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Original article
Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency
  1. Christopher Benjamin Jackson1,2,
  2. Jean-Marc Nuoffer3,
  3. Dagmar Hahn3,
  4. Holger Prokisch4,5,
  5. Birgit Haberberger4,
  6. Matthias Gautschi3,6,
  7. Annemarie Häberli3,
  8. Sabina Gallati1,
  9. André Schaller1
  1. 1Division of Human Genetics, Departments of Paediatrics and Clinical Research, University of Bern, Bern, Switzerland
  2. 2Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
  3. 3Institute of Clinical Chemistry, University Hospital Bern, Bern, Switzerland
  4. 4Institute of Human Genetics, Helmholtz Zentrum München, München, Germany
  5. 5Institute of Human Genetics, Technische Universität München, München, Germany
  6. 6Division of Paediatric Endocrinology, Diabetology and Metabolism, Department of Paediatrics, University of Bern, Bern, Switzerland
  1. Correspondence to Dr André Schaller, Division of Human Genetics, Departments of Paediatrics and Clinical Research, Inselspital Bern, Bern CH-3010, Switzerland; andre.schaller{at}insel.ch

Abstract

Background Defects of the mitochondrial respiratory chain complex II (succinate dehydrogenase (SDH) complex) are extremely rare. Of the four nuclear encoded proteins composing complex II, only mutations in the 70 kDa flavoprotein (SDHA) and the recently identified complex II assembly factor (SDHAF1) have been found to be causative for mitochondrial respiratory chain diseases. Mutations in the other three subunits (SDHB, SDHC, SDHD) and the second assembly factor (SDHAF2) have so far only been associated with hereditary paragangliomas and phaeochromocytomas. Recessive germline mutations in SDHB have recently been associated with complex II deficiency and leukodystrophy in one patient.

Methods and results We present the clinical and molecular investigations of the first patient with biochemical evidence of a severe isolated complex II deficiency due to compound heterozygous SDHD gene mutations. The patient presented with early progressive encephalomyopathy due to compound heterozygous p.E69 K and p.*164Lext*3 SDHD mutations. Native polyacrylamide gel electrophoresis and western blotting demonstrated an impaired complex II assembly. Complementation of a patient cell line additionally supported the pathogenicity of the novel identified mutations in SDHD.

Conclusions This report describes the first case of isolated complex II deficiency due to recessive SDHD germline mutations. We therefore recommend screening for all SDH genes in isolated complex II deficiencies. It further emphasises the importance of appropriate genetic counselling to the family with regard to SDHD mutations and their role in tumorigenesis.

  • succinate dehydrogenase
  • complex II deficiency
  • SDHD
  • mitochondrial disorder
  • encephalopathy

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