Genetic Identification Is Critical for the Diagnosis of Parkinsonism: A Chinese Pedigree with Early Onset of Parkinsonism

RESEARCH ARTICLE Genetic Identification Is Critical for the Diagnosis of Parkinsonism: A Chinese Pedigree with Early Onset of Parkinsonism Yang Yang1, Bei-sha Tang1,2,3,4, Ling Weng1, Nan Li1,3,4, Lu Shen1,2,3,4, Jian Wang5, Chuantao Zuo6, Xin-xiang Yan1,3,4, Kun Xia2, Ji-feng Guo1,2,3,4* 1 Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China, 2 State Key Laboratory of Medical Genetics, Changsha, 410078, Hunan, People’s Republic of China, 3 Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008, Hunan, People’s Republic of China, 4 Neurodegenerative Disorders Research Center, Central South University, Changsha, 410008, Hunan, People’s Republic of China, 5 Department of Neurology, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, 200040, Shanghai, People’s Republic of China, 6 PET Center, Huashan Hospital, Fudan University, 12 Wulumuqi Middle Road, 200040, Shanghai, People’s Republic of China * OPEN ACCESS Citation: Yang Y, Tang B-s, Weng L, Li N, Shen L, Wang J, et al. (2015) Genetic Identification Is Critical for the Diagnosis of Parkinsonism: A Chinese Pedigree with Early Onset of Parkinsonism. PLoS ONE 10(8): e0136245. doi:10.1371/journal. pone.0136245 Editor: Xiao-Jiang Li, Emory University, UNITED STATES Received: July 6, 2015 Accepted: August 2, 2015 Abstract Background A number of hereditary neurological diseases display indistinguishable features at the early disease stage. Parkinsonian symptoms can be found in numerous diseases, making it difficult to get a definitive early diagnosis of primary causes for patients with onset of parkinsonism. The accurate and early diagnosis of the causes of parkinsonian patients is important for effective treatments of these patients. Published: August 21, 2015 Copyright: © 2015 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This study was supported by the Major State Basic Research Development Program of China http://www.most.gov.cn (973 Program) (grant number 2011CB510000 to Bei-sha Tang), National Natural Science Foundation of China http://www.nsfc. gov.cn/ (grant number 81430023 to Bei-sha Tang, grant number 81130021 to Bei-sha Tang, grant number 81171198 to Xin-xiang Yan, grant number 81371405 to Ji-feng Guo, grant number 81361120404 to Bei-sha Tang, grant number Methods We have identified a Chinese family (82 family members over four generations with 21 affected individuals) that manifested the characterized symptoms of parkinsonism and was initially diagnosed as Parkinson’s disease. We followed up with the family for two years, during which we carried out clinical observations, Positron Emission Tomography-Computed Tomography neuroimaging analysis, and exome sequencing to correctly diagnose the case. Results During the two-year follow-up period, we performed comprehensive medical history collection, physical examination, and structural and functional neuroimaging studies of this Chinese family. We found that the patient exhibited progressive deteriorated parkinsonism with Parkinson disease-like neuropathology and also had a good response to the initial levodopa treatment. However, exome sequencing identified a missense mutation, N279K, in exon 10 PLOS ONE | DOI:10.1371/journal.pone.0136245 August 21, 2015 1 / 12 Genetic Identification Is Critical for the Diagnosis of Parkinsonism 81300980 to Nan Li). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. of MAPT gene, verifying that the early parkinsonian symptoms in this family are caused by the genetic mutation for hereditary frontotemporal lobar dementia. Conclusions For the inherited parkinsonian patients who even show the neuropathology similar to that in Parkinson’s disease and have initial response to levodopa treatment, genetic identification of the molecular basis for the disease is still required for defining the early diagnosis and correct treatment. Introduction Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. In addition to drug- or toxin-induced parkinsonism, a wide range of diseases may lead to a similar set of symptoms, including Parkinson’s disease, parkinsonism-plus, Wilson’s disease, progressive supranuclear palsy, and a handful of other neurological conditions [1]. The fact that parkinsonism could be the only symptom in the early stage of numerous diseases makes it difficult to get a definitive early diagnosis for the primary causes of parkinsonism. However, as the disease progresses, some other significant characteristics of the symptoms would come forth; therefore, many diagnoses rely on the disease progression and close clinical observations for identifying the underlying causes of patients with parkinsonism. Although the fast development of functional neuroimaging technologies, including MRI, Positron Emission Tomography-Computed Tomograph (PET-CT) and single-photon emission CT (SPECT) provide us with high precision approaches that are required in modern clinical practice, the early diagnosis of Parkinsonian patients can be achieved by genetic identification of the gene mutations. Mutations in genes at more than 20 loci are known to cause genetic parkinsonism [2,3], however, the number of corresponding genes that need to be screened could be substantially high. Compared to the traditional candidate gene screening that is expensive and ineffective, the next generation sequencing methods, such as whole-genome sequencing and exome sequencing, should allow for readily identifying the genetic bases of Mendelian diseases. Here we report the use of continued clinical observations, especially the functional neuroimaging studies, and the application of next generation sequencing methods to identify the genetic cause of a family with early parkinsonian symptoms. Materials and Methods 2.1 Subjects and Clinical Text The study was approved by the Ethics Committee of Xiangya Hospital affiliated to Central South University in China. Written informed consents were obtained from all subjects. We collected a four-generation Chinese family (Fig 1) with parkinsonism, characterized by early onset, rapid progression, rigidity, hypokinesia, postural instability, and in some individuals, tremor. All the available affected individuals (5 patients, including 1 male and 4 female) were subjected to thorough neurological examinations by two or more experienced neurologists. Data from other family members w (...truncated)