgements KN was supported by JSPS KAKENHI Grant Number 2586076 and 16K09678. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2016.10.018. References [1] A. Puschmann, Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations, Park. Relat. Disord. 19 (2013) 407e415. [2] M. Funayama, K. Ohe, T. Amo, N. Furuya, J. Yamaguchi, S. Saiki, et al., CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genomewide linkage and sequencing study, Lancet Neurol. 14 (2015) 274e282. [3] K. Ogaki, S. Koga, M.G. Heckman, F.C. Fiesel, M. Ando, C. Labbe, et al., Mitochondrial targeting sequence variants of the CHCHD2 gene are a risk for Lewy body disorders, Neurology 85 (2015) 2016e2025. [4] I.E. Jansen, J.M. Bras, S. Lesage, C. Schulte, J.R. Gibbs, M.A. Nalls, et al., CHCHD2 and Parkinson's disease, Lancet Neurol. 14 (2015) 678e679.
Aya Ikeda, Takashi Matsushima, Kensuke Daida, Sho Nakajima, Silvio Conedera, Yuanzhe Li Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
3
Hiroyo Yoshino Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan Genko Oyama Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Manabu Funayama Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan Kenya Nishioka Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Nobutaka Hattori* Department of Neurology, Juntendo University School of Medicine, 21-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo 1138421, Japan *
Corresponding author. E-mail address: [email protected] (N. Hattori). 4 August 2016
Please cite this article in press as: A. Ikeda, et al.A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease, Parkinsonism and Related Disorders (2016), http://dx.doi.org/10.1016/j.parkreldis.2016.10.018