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Article

Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset

by
Sara Capiau
1,*,
Joél Smet
2,3,
Boel De Paepe
2,3,
Yilmaz Yildiz
4,5,
Mutluay Arslan
6,
Olivier Stevens
7,
Maxime Verschoore
2,3,
Hedwig Stepman
1,
Sara Seneca
8,9 and
Arnaud Vanlander
2,3,*
1
Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium
2
Department of Child Neurology & Metabolism, Ghent University Hospital, 9000 Ghent, Belgium
3
Laboratory for Mitochondrial Investigations, Ghent University, 9000 Ghent, Belgium
4
Department of Pediatric Metabolism, Hacettepe University Ihsan Dogramaci Children’s Hospital, Hacettepe 06230, Turkey
5
Pediatric Metabolic Diseases Unit, Gülhane Training and Research Hospital of the University of Health Sciences, Gülhane 06010, Turkey
6
Department of Pediatric Neurology, Gülhane Training and Research Hospital of the University of Health Sciences, Gülhane 06010, Turkey
7
Department of Neurology, Maria Middelares General Hospital, 9000 Ghent, Belgium
8
Research Group Reproduction and Genetics (REGE), Free University Brussels (VUB), 1090 Brussels, Belgium
9
Centre for Medical Genetics, University Hospital Brussels, Free University Brussels (VUB), 1090 Brussels, Belgium
*
Authors to whom correspondence should be addressed.
Cells 2022, 11(3), 489; https://doi.org/10.3390/cells11030489
Submission received: 9 November 2021 / Revised: 22 January 2022 / Accepted: 26 January 2022 / Published: 30 January 2022
(This article belongs to the Section Mitochondria)
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Abstract

Human mitochondrial disease exhibits large variation of clinical phenotypes, even in patients with the same causative gene defect. We illustrate this heterogeneity by confronting clinical and biochemical data of two patients with the uncommon pathogenic homoplasmic NC_012920.1(MT-ATP6):m.9035T>C variant in MT-ATP6. Patient 1 presented as a toddler with severe motor and speech delay and spastic ataxia without extra-neurologic involvement. Patient 2 presented in adolescence with ataxia and ophthalmoplegia without cognitive or motor impairment. Respiratory chain complex activities were normal in cultured skin fibroblasts from both patients when calculated as ratios over citrate synthase activity. Native gels found presence of subcomplexes of complex V in fibroblast and/or skeletal muscle. Bioenergetic measurements in fibroblasts from both patients detected reduced spare respiratory capacities and altered extracellular acidification rates, revealing a switch from mitochondrial respiration to glycolysis to uphold ATP production. Thus, in contrast to the differing disease presentation, biochemical evidence of mitochondrial deficiency turned out quite similar. We conclude that biochemical analysis remains a valuable tool to confirm the genetic diagnosis of mitochondrial disease, especially in patients with new gene variants or atypical clinical presentation.
Keywords: ATP-synthase; complex V deficiency; MT-ATP6; NC_012920.1(MT-ATP6):m.9035T>C; p.L170P; genotype-phenotype correlation; mitochondrial disorder ATP-synthase; complex V deficiency; MT-ATP6; NC_012920.1(MT-ATP6):m.9035T>C; p.L170P; genotype-phenotype correlation; mitochondrial disorder
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MDPI and ACS Style

Capiau, S.; Smet, J.; De Paepe, B.; Yildiz, Y.; Arslan, M.; Stevens, O.; Verschoore, M.; Stepman, H.; Seneca, S.; Vanlander, A. Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset. Cells 2022, 11, 489. https://doi.org/10.3390/cells11030489

AMA Style

Capiau S, Smet J, De Paepe B, Yildiz Y, Arslan M, Stevens O, Verschoore M, Stepman H, Seneca S, Vanlander A. Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset. Cells. 2022; 11(3):489. https://doi.org/10.3390/cells11030489

Chicago/Turabian Style

Capiau, Sara, Joél Smet, Boel De Paepe, Yilmaz Yildiz, Mutluay Arslan, Olivier Stevens, Maxime Verschoore, Hedwig Stepman, Sara Seneca, and Arnaud Vanlander. 2022. "Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset" Cells 11, no. 3: 489. https://doi.org/10.3390/cells11030489

APA Style

Capiau, S., Smet, J., De Paepe, B., Yildiz, Y., Arslan, M., Stevens, O., Verschoore, M., Stepman, H., Seneca, S., & Vanlander, A. (2022). Clinical Heterogeneity in MT-ATP6 Pathogenic Variants: Same Genotype—Different Onset. Cells, 11(3), 489. https://doi.org/10.3390/cells11030489

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