Miguel M Pinto1, Soledad Monges2, Edoardo Malfatti3, Fabiana Lubieniecki2, Xavière Lornage4, Laura Alias5, Clémence Labasse3, Angéline Madelaine3, Michel Fardeau3, Jocelyn Laporte4, Eduardo F Tizzano6, Norma B Romero3. 1. Neurology Department, Hospital de Egas Moniz, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal. 2. Neuropediatric and Neuropathology Departments, National Pediatric Hospital J-P-Garrahan, Buenos Aires, Argentina. 3. Unité de Morphologie Neuromusculaire, Institut de Myologie, Sorbonne University, INSERM UMR 974, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, 75013, Paris, France. 4. Department of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM U1258, CNRS UMR7104, Université de Strasbourg, Illkirch, France. 5. Department of Genetics, Hospital Sant Pau and CIBERER, Barcelona, Spain. 6. Department of Clinical and Molecular Genetics and Rare Diseases Division, Hospital Vall d'Hebron and CIBERER, Barcelona, Spain.
Abstract
INTRODUCTION: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified. METHODS: Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described. RESULTS: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies. CONCLUSIONS: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.
INTRODUCTION: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified. METHODS: Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described. RESULTS: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies. CONCLUSIONS: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.
Authors: Anne Slavotinek; Doriana Misceo; Stephanie Htun; Linda Mathisen; Eirik Frengen; Michelle Foreman; Jennifer E Hurtig; Liz Enyenihi; Maria C Sterrett; Sara W Leung; Dina Schneidman-Duhovny; Juvianee Estrada-Veras; Jacque L Duncan; Charlotte A Haaxma; Erik-Jan Kamsteeg; Vivian Xia; Daniah Beleford; Yue Si; Ganka Douglas; Hans Einar Treidene; Ambro van Hoof; Milo B Fasken; Anita H Corbett Journal: Hum Mol Genet Date: 2020-08-03 Impact factor: 6.150