Nutrients (Aug 2022)
Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier
- Bigna K. Bölsterli,
- Eugen Boltshauser,
- Luigi Palmieri,
- Johannes Spenger,
- Michaela Brunner-Krainz,
- Felix Distelmaier,
- Peter Freisinger,
- Tobias Geis,
- Andrea L. Gropman,
- Johannes Häberle,
- Julia Hentschel,
- Bruno Jeandidier,
- Daniela Karall,
- Boris Keren,
- Annick Klabunde-Cherwon,
- Vassiliki Konstantopoulou,
- Raimund Kottke,
- Francesco M. Lasorsa,
- Christine Makowski,
- Cyril Mignot,
- Ruth O’Gorman Tuura,
- Vito Porcelli,
- René Santer,
- Kuntal Sen,
- Katja Steinbrücker,
- Steffen Syrbe,
- Matias Wagner,
- Andreas Ziegler,
- Thomas Zöggeler,
- Johannes A. Mayr,
- Holger Prokisch,
- Saskia B. Wortmann
Affiliations
- Bigna K. Bölsterli
- Department of Pediatric Neurology, University Children’s Hospital Zurich, 8032 Zurich, Switzerland
- Eugen Boltshauser
- Department of Pediatric Neurology (Emeritus), University Children’s Hospital Zurich, 8032 Zurich, Switzerland
- Luigi Palmieri
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy
- Johannes Spenger
- University Children’s Hospital, Paracelsus Medical University (PMU), 5020 Salzburg, Austria
- Michaela Brunner-Krainz
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, 8036 Graz, Austria
- Felix Distelmaier
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
- Peter Freisinger
- Department of Pediatrics, Klinikum Reutlingen, 72764 Reutlingen, Germany
- Tobias Geis
- University Children′s Hospital Regensburg (KUNO), Hospital St. Hedwig of the Order of St. John, University of Regensburg, 93049 Regensburg, Germany
- Andrea L. Gropman
- Division of Neurogenetics, Center for Neuroscience and Behavioral Medicine, Children’s National Hospital, Washington, DC 20010, USA
- Johannes Häberle
- Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, Switzerland
- Julia Hentschel
- Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 04103 Leipzig, Germany
- Bruno Jeandidier
- APHP, Service de Pédiatrie, CHU Jean Verdier, 93140 Bondy, France
- Daniela Karall
- Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Boris Keren
- Département de Génétique, Unité Fonctionnelle de Génomique du Développement, Hôpital Pitié-Salpêtrière, 75013 Paris, France
- Annick Klabunde-Cherwon
- Division of Paediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Vassiliki Konstantopoulou
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria
- Raimund Kottke
- Department of Diagnostic Imaging, University Children’s Hospital Zurich, 8032 Zurich, Switzerland
- Francesco M. Lasorsa
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy
- Christine Makowski
- Department of Paediatrics, Children’s Hospital Munich Schwabing, MüK and TUM, 80804 Munich, Germany
- Cyril Mignot
- Département de Génétique, Unité Fonctionnelle de Génomique du Développement, Hôpital Pitié-Salpêtrière, 75013 Paris, France
- Ruth O’Gorman Tuura
- Children’s Research Center, University Children’s Hospital Zurich, 8032 Zurich, Switzerland
- Vito Porcelli
- Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy
- René Santer
- Department of Pediatrics, University Medical Center Eppendorf, 20246 Hamburg, Germany
- Kuntal Sen
- Division of Neurogenetics, Center for Neuroscience and Behavioral Medicine, Children’s National Hospital, Washington, DC 20010, USA
- Katja Steinbrücker
- Department of Neuropediatrics, Paracelsus Medical University Hospital Salzburg, 5020 Salzburg, Austria
- Steffen Syrbe
- Division of Paediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Matias Wagner
- Institute of Human Genetics, School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Andreas Ziegler
- Division of Neuropaediatrics and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Thomas Zöggeler
- Clinic for Pediatrics, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Johannes A. Mayr
- University Children’s Hospital, Paracelsus Medical University (PMU), 5020 Salzburg, Austria
- Holger Prokisch
- Institute of Human Genetics, School of Medicine, Technical University of Munich, 81675 Munich, Germany
- Saskia B. Wortmann
- University Children’s Hospital, Paracelsus Medical University (PMU), 5020 Salzburg, Austria
- DOI
- https://doi.org/10.3390/nu14173605
- Journal volume & issue
-
Vol. 14,
no. 17
p. 3605
Abstract
The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits—mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.
Keywords
- mitochondrial disease
- epilepsy
- hepatopathy
- aspartate glutamate carrier 1 deficiency
- AGC1
- citrin deficiency
