Gudrun Schottmann1, Akosua Sarpong2, Carmen Lorenz3, Natalie Weinhold4, Esther Gill1, Lisa Teschner1, Sacha Ferdinandusse5, Ronald J A Wanders5, Alessandro Prigione3, Markus Schuelke1. 1. Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany. 2. Sozialpädiatrisches Zentrum Neuropädiatrie, Charité-Universitätsmedizin Berlin, Berlin, Germany. 3. Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany. 4. Sozialpädiatrisches Zentrum Stoffwechsel, Charité-Universitätsmedizin, 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 associated 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 followed 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 homozygous 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.
BACKGROUND: Recessive mutations in the 3-hydroxyisobutyryl-CoA hydrolase gene (HIBCH) are associated 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 followed 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 homozygous 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.