Genetic Forms of Parkinson's Disease

&NA; One of the greatest advances in Parkinson's disease (PD) research in the past two decades has been a better understanding of PD genetics. Of the many candidate genes investigated, the best studied include LRRK2, SNCA, VPS35, Parkin, PINK1, and DJ1. The authors review the key clinical features of these monogenic forms, as well as for the prevalent risk factor gene, GBA, including the phenotype, clinical course, and treatment response. They also outline areas for future investigation: longitudinal studies of PD's clinical course, the identification of its premotor manifestations, and its specific mechanisms of pathogenicity.

[1]  W. Voos,et al.  Mitochondrial quality control by the Pink1/Parkin system , 2016, Cell and Tissue Research.

[2]  L. Wilkins.  Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers , 2011, Neurology.

[3]  J. Burgunder,et al.  LRRK2 Gly2385Arg variant is a risk factor of Parkinson’s disease among Han‐Chinese from mainland China , 2008, European journal of neurology.

[4]  A. Singleton,et al.  A common genetic factor for Parkinson disease in ethnic Chinese population in Taiwan , 2006, BMC neurology.

[5]  P. Pramstaller,et al.  Association studies of Parkinson's disease and parkin polymorphisms , 2000, Annals of neurology.

[6]  Nicholas W Wood,et al.  A common LRRK2 mutation in idiopathic Parkinson's disease , 2005, The Lancet.

[7]  K. Marder,et al.  Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. , 2010, Archives of neurology.

[8]  I. Guella,et al.  The Asp620asn mutation in VPS35 is not a common cause of familial Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[9]  R. Wu,et al.  Lack of CHCHD2 mutations in Parkinson's disease in a Taiwanese population , 2016, Neurobiology of Aging.

[10]  S. Sawcer,et al.  Systematic Review and UK‐Based Study of PARK2 (parkin), PINK1, PARK7 (DJ‐1) and LRRK2 in early‐onset Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[11]  J. Hoenicka,et al.  The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia , 2004, Annals of neurology.

[12]  M. Farrer,et al.  The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients , 2005, Neuroscience Letters.

[13]  D. Berg,et al.  GBA-associated PD presents with nonmotor characteristics , 2011, Neurology.

[14]  A. Leutenegger,et al.  A new F‐box protein 7 gene mutation causing typical Parkinson's disease , 2015, Movement disorders : official journal of the Movement Disorder Society.

[15]  J. Aharon-Peretz,et al.  Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. , 2004, The New England journal of medicine.

[16]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[17]  M. Farrer,et al.  Expanding the clinical phenotype of SNCA duplication carriers , 2009, Movement disorders : official journal of the Movement Disorder Society.

[18]  A A Schäffer,et al.  Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27. , 1997, American journal of human genetics.

[19]  J. Houwing-Duistermaat,et al.  Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. , 2001, American journal of human genetics.

[20]  J. Hardy,et al.  Parkin disease: a clinicopathologic entity? , 2013, JAMA neurology.

[21]  A. Schapira,et al.  Glucocerebrosidase mutations and the pathogenesis of Parkinson disease , 2013, Annals of medicine.

[22]  K. Marder,et al.  Differential effects of severe vs mild GBA mutations on Parkinson disease , 2015, Neurology.

[23]  G. Deuschl,et al.  Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism , 2008, Neurology.

[24]  J. Aharon-Peretz,et al.  Mutations in the glucocerebrosidase gene and Parkinson disease: Phenotype–genotype correlation , 2005, Neurology.

[25]  K. Marder,et al.  Cognitive performance of GBA mutation carriers with early-onset PD , 2012, Neurology.

[26]  M. Farrer,et al.  VPS35 mutations in Parkinson disease. , 2011, American journal of human genetics.

[27]  M. Vidailhet,et al.  Large-scale screening of the Gaucher's disease-related glucocerebrosidase gene in Europeans with Parkinson's disease. , 2011, Human molecular genetics.

[28]  M. Farrer,et al.  A limited role for DJ1 in Parkinson disease susceptibility , 2004, Neurology.

[29]  K. Marder,et al.  Evaluation of 50 probands with early-onset Parkinson’s disease for Parkin mutations , 2002, Neurology.

[30]  K. Marder,et al.  Neuropsychological performance in LRRK2 G2019S carriers with Parkinson's disease. , 2014, Parkinsonism & related disorders.

[31]  A. Singleton,et al.  alpha-Synuclein locus triplication causes Parkinson's disease. , 2003, Science.

[32]  N. Bresolin,et al.  A novel homozygous PLA2G6 mutation causes dystonia-parkinsonism. , 2015, Parkinsonism & related disorders.

[33]  S E Ide,et al.  Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. , 1997, Science.

[34]  R. Lipton,et al.  Olfactory dysfunction in LRRK2 G2019S mutation carriers , 2011, Neurology.

[35]  B. Jeon,et al.  α-Synuclein gene duplication is present in sporadic Parkinson disease , 2008, Neurology.

[36]  A. Singleton,et al.  Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. , 2009, Brain : a journal of neurology.

[37]  A. Desautels,et al.  GBA mutations are associated with Rapid Eye Movement Sleep Behavior Disorder , 2015, Annals of clinical and translational neurology.

[38]  T. Foroud,et al.  Mutations in LRRK2 other than G2019S are rare in a north american–based sample of familial Parkinson's disease , 2006, Movement disorders : official journal of the Movement Disorder Society.

[39]  R. Wu,et al.  The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease , 2014, Neurology.

[40]  K. Kaestner,et al.  A Deleterious Mutation in DNAJC6 Encoding the Neuronal-Specific Clathrin-Uncoating Co-Chaperone Auxilin, Is Associated with Juvenile Parkinsonism , 2012, PloS one.

[41]  P. Pollak,et al.  Penetrance of Parkinson disease in glucocerebrosidase gene mutation carriers , 2012, Neurology.

[42]  Y. Agid,et al.  A multidisciplinary study of patients with early-onset PD with and without parkin mutations , 2009, Neurology.

[43]  D. Berg,et al.  GBA‐associated Parkinson's disease: Reduced survival and more rapid progression in a prospective longitudinal study , 2015, Movement disorders : official journal of the Movement Disorder Society.

[44]  Nir Giladi,et al.  The emerging role of SMPD1 mutations in Parkinson's disease: Implications for future studies. , 2015, Parkinsonism & related disorders.

[45]  A. Quattrone,et al.  Analysis of CHCHD2 gene in familial Parkinson's disease from Calabria , 2017, Neurobiology of Aging.

[46]  Tomoko Oeda,et al.  Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease , 2015, Neurobiology of Aging.

[47]  A. Tolun,et al.  DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability. , 2013, Parkinsonism & related disorders.

[48]  N. Brüggemann,et al.  A nonsense mutation in CHCHD2 in a patient with Parkinson disease , 2016, Neurology.

[49]  Nir Giladi,et al.  Occurrence of Parkinson's syndrome in type I Gaucher disease. , 1996, QJM : monthly journal of the Association of Physicians.

[50]  N. Hattori,et al.  An apparently sporadic case with parkin gene mutation in a Korean woman. , 2001, Archives of neurology.

[51]  Yih-Ru Wu,et al.  Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese , 2007, Journal of Neurology, Neurosurgery & Psychiatry.

[52]  Nicholas W. Wood,et al.  Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease , 2015, Neurology: Genetics.

[53]  Kazuko Hasegawa,et al.  An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family , 2005, Annals of neurology.

[54]  G. Schellenberg,et al.  A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2 , 2010, Neurology.

[55]  J. Jankovic,et al.  Heterogeneous phenotype in a family with compound heterozygous parkin gene mutations. , 2006, Archives of neurology.

[56]  Jeroen van Rooij,et al.  Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population , 2017, Neurobiology of Aging.

[57]  K. Marder,et al.  Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study , 2010, Journal of the International Neuropsychological Society.

[58]  Guiyou Liu,et al.  CHCHD2 and Parkinson's disease , 2015, The Lancet Neurology.

[59]  S. Pappatà,et al.  Mutation in the SYNJ1 Gene Associated with Autosomal Recessive, Early‐Onset Parkinsonism , 2013, Human mutation.

[60]  K. Marder,et al.  Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene , 2015, Movement disorders : official journal of the Movement Disorder Society.

[61]  藤原 幹夫.  Parkin as a tumor suppressor gene for hepatocellular carcinoma , 2010 .

[62]  J. Aharon-Peretz,et al.  SMPD1 mutations and Parkinson disease. , 2015, Parkinsonism & related disorders.

[63]  R. Cilia,et al.  DJ1 analysis in a large cohort of Italian early onset Parkinson Disease patients , 2013, Neuroscience Letters.

[64]  S. Minoshima,et al.  Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism , 1998, Nature.

[65]  S. Klebe,et al.  Identification of VPS35 mutations replicated in French families with Parkinson disease , 2012, Neurology.

[66]  G. Schellenberg,et al.  Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients , 2007, Annals of neurology.

[67]  B. Oostra,et al.  A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan , 2006, Neurogenetics.

[68]  Marc N. Offman,et al.  A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. , 2011, American journal of human genetics.

[69]  E. Sidransky,et al.  Glucocerebrosidase is present in α-synuclein inclusions in Lewy body disorders , 2010, Acta Neuropathologica.

[70]  J. Trojanowski,et al.  Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. , 2015, JAMA neurology.

[71]  Ekaterina Rogaeva,et al.  Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications. , 2013, JAMA neurology.

[72]  K. Lohmann,et al.  Clinical and demographic characteristics of PINK1 mutation carriers—A meta‐analysis , 2010, Movement disorders : official journal of the Movement Disorder Society.

[73]  A. Mirelman,et al.  A "dose" effect of mutations in the GBA gene on Parkinson's disease phenotype. , 2017, Parkinsonism & related disorders.

[74]  J. Hardy,et al.  Glucocerebrosidase mutations do not cause increased Lewy body pathology in Parkinson's disease. , 2011, Molecular genetics and metabolism.

[75]  N. Shimizu,et al.  Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: Evidence for variable homozygous deletions in the Parkin gene in affected individuals , 1998, Annals of neurology.

[76]  C. Sander,et al.  Somatic mutations of the Parkinson's disease–associated gene PARK2 in glioblastoma and other human malignancies , 2010, Nature Genetics.

[77]  E. Tolosa,et al.  Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study , 2008, The Lancet Neurology.

[78]  K. Marder,et al.  Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease. , 2009, Archives of neurology.

[79]  J. Haines,et al.  The alpha-synuclein gene is not a major risk factor in familial Parkinson disease. , 1999, Neurogenetics.

[80]  P. Lockhart,et al.  Mutations in RAB39B cause X-linked intellectual disability and early-onset Parkinson disease with α-synuclein pathology. , 2014, American journal of human genetics.

[81]  Philippe Amouyel,et al.  Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. , 2004, Lancet.

[82]  M. Nalls,et al.  Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data , 2016, The Lancet Neurology.

[83]  Marta Bonilla-Toribio,et al.  Genetic analysis of CHCHD2 in a southern Spanish population , 2017, Neurobiology of Aging.

[84]  M. T. Pellecchia,et al.  Olfactory dysfunction in Parkinsonism caused by PINK1 mutations , 2009, Movement disorders : official journal of the Movement Disorder Society.

[85]  Simon C. Potter,et al.  Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. , 2016, American journal of human genetics.

[86]  Xinglong Yang,et al.  Mutational scanning of the CHCHD2 gene in Han Chinese patients with Parkinson's disease and meta-analysis of the literature. , 2016, Parkinsonism & related disorders.

[87]  J. Parisi,et al.  Western Nebraska Family (Family D) with Autosomal Dominant Parkinsonism , 1995, Neurology.

[88]  W. Chung,et al.  Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes. , 2014, JAMA neurology.

[89]  M. Farrer,et al.  Parkinsonism in GTP cyclohydrolase 1 mutation carriers. , 2015, Brain : a journal of neurology.

[90]  A Dürr,et al.  Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. , 2004, Lancet.

[91]  N. Hattori,et al.  Absence of Lewy pathology associated with PINK1 homozygous mutation , 2016, Neurology.

[92]  D. Adams,et al.  PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice , 2010, Proceedings of the National Academy of Sciences.

[93]  J. Duda,et al.  Motor phenotype of LRRK2‐associated Parkinson's disease: A tunisian longitudinal study , 2015, Movement disorders : official journal of the Movement Disorder Society.

[94]  M. S. Luciano,et al.  LRRK2 G2019S mutations are associated with an increased cancer risk in Parkinson disease , 2010, Movement disorders : official journal of the Movement Disorder Society.

[95]  J. Haines,et al.  Parkin mutations and susceptibility alleles in late‐onset Parkinson's disease , 2003, Annals of neurology.

[96]  T. Caulfield,et al.  PINK1, Parkin, and Mitochondrial Quality Control: What can we Learn about Parkinson’s Disease Pathobiology? , 2016, Journal of Parkinson's disease.

[97]  K. Marder,et al.  Association of glucocerebrosidase mutations with dementia with lewy bodies. , 2009, Archives of neurology.

[98]  A. Bentivoglio,et al.  PINK1 mutations are associated with sporadic early‐onset parkinsonism , 2004, Annals of neurology.

[99]  M. Dorschner,et al.  The RAB39B p.G192R mutation causes X-linked dominant Parkinson’s disease , 2015, Molecular Neurodegeneration.

[100]  S. Lai,et al.  Contribution of glucocerebrosidase mutation in a large cohort of sporadic Parkinson’s disease in Taiwan , 2011, European journal of neurology.

[101]  E. Shin,et al.  The LRRK2 G2385R variant is a risk factor for sporadic Parkinson's disease in the Korean population. , 2010, Parkinsonism & related disorders.

[102]  N. Quinn,et al.  Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease , 2004, Neurology.

[103]  K. Marder,et al.  Frequency of parkin mutations in late‐onset Parkinson's disease , 2003, Annals of neurology.

[104]  R. Saunders-Pullman,et al.  Mood and cognition in leucine‐rich repeat kinase 2 G2019S Parkinson's disease , 2011, Movement disorders : official journal of the Movement Disorder Society.

[105]  H. Liany,et al.  A rare lysosomal enzyme gene SMPD1 variant (p.R591C) associates with Parkinson's disease , 2013, Neurobiology of Aging.

[106]  C. Tanner,et al.  Failure to find the alpha-synuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson's disease. , 1998, Neurology.

[107]  Nir Giladi,et al.  Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset , 2008, Neurology.

[108]  M. Polymeropoulos,et al.  Mapping of a Gene for Parkinson's Disease to Chromosome 4q21-q23 , 1996, Science.

[109]  R. Hilker,et al.  Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers , 2005, Annals of neurology.

[110]  K. Ohno,et al.  CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study , 2015, The Lancet Neurology.

[111]  A. Ishikawa,et al.  Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism , 1996, Neurology.

[112]  P. Pástor,et al.  PINK1-linked parkinsonism is associated with Lewy body pathology. , 2010, Brain : a journal of neurology.

[113]  C. Sue,et al.  The role of ATP13A2 in Parkinson's disease: Clinical phenotypes and molecular mechanisms , 2015, Movement disorders : official journal of the Movement Disorder Society.

[114]  K. Marder,et al.  Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations , 2009, Neurology.

[115]  W. Oyen,et al.  FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome , 2009, Neurology.

[116]  C. Klein,et al.  Early-onset parkinsonism associated with PINK1 mutations: Frequency, genotypes, and phenotypes , 2005, Neurology.

[117]  K. Marder,et al.  Lack of association between cancer history and PARKIN genotype: A family based study in PARKIN/Parkinson's Families , 2012, Genes, chromosomes & cancer.

[118]  Nicola Pavese,et al.  Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. , 2002, Brain : a journal of neurology.

[119]  A. López de Munain,et al.  LRRK2 G2019S and R1441G mutations associated with Parkinson’s disease are common in the Basque Country, but relative prevalence is determined by ethnicity , 2009, neurogenetics.

[120]  G. Logroscino,et al.  The parkin gene is not involved in late-onset Parkinson’s disease , 2001, Neurology.

[121]  N. Hattori,et al.  VPS35 mutation in Japanese patients with typical Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[122]  K. Marder,et al.  Distribution, type, and origin of Parkin mutations: Review and case studies , 2004, Movement disorders : official journal of the Movement Disorder Society.

[123]  N. Quinn,et al.  A heterozygous effect for PINK1 mutations in Parkinson's disease? , 2006, Annals of neurology.

[124]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[125]  U. Muthane,et al.  Evidence of mutations in RIC3 acetylcholine receptor chaperone as a novel cause of autosomal-dominant Parkinson's disease with non-motor phenotypes , 2016, Journal of Medical Genetics.

[126]  C. Croce,et al.  Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[127]  A. Bentivoglio,et al.  Phenotypic characterisation of autosomal recessive PARK6‐linked parkinsonism in three unrelated Italian families , 2001, Movement disorders : official journal of the Movement Disorder Society.

[128]  Wyeth W Wasserman,et al.  DNAJC13 mutations in Parkinson disease. , 2014, Human molecular genetics.

[129]  S. Tsuji,et al.  A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2–q13.1 , 2002, Annals of neurology.

[130]  M. Nalls,et al.  Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. , 2009, The New England journal of medicine.

[131]  Mathias Toft,et al.  Clinical features of LRRK2‐associated Parkinson's disease in central Norway , 2005, Annals of neurology.

[132]  A. Albanese,et al.  High frequency stimulation of the subthalamic nucleus is efficacious in Parkin disease , 2005, Journal of Neurology.

[133]  K. Marder,et al.  REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers , 2015, Movement disorders : official journal of the Movement Disorder Society.

[134]  W. Chung,et al.  Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations. , 2015, Brain : a journal of neurology.

[135]  M. Pericak-Vance,et al.  Identification of TMEM230 mutations in familial Parkinson’s disease , 2016, Nature Genetics.

[136]  B. Tang,et al.  TMEM230 mutation analysis in Parkinson's disease in a Chinese population , 2017, Neurobiology of Aging.

[137]  C. Mariani,et al.  Survival and dementia in GBA‐associated Parkinson's disease: The mutation matters , 2016, Annals of neurology.

[138]  K. Marder,et al.  Olfactory identification in LRRK2 G2019S mutation carriers: a relevant marker? , 2014, Annals of clinical and translational neurology.

[139]  J. Hardy,et al.  Genotype and phenotype in Parkinson's disease: Lessons in heterogeneity from deep brain stimulation , 2013, Movement disorders : official journal of the Movement Disorder Society.

[140]  J. Nutt,et al.  Cognitive and motor function in long-duration PARKIN-associated Parkinson disease. , 2014, JAMA neurology.

[141]  Patrizia Rizzu,et al.  Mutations in the DJ-1 Gene Associated with Autosomal Recessive Early-Onset Parkinsonism , 2002, Science.

[142]  A. Kortholt,et al.  Activation Mechanism of LRRK2 and Its Cellular Functions in Parkinson's Disease , 2016, Parkinson's disease.

[143]  J. Duda,et al.  Cognitive dysfunction in Tunisian LRRK2 associated Parkinson's disease. , 2012, Parkinsonism & related disorders.

[144]  Y. Agid,et al.  Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism , 1998, The Lancet.

[145]  K. Marder,et al.  Olfaction in Parkin heterozygotes and compound heterozygotes , 2010, Neurology.

[146]  E. Tolosa,et al.  Motor and nonmotor heterogeneity of LRRK2‐related and idiopathic Parkinson's disease , 2016, Movement disorders : official journal of the Movement Disorder Society.

[147]  Nobutaka Hattori,et al.  The LRRK2 I2012T, G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson's disease. , 2005, Parkinsonism & related disorders.

[148]  Nir Giladi,et al.  Arm swing as a potential new prodromal marker of Parkinson's disease , 2016, Movement disorders : official journal of the Movement Disorder Society.

[149]  N. Hattori,et al.  PARK6-linked autosomal recessive early-onset parkinsonism in Asian populations , 2004, Neurology.

[150]  E. Tan,et al.  Genetic analysis of CHCHD2 gene in Chinese Parkinson's disease , 2016, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[151]  Vincenzo Bonifati,et al.  A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease , 2005, The Lancet.

[152]  A. Brice,et al.  Parkinson's disease: from monogenic forms to genetic susceptibility factors. , 2009, Human molecular genetics.

[153]  Ronald Melki,et al.  G51D α‐synuclein mutation causes a novel Parkinsonian–pyramidal syndrome , 2013, Annals of neurology.

[154]  J. Aharon-Peretz,et al.  The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers , 2012, Neurology.

[155]  W. Mandemakers,et al.  DNAJC6 Mutations Associated With Early‐Onset Parkinson's Disease , 2016, Annals of neurology.

[156]  M. S. Luciano,et al.  Gender differences in the risk of familial parkinsonism: Beyond LRRK2? , 2011, Neuroscience Letters.

[157]  M. Stamelou,et al.  Motor and Nonmotor Features of Carriers of the p.A53T Alpha‐Synuclein Mutation: A Longitudinal Study , 2016, Movement disorders : official journal of the Movement Disorder Society.

[158]  V. Mok,et al.  LRRK2 Gly2385Arg mutation and clinical features in a Chinese population with early-onset Parkinson’s disease compared to late-onset patients , 2008, Journal of Neural Transmission.

[159]  A. Durr,et al.  A Novel Nonsense Mutation in DNAJC6 Expands the Phenotype of Autosomal‐Recessive Juvenile‐Onset Parkinson's Disease , 2016, Annals of neurology.

[160]  Clinical and Pathological Characteristics of LRRK2 G2019S Patients with PD , 2012, Journal of Molecular Neuroscience.

[161]  N. Hattori,et al.  Leucine-Rich Repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population , 2007, Neuroreport.

[162]  Christos Proukakis,et al.  A novel α-synuclein missense mutation in Parkinson disease , 2013, Neurology.

[163]  A. Mubaidin,et al.  Pallido‐pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor‐Rakeb syndrome , 1994, Acta neurologica Scandinavica.

[164]  Janel O. Johnson,et al.  Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. , 2004, Archives of neurology.

[165]  A. Bentivoglio,et al.  Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. , 2001, American journal of human genetics.

[166]  C. Klein,et al.  The many faces of alpha‐synuclein mutations , 2013, Movement disorders : official journal of the Movement Disorder Society.

[167]  K. Gehring,et al.  Structural studies of parkin and sacsin: Mitochondrial dynamics in neurodegenerative diseases , 2015, Movement disorders : official journal of the Movement Disorder Society.

[168]  R. Nussbaum,et al.  Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1 , 2004, Science.

[169]  J. Jankovic,et al.  Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation , 2005, Annals of neurology.

[170]  N. Hattori,et al.  Neuropsychiatric and cognitive features in autosomal‐recessive early parkinsonism due to PINK1 mutations , 2007, Movement disorders : official journal of the Movement Disorder Society.

[171]  W. Gibb,et al.  New pathologic observations in juvenile onset parkinsonism with dystonia , 1991, Neurology.

[172]  R. Krüger,et al.  Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. , 1998, Nature genetics.

[173]  K. Marder,et al.  Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study. , 2010, Archives of neurology.

[174]  M. T. Pellecchia,et al.  Impulsive-compulsive behaviors in parkin-associated Parkinson disease , 2016, Neurology.