482 Mishima T, et al. J Neurol Neurosurg Psychiatry 2018;89:482–487. doi:10.1136/jnnp-2017-316864 RESEARCH PAPER Establishing diagnostic criteria for Perry syndrome Takayasu Mishima, 1,2 Shinsuke Fujioka, 1 Hiroyuki Tomiyama, 3,4 Ichiro Yabe, 5 Ryoichi Kurisaki, 6 Naoki Fujii, 7 Ryuji Neshige, 8 Owen A Ross, 2,9 Matthew J Farrer, 10 Dennis W Dickson, 2 Zbigniew K Wszolek, 11 Nobutaka Hattori, 3,4 Yoshio Tsuboi 1 Movement disorders To cite: Mishima T, Fujioka S, Tomiyama H, et al. J Neurol Neurosurg Psychiatry 2018;89:482–487. 1 Department of Neurology, Fukuoka University School of Medicine, Fukuoka, Japan 2 Department of Neuroscience, Mayo Clinic, Jackonsville, Florida, USA 3 Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan 4 Department of Neuroscience for Neurodegenerative Disorders, Juntendo University School of Medicine, Tokyo, Japan 5 Department of Neurology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan 6 Department of Neurology, National Hospital Organization Kumamoto Minami National Hospital, Kumamoto, Japan 7 Department of Neurology, National Hospital Organization Omuta Hospital, Fukuoka, Japan 8 Neshige Neurological Clinic, Fukuoka, Japan 9 Department of Clinical Genomics, Mayo Clinic, Jacksonville, Florida, USA 10 Department of Medical Genetics, University of British Columbia, Vancouver, Canada 11 Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA Correspondence to Professor Yoshio Tsuboi, Department of Neurology, Fukuoka University, Fukoka 814-0180, Japan; tsuboi@cis. fukuoka-u.ac.jp Received 12 July 2017 Revised 19 September 2017 Accepted 18 October 2017 Published Online First 31 October 2017 ABSTRACT Objective To establish international diagnostic criteria for Perry syndrome, a disorder characterised by clinical signs of parkinsonism, depression/apathy, weight loss, respiratory symptoms, mutations in the DCTN1 gene and TAR DNA-binding protein 43 (TDP-43) pathology. Methods Data from the published literature and newly identifed patients were gathered and analysed during and after the International Symposium on Perry syndrome in Tokyo to identify diagnostic criteria for Perry syndrome. Results Eighty-seven patients with Perry syndrome carrying DCTN1 mutations from 20 families were included in this study, and common signs of the disorder were identifed, including parkinsonism (95.2% of patients), depression/apathy (71.4%), respiratory symptoms (66.7%) and weight loss (49.2%). Conclusions Based on our fndings, we propose the following defnitive diagnostic criteria for Perry syndrome: the presence of four cardinal signs of Perry syndrome, accompanied by a mutation in DCTN1; or a family history of the disease, parkinsonism and a mutation in DCTN1; or the presence of four cardinal signs and pathological fndings that include nigral neuronal loss and TDP-43 pathology. As patients with Perry syndrome present with uniform clinical, genetic and pathological features, we further propose the disorder be termed ’Perry disease.’ INTRODUCTION Perry syndrome was first reported by Perry et al in 1975 after study of a single affected Canadian family. 1 Perry syndrome is characterised by rapidly progressive parkinsonism often accompanied by depression/apathy, weight loss and central hypoven- tilation. 1–10 It is a rare hereditary disorder with an autosomal-dominant mode of inheritance. 1–10 In 2009, mutations in the DCTN1 gene (OMIM: 601143) were identified as the cause of Perry syndrome. 11 Prior to this discovery, DCTN1 muta- tions were identified as the cause of a form of distal spinal and bulbar muscular atrophy, known as distal hereditary motor neuropathy 7B (HMN7B). 12 To date, all DCTN1 mutations reported in patients with Perry syndrome have been confined to exon 2, suggesting this area is a mutational hot spot for the syndrome as well as an important site medi- ating function of the protein encoded by DCTN1. 11 Perry syndrome has been classified as a TAR DNA-binding protein 43 (TDP-43) proteinopathy based on pathological findings of TDP-43 inclu- sions, as seen in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 inclusions (FTLD-TDP). 13 14 Some patients with Perry syndrome show levodo- pa-responsive parkinsonism characterised by resting tremor, cogwheel rigidity, bradykinesia and postural instability reminiscent of Parkinson’s disease (PD) as well as autonomic dysfunction. Cardiac [123I]-me- taiodobenzylguanidine (MIBG) scintigraphy reveals reduced uptake of ligand, as is typically observed in sporadic PD. Therefore, Perry syndrome may be misdiagnosed as PD, especially during early- stage disease. 15–18 In addition, phenotypes similar to those observed in progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD) have been reported in patients with Perry syndrome. 16 19 Due to its rarity, a comprehensive and integrated understanding of clinical, genetic and patholog- ical features of Perry syndrome remains elusive. In addition, diverse clinical phenotypes and the lack of internationally accepted diagnostic criteria make diagnosis difficult. Therefore, development of consensus diagnostic criteria for Perry syndrome is essential to advance both clinical care and under- standing of disease mechanisms. The aim of this study was to identify epidemi- ological and clinical features associated with Perry syndrome based on a review of published case studies and to establish diagnostic criteria using this information. In support of this aim, we held an international meeting, the International Symposium on Perry Syndrome in Tokyo, devoted to developing consensus diagnostic criteria. We further reviewed and analysed reports of newly identified patients after the meeting. METHODS The International Symposium on Perry syndrome in Tokyo was held from 22 to –23 February 2011. Before the meeting, the organising committee searched the scientific literature to identify all known families with Perry syndrome. During the meeting, consensus methodologies were used to establish criteria for diagnosis of Perry syndrome. The meeting included clinicians, geneticists and neuropathologists with expertise in neurodegenera- tive disorders. After the meeting, new families with a history of Perry syndrome were included in our analysis by searching on PubMed for publications through 30 November 2016. The search terms used were ‘Perry syndrome’, ‘dynactin1’ and ‘DCTN1’. Inclusion criteria were (1) detailed clinical descrip- tions of parkinsonism in at least one family member and (2) genetically proven DCTN1 mutations. Data on June 6, 2020 by guest. Protected by copyright. http://jnnp.bmj.com/ J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2017-316864 on 31 October 2017. Downloaded from