<scp><i>ETFDH</i></scp> Mutations and Flavin Adenine Dinucleotide Homeostasis Disturbance Are Essential for Developing Riboflavin‐Responsive Multiple Acyl–Coenzyme <scp>A</scp> Dehydrogenation Deficiency

Xu, Jingwen; Li, Duoling; Lv, Jima; Xu, Xuebi; Wen, Bing; Lin, Pengfei; Liu, Fuchen; Ji, Kunqian; Jiang, Shan; Li, Honghao; Li, Wei; Zhao, Yuying; Zhao, Dandan; Pok, Joo Y.; Yan, Chuanzhu

doi:10.1002/ana.25338

Cited by 27 publications

(33 citation statements)

References 35 publications

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“…The accurate diagnosis benefits the treatment of our patient. Consistent with previous reports, supplementation of riboflavin, the precursor of flavin adenine dinucleotide (FAD), has improved muscle weakness of our patient harboring ETFDH variants (14). The ETFDH gene contains 13 exons and encodes a 617 amino acid ETFDH protein, which acts in conjunction with ETF to govern electron transport from several FAD-containing acyl-CoA dehydrogenases to the main respiratory chain in mitochondria.…”

Section: Discussionsupporting

confidence: 90%

“…The ETFDH gene contains 13 exons and encodes a 617 amino acid ETFDH protein, which acts in conjunction with ETF to govern electron transport from several FAD-containing acyl-CoA dehydrogenases to the main respiratory chain in mitochondria. FAD is a cofactor for ETFDH protein which is important for the enzyme catalytic activity, correct folding, and protein stability (14). Riboflavin supplements probably increase the intra-mitochondrial FAD concentration and ameliorate the effects of mutations that reduce the affinity of ETFDH protein for FAD (14).…”

Section: Discussionmentioning

confidence: 99%

“…FAD is a cofactor for ETFDH protein which is important for the enzyme catalytic activity, correct folding, and protein stability (14). Riboflavin supplements probably increase the intra-mitochondrial FAD concentration and ameliorate the effects of mutations that reduce the affinity of ETFDH protein for FAD (14). Especially, the therapeutic application of antisense oligonucleotide (ASO) is very promising for patients with FIGURE 3 | The minigene splicing assay in vitro for the synonymous variant c.579A>G based on the pSPL3 exon trapping vector.…”

Section: Discussionmentioning

confidence: 99%

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A Synonymous Variant c.579A>G in the ETFDH Gene Caused Exon Skipping in a Patient With Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report

Zeng

Wang

et al. 2020

Front. Pediatr.

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Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder characterized by a wide range of clinical features, including muscle weakness, hypoglycemia, metabolic acidosis, and multisystem dysfunctions. Loss-of-function mutations in the electron transfer flavoprotein dehydrogenase (ETFDH) gene are associated with MADD. Disease-causing synonymous variants in the ETFDH gene have not been reported so far. Methods: We reported the clinical course of a Chinese girl who was diagnosed with late-onset MADD by the whole exome sequencing. The effects of variants on mRNA splicing were analyzed through transcript analysis in vivo and minigene splice assay in vitro. Results: The 6-month-old girl initially showed muscle weakness, muscular hypotonia, mild myogenic damage, and fatty liver. The blood and urine metabolic screening by tandem mass spectrometry suggested MADD. Molecular analysis of ETFDH gene revealed two novel heterozygous variants, a frameshift mutation c.1812delG (p.V605Yfs * 34) in exon 13 and a synonymous variant c.579A>G (p.E193E) in exon 5. The transcript analysis in vivo exhibited that the synonymous variant c.579A>G caused exon 5 skipping. The minigene splice assay in vitro confirmed the alteration of ETFDH mRNA splicing which could lead to the production of a truncated protein. Supplementation of riboflavin, carnitine and low-fat diet improved the clinical symptoms. Conclusion: We firstly report a rare case of MADD with a pathogenic synonymous variant in the ETFDH gene which highlights the importance and necessity of bioinformatic analysis and functional testing for synonymous variants when searching for causative gene mutations. The results expand the spectrum of pathogenic variants in MADD.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Synonymous Variant c.579A>G in the ETFDH Gene Caused Exon Skipping in a Patient With Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report

Zeng

Wang

et al. 2020

Front. Pediatr.

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“…MADD (OMIM 231680) is an autosomal recessive inherited fatty acid and amino-acid metabolism disorder 4 . Most late-onset MADD can be corrected by therapeutic dosage of ribo avin, thus is regarded as ribo avin-responsive MADD 5 . Our patient was symptom-free soon after initiation of oral ribo avin treatment (100 mg/day).…”

Section: Discussionmentioning

confidence: 99%

Recurrent Abdominal Pain, Vomiting, Velvet-Like Changes in the Small Intestine in a Patient with Multiple Acyl-CoA dehydrogenation Deficiency

Shi

Liu

Meng

et al. 2020

Preprint

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BackgroundMultiple acyl-CoA dehydrogenation deficiency (MADD) is an inborn error of metabolism in fatty acid oxidation. We described an unusual case of recurrent vomiting and abdominal pain in a child with MADD, presenting with velvet-like changes in the small intestine. MethodsBecause of prominent gastrointestinal manifestations and small intestine ulcers, the patient was first diagnosed as Crohn’s disease. The patient was admitted to our institution because of recurrent symptoms despite treatment. Upper and lower endoscopy, computed tomography and trios exome sequencing were performed. ResultsThis patient underwent a repeated video endoscopy, which showed velvet-like changes in the small intestine rather than ulcers. Liver steatosis was identified by computed tomography. Serum tandem mass spectrometry showed elevated C8 and C10. Trios exome sequencing revealed compound heterozygous variants of c.250G>A, 524G>A in ETFDH. The diagnosis of multiple acyl-CoA dehydrogenation deficiency was made. Patient responded to oral riboflavin treatment. ConclusionWith this case, we aimed to highlight the importance of tandem mass spectrometry and genetic sequencing, especially when the endoscopic findings are not pathognomonic in pediatric cases with recurrent gastrointestinal complaints. We confirmed the diagnosis with next generation sequencing, and described unusual findings of velvet-like changes mimicking ulcers in the small intestine in this patient with MADD.

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“…Therapeutisch wichtig sind neben der Vermeidung kataboler Zustände (insbesondere kein Fasten) eine fettarme Diät sowie die Einnahme von Riboflavin. Dessen Metabolite sind wichtige Kofaktoren der Elektron-Transfer-Flavoprotein-Dehydrogenase (ETFDH), durch die Supplementation mit Riboflavin kann in vielen Fällen der bestehende ETFDH-Defekt abgemildert werden [3,6,9]. Zudem kann ergänzend die Substitution von Koenzym Q bzw.…”

Section: Therapieunclassified

Multipler Acyl-CoA-Dehydrogenase-Mangel/Glutarazidurie Typ II: schwierige Diagnose, einfache Therapie

et al. 2020

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ETFDH Mutations and Flavin Adenine Dinucleotide Homeostasis Disturbance Are Essential for Developing Riboflavin‐Responsive Multiple Acyl–Coenzyme A Dehydrogenation Deficiency

Cited by 27 publications

References 35 publications

A Synonymous Variant c.579A>G in the ETFDH Gene Caused Exon Skipping in a Patient With Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report

A Synonymous Variant c.579A>G in the ETFDH Gene Caused Exon Skipping in a Patient With Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency: A Case Report

Recurrent Abdominal Pain, Vomiting, Velvet-Like Changes in the Small Intestine in a Patient with Multiple Acyl-CoA dehydrogenation Deficiency

Multipler Acyl-CoA-Dehydrogenase-Mangel/Glutarazidurie Typ II: schwierige Diagnose, einfache Therapie

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