Clinical findings of a myoclonus-dystonia family with two distinct mutations D. Doheny, MS; F. Danisi, MD; C. Smith, MS; C. Morrison, PhD; M. Velickovic, MD; D. de Leon, MS; S.B. Bressman, MD; J. Leung, BS; L. Ozelius, PhD; C. Klein, MD; X.O. Breakefield, PhD; M.F. Brin, MD; and J.M. Silverman, PhD Abstract—Myoclonus-dystonia has recently been associated with mutations in the epsilon-sarcoglycan gene (SCGE) on 7q21. Previously, the authors reported a patient with myoclonus-dystonia and an 18-bp deletion in the DYT1 gene on 9q34. The authors have now re-evaluated the patient harboring this deletion for mutations in the SGCE gene and identified a missense change. In the current study, the authors describe the clinical details of this family carrying mutations in two different dystonia genes. Further analysis of these mutations separately and together in cell culture and in animal models should clarify their functional consequences. NEUROLOGY 2002;59:1244 –1246 Myoclonus-dystonia is a movement disorder charac- terized by involuntary jerks and dystonic movements and postures of variable expression. 1 A major locus for myoclonus-dystonia has been linked to chromosome 7q21, 2,3 which harbors the gene for epsilon-sarcoglycan (SGCE) 4 in which several loss-of-function mutations have been identified. 4 Two additional loci have been implicated in myoclonus-dystonia: a missense change in the D2 dopamine receptor (DRD2) gene on 11q23 5 and a novel 18-bp deletion mutation in the DYT1 gene 6 on 9q34. Methods. The family was identified after the evaluation of motor symptoms in one patient. Patients provided medical history, underwent a videotaped neurologic examination, psychiatric evaluation, and neuropsychological testing, and donated a blood sample for molecular analysis. The motor examination included assessment of myoclo- nus and dystonia. The diagnoses of dystonia and myoclo- nus were established according to published criteria. 1 The videotape was reviewed by a movement disorder specialist blinded to the subject’s position in the family and the ex- amination findings. Based on a consensus of the examina- tion diagnosis and the video review, each individual was rated as “definite,” “probable,” “possible,” “unaffected,” or “unrateable” for dystonia and myoclonus. Psychiatric diagnostic interviews were performed using the Diagnostic Interview for Genetic Studies (DIGS) 7 and the Yale–Brown Obsessive Compulsive Scale (YBOCS). The DIGS, a semistructured interview, includes questions on psychiatric history and symptoms of depression, mania, substance abuse, personality disorder traits, obsessive- compulsive and other anxiety disorders, and psychosis, as well as a written narrative. The YBOCS is a 10-item scale that measures the severity of symptoms of obsessive- compulsive disorder. A battery of standardized neuropsychological tests was administered to assess a range of cognitive functions, with particular emphasis on executive functions. Test variables were standardized to age-corrected and education- corrected z-scores using published normative tables. Results. The pedigree of the family is shown in the fig- ure. The findings of the motor examination, genetic analy- sis, psychiatric evaluation, and neuropsychological testing for each individual are presented in the supplementary tables on the Neurology Web site (Go to www.neurology- .org and scroll down the Table of Contents to find the title link to this article). Clinical Findings. Index case (V-11). Onset occurred at age 5, with jerky movements of the legs, followed by upper limb involvement. By age 14 the jerky movements had worsened and progressed to the head. A head tilt was noted at age 20. Motor examination revealed myoclonus of Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Con- tents for the October 22 issue to find the link for this article. See also pages 1130, 1183, 1187, and 1241 From the Department of Neurology (Drs. Danisi, Morrison, Velickovic, Brin, and Silverman, D. Doheny and C. Smith), Mount Sinai School of Medicine, and Department of Neurology (D. de Leon and Dr. Bressman), Beth Israel Medical Center, New York, NY; Department of Neurology (J. Leung and X. Breakefield), Massachusetts General Hospital and Harvard Medical School, Charlestown, MA; Department of Molecular Genetics (Dr. Ozelius), Albert Einstein College of Medicine, Bronx, NY; and Department of Neurology (Dr. Klein), Medical University of Lübeck, Germany. The clinical (D.D., M.F.B., F.D., M.V.), psychiatric (J.S., C.S.), and neuropsychological (C.M.) work was funded in part by the Bachmann-Strauss Dystonia and Parkinson Foundation, Inc. Also supported by the Fritz Thyssen Foundation and the Deutsche Forschungsgemeinschaft (C.K.), the Myoclonus Foundation (L.O.), and National Institute of Neurological Disorders and Stroke grants NS28384 (X.O.B., J.L.), and NS37409 (X.O.B., L.O.). Received February 1, 2002. Accepted in final form May 29, 2002. Address correspondence and reprint requests to Dana O. Doheny, MS, Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-51A, Box 1052, New York, NY; e-mail: Dana.Doheny@mssm.edu 1244 Copyright © 2002 by AAN Enterprises, Inc.