Myoclonus dystonia syndrome (MDS) is a young-onset movement disorder. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. We assembled the largest cohort of MDS patients to date, and determined the frequency and type of SGCE mutations. The aim was to establish the motor phenotype in mutation carriers and utility of current diagnostic criteria. Eighty-nine probands with clinical features compatible with MDS were recruited from the UK and Ireland. Patients were phenotypically classified as “definite”, “probable” or “possible” MDS according to previous guidelines. SGCE was analyzed using direct sequencing and copy number variant analysis. In those where no mutation was found, DYT1 (GAG deletion), GCH1, THAP1 and NKX2.1 genes were also sequenced. Nineteen (21.3 %) probands had an SGCE mutation. Three patterns of motor symptoms emerged: (1) early childhood onset upper body myoclonus and dystonia, (2) early childhood onset lower limb dystonia, progressing later to more pronounced myoclonus and upper body involvement, and (3) later childhood onset upper body myoclonus and dystonia with evident cervical involvement. Five probands had large contiguous gene deletions ranging from 0.7 to 2.3 Mb in size with distinctive clinical features, including short stature, joint laxity and microcephaly. Our data confirms that SGCE mutations are most commonly identified in MDS patients with (1) age at onset ≤10 years and (2) predominant upper body involvement of a pure myoclonus-dystonia. Cases with whole SGCE gene deletions had additional clinical characteristics, which are not always predicted by deletion size or gene involvement.
Myoclonus Dystonia Genetic and inherited disorders SGCE
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We would like to thank the patients and their relatives for participating in this study as well as the British Neurological Surveillance Unit (BNSU) for their assistance with notification of cases. We would also like to thank Dr. Daniel Lumsden for his assistance with data collection. KJP is funded by an Ipsen Clinical Research Fellowship and supported by the Welsh Clinical Academic Track (WCAT) program. MAK is funded by GOSHCC and is a Wellcome Trust Intermediate Clinical Fellow. GK is funded by the Wellcome Trust and Medical Research Council. JPL is funded by grants from Action Medical Research, The Dystonia Society UK and Guy’s and St Thomas’ Charity. MS is funded by Parkinson’s UK, East Kent and King’s College Hospital Foundation Trusts. MDK is funded by the Children’s fund for health at The Children’s University Hospital, Temple Street, Dublin. TTW is funded by the Brain Research Trust, Cure Huntington’s Disease Initiative, The Dystonia Society, Bachmann-Strauss Dystonia Parkinson Foundation and NHS Innovations Ltd. HRM is funded by the Medical Research Council and Parkinson’s UK.
Conflicts of interest
Dr JP Lin has received unrestricted educational support and Honoraria for lecturing from Medtronic Ltd. Dr Pall has received an educational grant from Medtronic to attend a movement disorders meeting. Dr B Lynch has received funding from Viropharma to attend an advisory group and epilepsy meeting. Dr Samuel has received Honoraria and sponsorship for education meetings from Medtronic, UCB, St Jude Medical Inc, Boehrinher-Ingelheim, Ipsen and Solvay. Professor Morris is on the advisory board to tev and Solvay has received speaker’s fees from UCB and Teva and a travel grant from Teva. Drs Peall, Kurian, Wardle, Waite, Hedderly, Smith, Whone, White, Lux, Jardine, O’Riordan and Professors Lynch, King, Chinnery, Warner, Blake and Owen have no conflicts of interest.
This study has been approved by the appropriate ethics committee and therefore has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All participants in this study gave their informed consent prior to their inclusion in this study.
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