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October 2018; 4 (5) ArticleOpen Access

Bioenergetics in fibroblasts of patients with Huntington disease are associated with age at onset

Sarah L. Gardiner, Chiara Milanese, Merel W. Boogaard, Ronald A.M. Buijsen, Marye Hogenboom, Raymund A.C. Roos, Pier G. Mastroberardino, Willeke M.C. van Roon-Mom, N. Ahmad Aziz
First published October 4, 2018, DOI: https://doi.org/10.1212/NXG.0000000000000275
Sarah L. Gardiner
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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Chiara Milanese
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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Merel W. Boogaard
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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Ronald A.M. Buijsen
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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Marye Hogenboom
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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Raymund A.C. Roos
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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Pier G. Mastroberardino
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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Willeke M.C. van Roon-Mom
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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N. Ahmad Aziz
From the Department of Neurology (S.L.G., M.H., R.A.C.R., N.A.A.), Department of Human Genetic (S.L.G., R.A.M.B., W.M.C.v.R.-M.), and Department of Clinical Genetics (M.W.B.), Leiden University Medical Centre, Leiden; Department of Molecular Genetics (C.M., P.G.M.), Erasmus Medical Centre, Rotterdam, The Netherlands; and German Center for Neurodegenerative Diseases (DZNE) (N.A.A.), Bonn, Germany.
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Citation
Bioenergetics in fibroblasts of patients with Huntington disease are associated with age at onset
Sarah L. Gardiner, Chiara Milanese, Merel W. Boogaard, Ronald A.M. Buijsen, Marye Hogenboom, Raymund A.C. Roos, Pier G. Mastroberardino, Willeke M.C. van Roon-Mom, N. Ahmad Aziz
Neurol Genet Oct 2018, 4 (5) e275; DOI: 10.1212/NXG.0000000000000275

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Abstract

Objective We aimed to assess whether differences in energy metabolism in fibroblast cell lines derived from patients with Huntington disease were associated with age at onset independent of the cytosine-adenine-guanine (CAG) repeat number in the mutant allele.

Methods For this study, we selected 9 pairs of patients with Huntington disease matched for mutant CAG repeat size and sex, but with a difference of at least 10 years in age at onset, using the Leiden Huntington disease database. From skin biopsies, we isolated fibroblasts in which we (1) quantified the ATP concentration before and after a hydrogen-peroxide challenge and (2) measured mitochondrial respiration and glycolysis in real time, using the Seahorse XF Extracellular Flux Analyzer XF24.

Results The ATP concentration in fibroblasts was significantly lower in patients with Huntington disease with an earlier age at onset, independent of calendar age and disease duration. Maximal respiration, spare capacity, and respiration dependent on complex II activity, and indices of mitochondrial respiration were significantly lower in patients with Huntington disease with an earlier age at onset, again independent of calendar age and disease duration.

Conclusions A less efficient bioenergetics profile was found in fibroblast cells from patients with Huntington disease with an earlier age at onset independent of mutant CAG repeat size. Thus, differences in bioenergetics could explain part of the residual variation in age at onset in Huntington disease.

Glossary

CAG=
cytosine-adenine-guanine;
ECAR=
extracellular acidification rate;
OCR=
oxygen consumption rate

Footnotes

  • ↵* Completed the statistical analysis.

  • Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG.

  • The Article Processing charge was funded by the authors.

  • Received May 4, 2018.
  • Accepted in final form August 8, 2018.
  • Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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