Nutritional interventions in primary mitochondrial disorders: Developing an evidence base

Kathryn M Camp¹, Danuta Krotoski², Melissa A Parisi³, Katrina A Gwinn⁴, Bruce H Cohen⁵, Christine S Cox⁶, Gregory M Enns⁷, Marni J Falk⁸, Amy C Goldstein⁹, Rashmi Gopal-Srivastava¹⁰, Gráinne S Gorman¹¹, Stephen P Hersh¹², Michio Hirano¹³, Freddie Ann Hoffman¹⁴, Amel Karaa¹⁵, Erin L MacLeod¹⁶, Robert McFarland¹⁷, Charles Mohan¹⁸, Andrew E Mulberg¹⁹, Joanne C Odenkirchen²⁰, Sumit Parikh²¹, Patricia J Rutherford²², Shawne K Suggs-Anderson²³, W H Wilson Tang²⁴, Jerry Vockley²⁵, Lynne A Wolfe²⁶, Steven Yannicelli²⁷, Philip E Yeske²⁸, Paul M Coates²⁹

Affiliations

¹ Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: campkm@od.nih.gov.
² Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: krotoskd@mail.nih.gov.
³ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: parisima@mail.nih.gov.
⁴ National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gwinnk@ninds.nih.gov.
⁵ Department of Pediatrics, Akron Children's Hospital, Akron, OH 44308, USA. Electronic address: bcohen@chmca.org.
⁶ MitoAction, Boston, MA 02205, USA. Electronic address: outreach@mitoaction.org.
⁷ Division of Medical Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: genns@stanford.edu.
⁸ The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: falkm@email.chop.edu.
⁹ Division of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: amy.goldstein@chp.edu.
¹⁰ National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rashmi.gopal-srivastava@nih.gov.
¹¹ Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: grainne.gorman@newcastle.ac.uk.
¹² J. Willard & Alice S. Marriott Foundation, Bethesda, MD 20817, USA. Electronic address: hershs@starpower.net.
¹³ Columbia University Medical Center, New York, NY 10032, USA. Electronic address: mh29@cumc.columbia.edu.
¹⁴ HeteroGeneity, LLC, Washington, DC 20011, USA. Electronic address: fhoffman@heterogeneity-LLC.com.
¹⁵ Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: akaraa@mgh.harvard.edu.
¹⁶ Division of Genetics and Metabolism, Children's National Health System, Washington, DC 20010, USA. Electronic address: emacleod@childrensnational.org.
¹⁷ Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: robert.mcfarland@newcastle.ac.uk.
¹⁸ United Mitochondrial Disease Foundation, Pittsburgh, PA 15239, USA. Electronic address: chuckm@umdf.org.
¹⁹ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20903, USA. Electronic address: amulberg@amicusrx.com.
²⁰ National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jo21x@nih.gov.
²¹ Neurosciences, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: parikhs@ccf.org.
²² Vitaflo International Ltd, Liverpool L34BQ, UK. Electronic address: triciarutherford@vitaflo.co.uk.
²³ Office of Nutrition and Food Labeling, Food and Drug Administration, College Park, MD 20740, USA. Electronic address: shawne.suggs-anderson@fda.hhs.gov.
²⁴ Center for Clinical Genomics, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: tangw@ccf.org.
²⁵ University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. Electronic address: gerard.vockley@chp.edu.
²⁶ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lynne.wolfe@nih.gov.
²⁷ Medical and Scientific Affairs, Nutricia North America, Rockville, MD 20850, USA. Electronic address: steven.yannicelli@nutricia.com.
²⁸ United Mitochondrial Disease Foundation, Pittsburgh, PA 15239, USA. Electronic address: philip.yeske@umdf.org.
²⁹ Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: coatesp@od.nih.gov.

PMID: 27665271
PMCID: PMC5083179
DOI: 10.1016/j.ymgme.2016.09.002

Review

Nutritional interventions in primary mitochondrial disorders: Developing an evidence base

Kathryn M Camp et al. Mol Genet Metab. 2016 Nov.

. 2016 Nov;119(3):187-206.

doi: 10.1016/j.ymgme.2016.09.002. Epub 2016 Sep 20.

Authors

Affiliations

¹ Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: campkm@od.nih.gov.
² Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: krotoskd@mail.nih.gov.
³ Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: parisima@mail.nih.gov.
⁴ National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gwinnk@ninds.nih.gov.
⁵ Department of Pediatrics, Akron Children's Hospital, Akron, OH 44308, USA. Electronic address: bcohen@chmca.org.
⁶ MitoAction, Boston, MA 02205, USA. Electronic address: outreach@mitoaction.org.
⁷ Division of Medical Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: genns@stanford.edu.
⁸ The Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: falkm@email.chop.edu.
⁹ Division of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: amy.goldstein@chp.edu.
¹⁰ National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: rashmi.gopal-srivastava@nih.gov.
¹¹ Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: grainne.gorman@newcastle.ac.uk.
¹² J. Willard & Alice S. Marriott Foundation, Bethesda, MD 20817, USA. Electronic address: hershs@starpower.net.
¹³ Columbia University Medical Center, New York, NY 10032, USA. Electronic address: mh29@cumc.columbia.edu.
¹⁴ HeteroGeneity, LLC, Washington, DC 20011, USA. Electronic address: fhoffman@heterogeneity-LLC.com.
¹⁵ Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: akaraa@mgh.harvard.edu.
¹⁶ Division of Genetics and Metabolism, Children's National Health System, Washington, DC 20010, USA. Electronic address: emacleod@childrensnational.org.
¹⁷ Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: robert.mcfarland@newcastle.ac.uk.
¹⁸ United Mitochondrial Disease Foundation, Pittsburgh, PA 15239, USA. Electronic address: chuckm@umdf.org.
¹⁹ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20903, USA. Electronic address: amulberg@amicusrx.com.
²⁰ National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jo21x@nih.gov.
²¹ Neurosciences, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: parikhs@ccf.org.
²² Vitaflo International Ltd, Liverpool L34BQ, UK. Electronic address: triciarutherford@vitaflo.co.uk.
²³ Office of Nutrition and Food Labeling, Food and Drug Administration, College Park, MD 20740, USA. Electronic address: shawne.suggs-anderson@fda.hhs.gov.
²⁴ Center for Clinical Genomics, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: tangw@ccf.org.
²⁵ University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. Electronic address: gerard.vockley@chp.edu.
²⁶ National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lynne.wolfe@nih.gov.
²⁷ Medical and Scientific Affairs, Nutricia North America, Rockville, MD 20850, USA. Electronic address: steven.yannicelli@nutricia.com.
²⁸ United Mitochondrial Disease Foundation, Pittsburgh, PA 15239, USA. Electronic address: philip.yeske@umdf.org.
²⁹ Office of Dietary Supplements, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: coatesp@od.nih.gov.

PMID: 27665271
PMCID: PMC5083179
DOI: 10.1016/j.ymgme.2016.09.002

Abstract

In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

Keywords: Dietary supplements; Medical foods; Mitochondrial disease; Nutritional interventions; OXPHOS; Primary mitochondrial disorders.

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References

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Nutritional interventions in primary mitochondrial disorders: Developing an evidence base

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Nutritional interventions in primary mitochondrial disorders: Developing an evidence base

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