Helene Bruhn1, Kristin Samuelsson1, Florian A Schober1, Martin Engvall1, Nicole Lesko1, Rolf Wibom1, Inger Nennesmo1, Javier Calvo-Garrido1, Rayomand Press1, Henrik Stranneheim1, Christoph Freyer1, Anna Wedell1, Anna Wredenberg1. 1. Department of Medical Biochemistry and Biophysics (H.B., R.W., C.F., A. Wredenberg), Karolinska Institutet; Centre for Inherited Metabolic Diseases (H.B., R.W., C.F., M.E., N.L., H.S., A. Wedell, A. Wredenberg), Karolinska University Hospital; Department of Clinical Neuroscience (K.S., R.P.), Karolinska Institutet; Department of Neurology (K.S., R.P.), Karolinska University Hospital; Department of Molecular Medicine and Surgery (F.A.S., M.E., N.L., J.C.-G., H.S., A. Wedell), Karolinska Institutet; Department of Pathology (I.N.), Karolinska University Hospital; and Science for Life Laboratory (H.S.), Karolinska Institutet, Stockholm, Sweden.
Abstract
OBJECTIVE: To investigate the pathogenicity of a novel MT-ND3 mutation identified in a patient with adult-onset sensorimotor axonal polyneuropathy and report the clinical, morphologic, and biochemical findings. METHODS: Clinical assessments and morphologic and biochemical investigations of skeletal muscle and cultured myoblasts from the patient were performed. Whole-genome sequencing (WGS) of DNA from skeletal muscle and Sanger sequencing of mitochondrial DNA (mtDNA) from both skeletal muscle and cultured myoblasts were performed. Heteroplasmic levels of mutated mtDNA in different tissues were quantified by last-cycle hot PCR. RESULTS: Muscle showed ragged red fibers, paracrystalline inclusions, a significant reduction in complex I (CI) respiratory chain (RC) activity, and decreased adenosine triphosphate (ATP) production for all substrates used by CI. Sanger sequencing of DNA from skeletal muscle detected a unique previously unreported heteroplasmic mutation in mtDNA encoded MT-ND3, coding for a subunit in CI. WGS confirmed the mtDNA mutation but did not detect any other mutation explaining the disease. Cultured myoblasts, however, did not carry the mutation, and RC activity measurements in myoblasts were normal. CONCLUSIONS: We report a case with adult-onset sensorimotor axonal polyneuropathy caused by a novel mtDNA mutation in MT-ND3. Loss of heteroplasmy in blood, cultured fibroblasts and myoblasts from the patient, and normal measurement of RC activity of the myoblasts support pathogenicity of the mutation. These findings highlight the importance of mitochondrial investigations in patients presenting with seemingly idiopathic polyneuropathy, especially if muscle also is affected.
OBJECTIVE: To investigate the pathogenicity of a novel MT-ND3 mutation identified in a patient with adult-onset sensorimotor axonal polyneuropathy and report the clinical, morphologic, and biochemical findings. METHODS: Clinical assessments and morphologic and biochemical investigations of skeletal muscle and cultured myoblasts from the patient were performed. Whole-genome sequencing (WGS) of DNA from skeletal muscle and Sanger sequencing of mitochondrial DNA (mtDNA) from both skeletal muscle and cultured myoblasts were performed. Heteroplasmic levels of mutated mtDNA in different tissues were quantified by last-cycle hot PCR. RESULTS: Muscle showed ragged red fibers, paracrystalline inclusions, a significant reduction in complex I (CI) respiratory chain (RC) activity, and decreased adenosine triphosphate (ATP) production for all substrates used by CI. Sanger sequencing of DNA from skeletal muscle detected a unique previously unreported heteroplasmic mutation in mtDNA encoded MT-ND3, coding for a subunit in CI. WGS confirmed the mtDNA mutation but did not detect any other mutation explaining the disease. Cultured myoblasts, however, did not carry the mutation, and RC activity measurements in myoblasts were normal. CONCLUSIONS: We report a case with adult-onset sensorimotor axonal polyneuropathy caused by a novel mtDNA mutation in MT-ND3. Loss of heteroplasmy in blood, cultured fibroblasts and myoblasts from the patient, and normal measurement of RC activity of the myoblasts support pathogenicity of the mutation. These findings highlight the importance of mitochondrial investigations in patients presenting with seemingly idiopathic polyneuropathy, especially if muscle also is affected.
Authors: K M Clark; L A Bindoff; R N Lightowlers; R M Andrews; P G Griffiths; M A Johnson; E J Brierley; D M Turnbull Journal: Nat Genet Date: 1997-07 Impact factor: 38.330
Authors: Charalampos L Karadimas; Tuan H Vu; Stephen A Holve; Penelope Chronopoulou; Catarina Quinzii; Stanley D Johnsen; Janice Kurth; Elizabeth Eggers; Lluis Palenzuela; Kurenai Tanji; Eduardo Bonilla; Darryl C De Vivo; Salvatore DiMauro; Michio Hirano Journal: Am J Hum Genet Date: 2006-06-28 Impact factor: 11.025
Authors: Timothy Harrower; Joanna D Stewart; Gavin Hudson; Henry Houlden; Graham Warner; Dominic G O'Donovan; Leslie J Findlay; Robert W Taylor; Rajith De Silva; Patrick F Chinnery Journal: Arch Neurol Date: 2008-01