A Movement Disorder With Dystonia and Ataxia Caused by a Mutation in the HIBCH Gene Gudrun Schottmann, MD, 1 Akosua Sarpong, MD, 2 Carmen Lorenz, 3 Natalie Weinhold, MD, 4 Esther Gill, 1 Lisa Teschner, 1 Sacha Ferdinandusse, PhD, 5 Ronald J. A. Wanders, PhD, 5 Alessandro Prigione, MD, PhD, 3 and Markus Schuelke, MD 1 * 1 Department of Neuropediatrics and NeuroCure Clinical Research Center, Charit e-Universit€ atsmedizin Berlin, Berlin, Germany 2 Sozialp€ adiatrisches Zentrum Neurop€ adiatrie, Charit e- Universit€ atsmedizin Berlin, Berlin, Germany 3 Max Delbr€ uck Center for Molecular Medicine (MDC), Berlin-Buch, Germany 4 Sozialp€ adiatrisches Zentrum Stoffwechsel, Charit e-Universit€ atsmedizin, Berlin, German 5 Department of Clinical Chemistry and Pediatrics, Emma Children’s Hospital, University of Amsterdam, Amsterdam, The Netherlands Abstract Background: Recessive mutations in the 3- hydroxyisobutyryl-CoA hydrolase gene ( HIBCH) are associ- ated with a rare neurodegenerative disease that affects the basal ganglia. Most patients die during infancy or early childhood. Here we describe 5 adolescent and adult patients from 2 unrelated families, who presented with a movement disorder and MRI features suggestive of Leigh syndrome. Methods: Clinical and metabolic assessment was fol- lowed by autozygosity mapping and whole exome and Sanger sequencing. HIBCH enzyme activity and the bioenergetic profile were determined in patient fibroblasts. Results: The movement disorder was dominated by ataxia in one family and by dystonia in the other. All affected family members carried the identical homozy- gous c.913A>G (p.T305A) HIBCH mutation. Enzyme activity was reduced, and a valine challenge reduced the oxygen consumption rate. Conclusions: We report the first adult patients with HIBCH deficiency and a disease course much milder than previously reported, thereby expanding the HIBCH- associated phenotypic spectrum. V C 2016 International Parkinson and Movement Disorder Society Key Words: HIBCH gene; ataxia; dystonia; basal ganglia necrosis; valine metabolism; Leigh syndrome Recessive mutations in the HIBCH gene are the cause of a rare neurodegenerative disorder resembling Leigh syndrome (OMIM#256000). 1 HIBCH encodes 3-hydroxyisobutyryl-CoA hydrolase, which is a mem- ber of the crotonase superfamily and catalyzes the fifth degradation step of valine from 3-hydroxyisobutyryl- CoA to free 3-hydroxyisobutyric acid. 2 The enzyme is located in the mitochondrial matrix and highly expressed in liver and kidney and less in heart, muscle, and brain. 3 Metabolic intermediates of this pathway may affect energy metabolism, notably in astroglia. 4 To date, 11 patients from 8 families aged 3 months to 13 years have been reported. 1,5-10 In these patients the disease manifested during early infancy with generalized hypotonia, feeding difficulties, and severe global retar- dation. Cranial magnetic resonance imaging (cMRI) showing bilateral basal ganglia necroses was suggestive of Leigh syndrome. The clinical course was character- ized by a continuous decline in psychomotor capabil- ities 5-8,11 or by secondary regression triggered by febrile infections and metabolic crisis. 1,9,10 Additional variable features comprised dystonia, seizures, ataxia, optic nerve atrophy, and, in 1 case, complex congenital mal- formations. 11 Six of the reported patients died in infancy or early childhood. In most patients elevated concentrations of hydroxy-C4-carnitine were found by mass spectrometry, which was hence suggested as a bio- marker for the disease. 5 Other biomarkers for mito- chondrial dysfunction, for example, lactic acidemia and deficiencies of isolated respiratory chain complexes, were only inconsistently abnormal. Here we report on 5 additional 12- to 43-year-old patients from 2 unrelated families. Despite an identical HIBCH mutation, the clinical phenotype differed between the families. Patients from 1 family suffered from a predominant spastic-dystonic movement disorder triggered by infection, whereas those from the other family had a nonprogressive ataxia as their main clinical ------------------------------------------------------------ *Correspondence to: Prof. Markus Schuelke, MD, Department of Neuropediatrics, Charit e-Universit€ atsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany, E-mail: markus.schuelke@charite.de Relevant conflicts of interest/financial disclosures: The authors declare no competing financial or commercial interests. Funding agencies: We acknowledge the financial support of the Deut- sche Forschungsgemeinschaft (DFG; PR1527/1-1 and SCHU1187/4-1, to A.P. and M.S.; NeuroCure Exc. 257, to M.S.), the Berlin Institute of Health (BIH; to A.P. and M.S. in the form of a PhD fellowship to C.L.), and the Bundesministerium f€ ur Bildung und Forschung (BMBF; grant AZ.031A318, to A.P.). Received: 18 February 2016; Revised: 20 May 2016; Accepted: 22 May 2016 Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26704 BRIEF REPORT Movement Disorders, Vol. 00, No. 00, 2016 1