Bruhn Helene, Samuelsson Kristin, Schober Florian A, Engvall Martin, Lesko Nicole, Wibom Rolf, Nennesmo Inger, Calvo-Garrido Javier, Press Rayomand, Stranneheim Henrik, Freyer Christoph, Wedell Anna, Wredenberg Anna
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.
Neurol Genet. 2021 Mar 15;7(2):e566. doi: 10.1212/NXG.0000000000000566. eCollection 2021 Apr.
To investigate the pathogenicity of a novel mutation identified in a patient with adult-onset sensorimotor axonal polyneuropathy and report the clinical, morphologic, and biochemical findings.
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.
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 , 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.
We report a case with adult-onset sensorimotor axonal polyneuropathy caused by a novel mtDNA mutation in . 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.
研究在一名成年起病的感觉运动性轴索性多神经病患者中鉴定出的一种新突变的致病性，并报告临床、形态学和生化检查结果。
对该患者的骨骼肌和培养的成肌细胞进行临床评估、形态学和生化检查。对骨骼肌DNA进行全基因组测序（WGS），对骨骼肌和培养的成肌细胞的线粒体DNA（mtDNA）进行桑格测序。通过最后一轮热启动PCR定量不同组织中突变mtDNA的异质性水平。
肌肉显示破碎红纤维、副结晶包涵体，复合体I（CI）呼吸链（RC）活性显著降低，CI使用的所有底物的三磷酸腺苷（ATP）生成减少。骨骼肌DNA的桑格测序检测到mtDNA编码的 中一个独特的、以前未报道的异质性突变，该基因编码CI中的一个亚基。WGS证实了mtDNA突变，但未检测到任何其他可解释该疾病的突变。然而，培养的成肌细胞未携带该突变，成肌细胞中的RC活性测量结果正常。
我们报告了一例由 中一种新的mtDNA突变引起的成年起病的感觉运动性轴索性多神经病病例。患者血液、培养的成纤维细胞和成肌细胞中异质性的丧失，以及成肌细胞RC活性的正常测量支持了该突变的致病性。这些发现突出了对看似特发性多神经病患者进行线粒体检查的重要性，特别是在肌肉也受到影响的情况下。
