期刊
NUTRIENTS
卷 14, 期 17, 页码 -出版社
MDPI
DOI: 10.3390/nu14173605
关键词
mitochondrial disease; epilepsy; hepatopathy; aspartate glutamate carrier 1 deficiency; AGC1; citrin deficiency; Citrullinemia; treatment; modified Atkins diet; serine
资金
- Children's Research Center
- Austrian Science Fund [FWF 4704-B]
- BMBF (German Federal Ministry of Education and Research) [01GM1906B]
- PerMiM Personalized Mitochondrial Medicine [01KU2016A]
- E-Rare project GENOMIT: Mitochondrial Disorders: from a world-wide registry to medical genomics, toward molecular mechanisms and new therapies [01GM1207]
- Austrian Science Fund (FWF) [I4695-B]
- German Research Foundation/Deutsche Forschungsgemeinschaft [DI 1731/2-2]
- Elterninitiative Kinderkrebsklinik e.V. (Dusseldorf, Germany) [701900167]
- Swiss National Science Foundation [320030_176088]
- [ERAPERMED2019-310]
- Swiss National Science Foundation (SNF) [320030_176088] Funding Source: Swiss National Science Foundation (SNF)
- Austrian Science Fund (FWF) [I4695] Funding Source: Austrian Science Fund (FWF)
Defects in the mitochondrial malate aspartate shuttle system and mitochondrial pyruvate carrier 1 are associated with neurological phenotypes and hepatopathic-neuropsychiatric phenotypes. Ketogenic diets and carbohydrate-restricted/fat-enriched diets are effective interventions. Early (genetic) diagnosis is crucial for initiating proper treatment.
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.
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