Themitochondrialmalate aspartate shuttle system(MAS)maintains the cytosolicNAD+/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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:88529 |
| Date | 07 December 2023 |
| Creators | Bölsterli, Bigna K., Boltshauser, Eugen, Palmieri, Luigi, Spenger, Johannes, Brunner-Krainz, Michaela, Distelmaier, Felix, Freisinger, Peter, Geis, Tobias, Gropman, Andrea L., Häberle, Johannes, Hentschel, Julia, Jeandidier, Bruno, Karall, Daniela, Keren, Boris, Klabunde-Cherwon, Annick, Konstantopoulou, Vassiliki, Kottke, Raimund, Lasorsa, Francesco M., Makowski, Christine, Mignot, Cyril, O'Gorman Tuura, Ruth, Porcelli, Vito, Santer, René, Sen, Kuntal, Steinbrücker, Katja, Syrbe, Steffen, Wagner, Matias, Ziegler, Andreas, Zöggeler, Thomas, Mayr, Johannes A., Prokisch, Holger, Wortmann, Saskia B. |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 3605 |
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