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Aberrant synthesis of ATP synthase resulting from a novel deletion in mitochondrial DNA in an African patient with progressive external ophthalmoplegia

  • Case Report
  • Published:
Journal of Inherited Metabolic Disease

Abstract

A young, adult, African male patient presented with progressive proximal muscle weakness, external ophthalmoplegia and ptosis, as well as cardiac conduction abnormalities resembling Kearns–Sayre syndrome (KSS). Magnetic resonance imaging (MRI) of the brain revealed normal basal ganglia but bilateral well-circumscribed lesions in the cerebellar peduncles. Enzyme deficiencies in oxidative phosphorylation (OXPHOS) complexes I, IV and V was measured in muscle tissue. Blue native polyacrylamide gel electrophoresis (BN-PAGE) confirmed decreased protein content and activity of these complexes and revealed the presence of two catalytically active complex V sub-complexes. Upon investigation by molecular genetics, the mitochondrial DNA (mtDNA) copy number was found to be elevated and a novel deletion of 3431 bp was found in 80% of muscle mtDNA between positions 7115 and 10546, flanked by a 5 bp direct repeat sequence. In addition, it could also be concluded that the absence of mtDNA-encoded ATPase6 and ATPase8 genes in this patient clearly resulted in aberrant synthesis of ATP synthase.

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Abbreviations

BN-PAGE:

blue native polyacrylamide gel electrophoresis

ECG:

electrocardiogram

EMG:

electromyogram

MRI:

magnetic resonance imaging

FLAIR:

fluid-attenuated inversion-recovery

DWI:

diffusion-weighted imaging

HbA1C :

glycohaemoglobin

mtDNA:

mitochondrial DNA

OXPHOS:

oxidative phosphorylation

ROS:

reactive oxygen species

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Acknowledgements

The authors would like to thank the Medical Research Council of South Africa for financial support.

Author information

Authors and Affiliations

  1. Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa

    Francois H. van der Westhuizen, Oksana Levanets, Madelein Meissner-Roloff & Roan Louw

  2. Department of Paediatrics, Division of Paediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium

    Joél Smet & Rudy Van Coster

  3. Department of Paediatrics, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa

    Izelle Smuts

  4. P.O. Box 32781, Totiusdal, 0134, South Africa

    Izelle Smuts

Authors
  1. Francois H. van der Westhuizen
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  2. Joél Smet
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  3. Oksana Levanets
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  4. Madelein Meissner-Roloff
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  5. Roan Louw
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  6. Rudy Van Coster
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  7. Izelle Smuts
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Corresponding author

Correspondence to Izelle Smuts.

Additional information

Communicated by: Shamima Rahman

References to electronic databases: Progressive external ophthalmoplegia: OMIM 157640, 609286, 258450, 610131, 609283, 258400. Retinitis pigmentosa: OMIM 600105, 608133, 500004, 612572, 312612, 268025, 268000, 312600, 300389, 180104. Kearns–Sayre syndrome: OMIM 530000. Pearson marrow–pancreas syndrome: OMIM 557000. ATP:creatine N-phosphotransferase (creatine kinase): EC 2.7.3.2. NADH:ubiquinone oxidoreductase (complex I): EC 1.6.5.3. Succinate:ubiquinone oxidoreductase (complex II): EC 1.3.5.1. Ubiquinol:ferricytochrome-c oxidoreductase (complex III): EC 1.10.2.2. Ferrocytochrome-c:oxygen oxidoreductase (complex IV): EC 1.9.3.1. ATP phosphohydrolase (complex V): EC 3.6.1.3. Pyruvate:[dihydrolipoyllysine-residue acetyltransferase]-lipoyllysine 2-oxidoreductase (decarboxylating, acceptor-acetylating; pyruvate dehydrogenase complex): EC 1.2.4.1. Acetyl-CoA:oxaloacetate C-acetyltransferase [thioester-hydrolysing, (pro-S)-carboxymethyl forming] (citrate synthase): EC 2.3.3.1. Deoxynucleoside-triphosphate:DNA deoxynucleotidyltransferase (DNA-directed; DNA polymerase gamma): EC 2.7.7.7.

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van der Westhuizen, F.H., Smet, J., Levanets, O. et al. Aberrant synthesis of ATP synthase resulting from a novel deletion in mitochondrial DNA in an African patient with progressive external ophthalmoplegia. J Inherit Metab Dis 33 (Suppl 3), 55–62 (2010). https://doi.org/10.1007/s10545-009-9020-y

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  • DOI: https://doi.org/10.1007/s10545-009-9020-y

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