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Variable penetrance of a familial progressive necrotising encephalopathy due to a novel tRNAIle homoplasmic mutation in the mitochondrial genome
  1. A Limongelli1,*,
  2. J Schaefer2,*,
  3. S Jackson2,
  4. F Invernizzi1,
  5. Y Kirino3,
  6. T Suzuki3,
  7. H Reichmann2,
  8. M Zeviani1
  1. 1Unit of Molecular Neurogenetics–Pierfranco and Luisa Mariani Centre for the Study of Children’s Mitochondrial Disorders, National Neurological Institute “Carlo Besta”, Milan, Italy
  2. 2Neurological Clinics, School of Medicine, Technical University, Dresden, Germany
  3. 3Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan
  1. Correspondence to:
 M Zeviani
 MD, PhD, Unit of Molecular Neurogenetics, National Neurological Institute “Carlo Besta”, via Temolo 4, 20133 Milan, Italy;;


Introduction: We present a family comprising a clinically normal mother and two daughters, each with severe encephalopathy with onset in late childhood. A third daughter had died previously of an earlier onset but neuropathologically similar disease.

Methods: Sequence analysis of the entire mtDNA was carried out in muscle, fibroblasts, and lymphocytes of the affected daughters and unaffected mother. Biochemical analysis of individual respiratory chain enzymes was performed on the same tissues, and on several transmitochondrial cybrid clones containing the nucleus of a 143B.206 osteosarcoma cell line and the mutant mtDNA.

Results: Genetic analyses revealed in both daughters and mother the presence of a novel mutation in the tRNAIle gene of mtDNA, which was homoplasmic in fibroblasts, lymphocytes, and skeletal muscle of the two patients. It was also homoplasmic in fibroblast and skeletal muscle samples of the mother, and approximately 97% heteroplasmic in her lymphocytes. Combined defects of complexes I and IV of the mitochondrial respiratory chain were found not only in fibroblasts of the two probands, but surprisingly also in those of their clinically unaffected mother. The respiratory chain defect segregated in transmitochondrial cybrids containing the nucleus of a 143B.206 osteosarcoma cell line and the mutant mtDNA, indicating that the latter was responsible for the biochemical phenotype.

Discussion: Our results support the concept that homoplasmic mutations in tRNA genes can be responsible for mitochondrial disorders characterised by extremely variable penetrance. Albeit still unexplained, this phenomenon has important consequences in the nosological characterisation, clinical management, and genetic counselling of mitochondrial disorders.

  • cybrid
  • encephalopathy
  • homoplasmy
  • mitochondrial genome
  • mutation
  • BAEP, brainstem auditory evoked potential
  • LHON, Leber’s hereditary optic neuropathy
  • MEP, motor evoked potential
  • MIHL, maternally inherited hearing loss
  • OXPHOS, oxidative phosphorylation
  • PCR, polymerase chain reaction
  • RFLP restriction fragment length polymorphism
  • SSEP, somatosensory evoked potentials

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  • * These authors contributed equally to this work.

  • Supported by Fondazione Telethon-Italy (grant GGP030039 to MZ), Fondazione Pierfranco e Luisa Mariani (Ricerca 2000 to MZ), Ricerca Finalizzata Ministero della Salute RF-2002/158 (to MZ), Fondazione Cariplo (to MZ), MitEuro network grant from the European Union Framework Program 5 (to MZ), DFG-Scha 551/2–1 (to JS), and InnoRegio BioMet (to SJ).

  • Conflicts of interest: none declared.