Mitochondrial Diseases Caused by Mutations in Inner Membrane Chaperone Proteins
This chapter summarizes current knowledge of several disorders associated with the dysfunction of the mitochondrial membrane chaperone proteins, and pays particular attention to the X-linked recessive Mohr–Tranebjaerg syndrome (MTS), also called deafness-dystonia-optic neuronopathy syndrome (DDON syndrome), caused by mutations in TIMM8A.
The human disorders associated with mutations in the chaperone genes present clinically with extremely different phenotypes. Even within MTS, there is considerable variability of clinical symptoms. However, some characteristic clinical abnormalities include early-onset profound hearing impairment, dystonia, later occurrence of optic atrophy of cerebral origin (optic neuronopathy), and often serious personality changes with loss of inhibition and cognitive decline. In addition, the majority of patients have some degree of learning disability during childhood. Neuropathological abnormalities include general brain atrophy, particularly of visual cortex, with histological examinations of temporal bones showing a complete loss of neurons with relative preservation of other components of the auditory pathways, typical of auditory neuropathy. Although MTS is an X-linked disorder which is more often observed in males, affected females have also been described.
The mechanisms leading to neurodegeneration in MTS do not correlate to abnormal oxidative phosphorylation (OXPHOS) function, but there is recent evidence for morphologically abnormal mitochondria in fibroblasts from patients. Much more research is needed to understand the pathology. MTS should be suspected in males with hearing impairment and dystonia, but should also be considered in females with the appropriate clinical symptoms.
KeywordsDeafblindness TIMM8A Mitochondrial Neurodegeneration Syndrome
Some of the work took place at the Wilhelm Johannsen Center for Functional Genome Research, established by the Danish National Research Foundation. We acknowledge thefinancial support to the project by the Lundbeck Foundation, grant R9-A918. The data compiled here are the result of dedicated collaborative work and inspiring discussions since the 1990s involving many people: Marijke van Ghelue, Mona Nystad, Department of medical Genetics, University Hospital of Northern Norway, N-Tromsø, Norway; David Scheie, Department of Pathology, University Hospital, Oslo, Norway; Marianne Lodahl and Nanna Dahl Rendtorff, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Denmark.
We would like to acknowledge and thank the colleagues allowing us to briefly mention unpublished MTS patients: Mary Ellen Conley, MD, West Research Tower, LeBonHeur Children’s Hospital, Memphis TN; Dirk Kunst, Department of Otorhinolaryngology, Head and Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands and Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, the Netherlands; Irene Stolte-Dijkstra, Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Alain Verloes, M.D., Ph.D, Department of Genetics, Robert Debre Hospital, Referring Centre for developmental abnormalities and syndromic malformations, Paris, France; John Tolmie, and Katherine McWilliams, Clinical Genetics, Ferguson-Smith Centre, Glasgow, Scotland; Miles Humberstones, MD, Department of Neurology, Nottingham University Hospital, Nottingham, UK; Jan Ulrik Prause, MD, PhD, Department of Eye Pathology, University of Copenhagen, Denmark; Henning Laursen, MD,PhD; Department of Neuropathology, University Hospital of Copenhagen, Denmark; Saumil Merchant, MD, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA; Kirsty Gardner-Berry, BSc, Department of Audiology, SCIC, Gladesville Hospital, Gladesville, NSW, Australia; Graham Reynolds, MD, Department of Paediatrics and Child Health, ANU Medical School, Canberra Hospital, Australia; Melanie Wong, Department of Allergy and Immunology, Children’s Hospital, Westmead, NSW, Australia.
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