Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Repp, Birgit; Mastantuono, Elisa; Alston, Charlotte L.; Schiff, Manuel; Haack, Tobias B.; Rötig, Agnès; Ardissone, Anna; Lombès, Anne; Catarino, Claudia B.; Diodato, Daria; Schottmann, Gudrun; Poulton, Joanna; Burlina, Alberto; Jonckheere, An I.; Münnich, Arnold; Rolinski, Boris; Ghezzi, Daniele; Rokicki, Dariusz; Wellesley, Diana; Martinelli, Diego; Ding, Weijun; Lamantea, Eleonora; Østergaard, Elsebet; Pronicka, Ewa; Pierre, Germaine; Smeets, Hubert J.M.; Wittig, Ilka; Scurr, Ingrid; Coo, I.F.M. de; Moroni, Isabella; Smet, Joél; Mayr, Johannes A.; Dai, Lifang; Meırleır, Linda De; Schuelke, Markus; Zeviani, Massimo; Morscher, Raphael J.; McFarland, Robert; Seneca, Sara; Klopstock, Thomas; Meitinger, Thomas; Wieland, Thomas; Strom, Tim M.; Herberg, Ulrike; Ahting, Uwe; Sperl, Wolfgang; Nassogne, Marie‐Cécile; Han, Ling; Fang, Fang; Freisinger, Peter; Coster, Rudy Van; Strecker, Valentina; Taylor, Robert W.; Häberle, Johannes; Vockley, Jerry; Prokisch, Holger; Wortmann, Saskia B.

doi:10.1186/s13023-018-0784-8

Cited by 69 publications

(73 citation statements)

References 35 publications

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“…45 Therapeutic response to riboflavin supplementation was reported in 65% of treated patients in one large multinational cohort of ACAD9 deficiency. 48 Riboflavin responsiveness has also been reported in other forms of complex I deficiency. 49 It is possible that FMN may stabilize the complex I holoenzyme.…”

Section: Disorders Of the Human Flavoproteomementioning

confidence: 96%

Disorders of riboflavin metabolism

Balasubramaniam

Christodoulou

Rahman

2019

J of Inher Metab Disea

105

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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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Section: Disorders Of the Human Flavoproteomementioning

confidence: 96%

Disorders of riboflavin metabolism

Balasubramaniam

Christodoulou

Rahman

2019

J of Inher Metab Disea

105

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“…We report the first description of a successful pregnancy of a woman with mitochondrial cardiomyopathy and myopathy related to ACAD9 . Most of the historical cases with ACAD9 deficiency including our patient's brother died in early childhood 5 . Due to early riboflavin treatment our patient achieved adulthood and is now 29 years old.…”

Section: Discussionmentioning

confidence: 80%

“…Haack et al 10 tested in 2010 the impact of riboflavin supplementation on mutant cell cultures from two patients with ACAD9 mutations and found a significant increase in complex I activity. Repp et al 5 reported patients with predominant myopathic features who had alleviation of symptoms with riboflavin treatment. There was a significant increase in survival in the treated group.…”

Section: Discussionmentioning

confidence: 99%

“…ACAD9 belongs to a group of ACADs that act on fatty acids containing 14 to 20 carbons, and also plays a role as an assembly factor for mitochondrial respiratory chain complex I 1‐3 . He et al 4 were the first to establish the clinical phenotype of ACAD9 deficiency (OMIM# 611103), that was later broadened to include: myopathy, exercise intolerance, lactic acidosis, cardiac involvement (cardiomyopathy, heart failure, arrhythmia), central nervous system symptoms (developmental delay, intellectual deficits, seizures, encephalopathy), renal dysfunction, optic atrophy, liver dysfunction, ovarian failure, and death in infancy 2,5‐7 …”

Section: Introductionmentioning

confidence: 99%

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Successful pregnancy in a patient with mitochondrial cardiomyopathy due to ACAD9 deficiency

et al. 2020

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Acyl‐CoA dehydrogenase family member 9 (ACAD9) is an enzyme essential for the assembly of mitochondrial respiratory chain complex I. ACAD9 deficiency can cause lactic acidosis, myopathy, cardiomyopathy, intellectual disability, and early demise. We present a patient with mitochondrial myopathy, hypertrophic cardiomyopathy, and epilepsy due to recessive ACAD9 mutations. A muscle biopsy depicted ragged red fibers, and decreased activity of complex I of the respiratory chain. Treatment with riboflavin was initiated at the age of 4 years due to complex I deficiency (before the genetic diagnosis), resulting in symptomatic improvement of the cardiomyopathy, exercise intolerance, and lactate levels. A novel homozygous ACAD9 mutation was found: c.398G>A; p.Ser133Asn at the age of 23 years. Three years later she sustained a normal pregnancy, and gave birth to a healthy baby girl delivered by an elective Cesarean section. To the best of our knowledge, this is the first description of a successful pregnancy and delivery in a patient with this rare mitochondrial disease.

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“…show that riboflavin can be beneficial for patients with ACAD9 gene defects [66][67][68], high-fat diet for those with TMEM126B gene defects [69] and thiamine for those with SLC19A3 gene defects as reported in Chapter 4, [70][71][72]. Early start with these treatments prevents symptoms from occurring and can be lifesaving, for example, by preventing fatal Leigh Syndrome in patients with SLC19A3…”

Section: Treatment and Prevention Of Mitochondrial Diseasementioning

confidence: 97%

Resolving the role of genetic defects and mtDNA copy number in mitochondrial disease and development

Kamps

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Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

Cited by 69 publications

References 35 publications

Disorders of riboflavin metabolism

Disorders of riboflavin metabolism

Successful pregnancy in a patient with mitochondrial cardiomyopathy due to ACAD9 deficiency

Resolving the role of genetic defects and mtDNA copy number in mitochondrial disease and development

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