An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency

Mosegaard, Signe; Bruun, Georg M.; Flyvbjerg, Karen Freund; Bliksrud, Yngve Thomas; Gregersen, Niels; Dembić, Maja; Annexstad, Ellen; Tangeraas, Trine; Olsen, Rikke K.J.; Andresen, Brage S.

doi:10.1016/j.ymgme.2017.10.014

Cited by 48 publications

(52 citation statements)

References 33 publications

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“…In a few cases, the diagnostic process was time- consuming due to the processing of fibroblast cultures followed by enzyme analysis (CPT-I and MSUD). In an extreme case (transient riboflavin responsive MADD), the final diagnosis was eventually confirmed after 704 days by a research project [ 16 ]. During 2012–2014, the median time to diagnostic confirmation was 9 days (2–704 days), compared to the median of 7 days (3–31 days) in the years 2015–2020.…”

Section: Resultsmentioning

confidence: 99%

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses

Tangeraas

Sæves

Klingenberg

et al. 2020

IJNS

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In 2012, the Norwegian newborn screening program (NBS) was expanded (eNBS) from screening for two diseases to that for 23 diseases (20 inborn errors of metabolism, IEMs) and again in 2018, to include a total of 25 conditions (21 IEMs). Between 1 March 2012 and 29 February 2020, 461,369 newborns were screened for 20 IEMs in addition to phenylketonuria (PKU). Excluding PKU, there were 75 true-positive (TP) (1:6151) and 107 (1:4311) false-positive IEM cases. Twenty-one percent of the TP cases were symptomatic at the time of the NBS results, but in two-thirds, the screening result directed the exact diagnosis. Eighty-two percent of the TP cases had good health outcomes, evaluated in 2020. The yearly positive predictive value was increased from 26% to 54% by the use of the Region 4 Stork post-analytical interpretive tool (R4S)/Collaborative Laboratory Integrated Reports 2.0 (CLIR), second-tier biochemical testing and genetic confirmation using DNA extracted from the original dried blood spots. The incidence of IEMs increased by 46% after eNBS was introduced, predominantly due to the finding of attenuated phenotypes. The next step is defining which newborns would truly benefit from screening at the milder end of the disease spectrum. This will require coordinated international collaboration, including proper case definitions and outcome studies.

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Section: Resultsmentioning

confidence: 99%

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses

Tangeraas

Sæves

Klingenberg

et al. 2020

IJNS

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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%

“…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. [26][27][28][29][30][31][32][33] 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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“…Type 2 riboflavin transporter deficiency neuronopathy, or Brown‐Vialetto‐Van Laere syndrome‐2 (BVVLS2) is caused by mutations in SLC52A2 . Haploinsufficiency of the SLC52A1 riboflavin transporter (OMIM #615026) has been reported in two neonates, associated with maternal riboflavin deficiency, who developed transient severe symptoms resembling multiple acyl‐CoA dehydrogenase deficiency (MADD), which resolved with oral supplementation of riboflavin . Disorders of riboflavin transport are discussed in detail in the accompanying review in this issue of the Journal of Inherited Metabolic Disease …”

Section: Riboflavin Disorders In Humansmentioning

confidence: 99%

Disorders of riboflavin metabolism

Balasubramaniam

Christodoulou

Rahman

2019

J of Inher Metab Disea

109

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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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An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency

Cited by 48 publications

References 33 publications

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses

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

Disorders of riboflavin metabolism

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