<i>SLC25A32</i> Mutations and Riboflavin-Responsive Exercise Intolerance

Schiff, Manuel; Veauville-Merllié, Alice; Su, Chen; Tzagoloff, Alexander; Rak, Malgorzata; Baulny, Hélène Ogier de; Boutron, Audrey; Smedts-Walters, Hélène; Romero, Norma B.; Rigal, Odile; Rustin, Pierre; Vianey‐Saban, Christine; Acquaviva‐Bourdain, Cécile

doi:10.1056/nejmc1513610

Cited by 95 publications

(85 citation statements)

References 5 publications

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“…Therefore, the authors propose confirmation and validation in a larger (international) patient population, possibly with the help of international networks such as “INFORM” and “MetabERN” (European Reference Network for Hereditary Metabolic Disorders). Finally, genetic defects in at least five other metabolic pathways dependent of flavin adenine dinucleotides are recognized to cause clinical and biochemical MADD‐like profiles . Although promotor region‐ or intronic variants might have been overlooked, it can also not be excluded that patients in whom DNA analysis only demonstrated one genetic variant, actually suffer from an MADD‐like disease.…”

Section: Discussionmentioning

confidence: 99%

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Rijt

Ferdinandusse

Giannopoulos

et al. 2019

J of Inher Metab Disea

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Summary Multiple acyl‐CoA dehydrogenase deficiency (MADD) is an ultra‐rare inborn error of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual phenotypes and treatment response can vary markedly. We aimed to identify markers that predict MADD phenotypes. We performed a retrospective nationwide cohort study; then developed an MADD‐disease severity scoring system (MADD‐DS3) based on signs and symptoms with weighed expert opinions; and finally correlated phenotypes and MADD‐DS3 scores to FAO flux (oleate and myristate oxidation rates) and acylcarnitine profiles after palmitate loading in fibroblasts. Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD‐DS3 entails enumeration of eight domain scores, which are calculated by averaging the relevant symptom scores. Lifetime MADD‐DS3 scores of patients in our cohort ranged from 0 to 29. FAO flux and [U‐13C]C2‐, C5‐, and [U‐13C]C16‐acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all P < .05) and strongly correlated to MADD‐DS3 scores (oleate: r = −.86; myristate: r = −.91; [U‐13C]C2‐acylcarnitine: r = −.96; C5‐acylcarnitine: r = .97; [U‐13C]C16‐acylcarnitine: r = .98, all P < .01). Functional studies in fibroblasts were found to differentiate between neonatal and later onset MADD‐patients and were correlated to MADD‐DS3 scores. Our data may improve early prediction of disease severity in order to start (preventive) and follow‐up treatment appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs.

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Section: Discussionmentioning

confidence: 99%

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Rijt

Ferdinandusse

Giannopoulos

et al. 2019

J of Inher Metab Disea

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“…Muscle biopsy revealed ragged‐red fibres, lipid storage and fibres with decreased staining for succinate dehydrogenase (SDH, FAD‐dependent mitochondrial respiratory chain complex II), and cytochrome c oxidase (COX, mitochondrial respiratory chain complex IV) in both patients. Deficiency of complex II was demonstrated in muscle from the second patient and cultured skin fibroblasts from the first patient . Both patients had dramatic improvements in the clinical and biochemical abnormalities following oral riboflavin supplementation, including improved exercise tolerance and endurance …”

Section: Riboflavin Disorders In Humansmentioning

confidence: 95%

“…Deficiency of complex II was demonstrated in muscle from the second patient and cultured skin fibroblasts from the first patient . Both patients had dramatic improvements in the clinical and biochemical abnormalities following oral riboflavin supplementation, including improved exercise tolerance and endurance …”

Section: Riboflavin Disorders In Humansmentioning

confidence: 95%

Disorders of riboflavin metabolism

Balasubramaniam

Christodoulou

Rahman

2019

J of Inher Metab Disea

102

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Riboflavin (vitamin B2), a water‐soluble vitamin, is an essential nutrient in higher organisms as it is not endogenously synthesised, with requirements being met principally by dietary intake. Tissue‐specific transporter proteins direct riboflavin to the intracellular machinery responsible for the biosynthesis of the flavocoenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These flavocoenzymes play a vital role in ensuring the functionality of a multitude of flavoproteins involved in bioenergetics, redox homeostasis, DNA repair, chromatin remodelling, protein folding, apoptosis, and other physiologically relevant processes. Hence, it is not surprising that the impairment of flavin homeostasis in humans may lead to multisystem dysfunction including neuromuscular disorders, anaemia, abnormal fetal development, and cardiovascular disease. In this review, we provide an overview of riboflavin absorption, transport, and metabolism. We then focus on the clinical and biochemical features associated with biallelic FLAD1 mutations leading to FAD synthase deficiency, the only known primary defect in flavocoenzyme synthesis, in addition to providing an overview of clinical disorders associated with nutritional deficiency of riboflavin and primary defects of riboflavin transport. Finally, we give a brief overview of disorders of the cellular flavoproteome. Because riboflavin therapy may be beneficial in a number of primary or secondary disorders of the cellular flavoproteome, early recognition and prompt management of these disorders is imperative.

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“…Riboflavin responsiveness was observed in cases with mutations expressing proteins with residual enzyme activity (Olsen et al, 2016). Schiff et al (2016) reported on a unique case of a 14-year old girl with recurrent exercise intolerance and biochemical features of the MADD syndrome, which both responded promptly to high doses of riboflavin. The authors identified a mutation of the FAD transporter (coded for by SLC52A32) that transports FAD from the cytosol to the mitochondrion where the flavoprotein dehydrogenases are located.…”

Section: 6mentioning

confidence: 99%

Dietary Reference Values for riboflavin

Products¹,

Turck²,

Bresson³

et al. 2017

EFS2

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Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) derives dietary reference values (DRVs) for riboflavin. The Panel considers that the inflection point in the urinary riboflavin excretion curve in relation to riboflavin intake reflects body saturation and can be used as a biomarker of adequate riboflavin status. The Panel also considers that erythrocyte glutathione reductase activation coefficient is a useful biomarker, but has limitations. For adults, the Panel considers that average requirements (ARs) and population reference intakes (PRIs) can be determined from the weighted mean of riboflavin intake associated with the inflection point in the urinary riboflavin excretion curve reported in four intervention studies. PRIs are derived for adults and children assuming a coefficient of variation of 10%, in the absence of information on the variability in the requirement and to account for the potential effect of physical activity and the methylenetetrahydrofolate reductase 677TT genotype. For adults, the AR and PRI are set at 1.3 and 1.6 mg/day. For infants aged 7-11 months, an adequate intake of 0.4 mg/day is set by upward extrapolation from the riboflavin intake of exclusively breastfed infants aged 0-6 months. For children, ARs are derived by downward extrapolation from the adult AR, applying allometric scaling and growth factors and considering differences in reference body weight. For children of both sexes aged 1-17 years, ARs range between 0.5 and 1.4 mg/day, and PRIs between 0.6 and 1.6 mg/day. For pregnant or lactating women, additional requirements are considered, to account for fetal uptake and riboflavin accretion in the placenta during pregnancy or the losses through breast milk, and PRIs of 1.9 and 2.0 mg/day, respectively, are derived.

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SLC25A32 Mutations and Riboflavin-Responsive Exercise Intolerance

Cited by 95 publications

References 5 publications

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Prediction of disease severity in multiple acyl‐CoA dehydrogenase deficiency: A retrospective and laboratory cohort study

Disorders of riboflavin metabolism

Dietary Reference Values for riboflavin

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