Table 1.
Overview of riboflavin-responsive disorders.
| Disorder | OMIM# | Gene(s) (Gene ID) | Clinical Response | Biochemical Response | References |
|---|---|---|---|---|---|
| Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) | #231680 |
ETFA (2108) ETFB (2109) ETFDH (2110) |
Several studies documenting complete or partial recovery in patients with mild missense variants. Not effective in patients with more severe missense variants or biallelic LOF variants | Significant reduction or normalization of multiple urinary organic acids and blood acylcarnitine excretion. Significant increases in ETF-QO protein or fatty acid oxidation flux in patients’ cultured fibroblasts upon supplementation with riboflavin | [75,82] |
| Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCADD) | #201470 | ACADS (35) | Two single studies; indications of clinical improvement in 4/16 patients. The four patients were compound heterozygous for c.625G>A susceptibility variant and a rare missense variant. A clear clinical improvement reported in one patient with homozygous c.625G>A susceptibility variant | All patients clinically responding to riboflavin treatment had decreased or normalized urinary organic acids excretion and/or decreased butyrylcarnitine in blood. One patient responded biochemically but not clinically | [83,87] |
| Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) | #201450 | ACADM (34) | NR | Two studies; significant increase of MCAD enzyme activity in cultured lymphocytes from 5/5 patients. The genetic characterization of the patients was not reported. In a study of 17 patients with ACADM missense variants, patients supplemented with riboflavin and carnitine (6) did not display blood markers of oxidative damage when compared with carnitine supplemented (7) and non-supplemented (14) patients | [88,89] |
| ACAD9 Deficiency or Mitochondrial Complex I Deficiency Nuclear type 20 (MC1DN20) | #611126 | ACAD9 (28976) | Several studies. In one comprehensive study, riboflavin treatment resulted in clinical improvement in 20/31 patients. Responsive patients carried missense variants | Significant increase of complex I activity was seen upon supplementation with riboflavin in fibroblasts derived from 9/15 patients | [91] |
| Mitochondrial Complex II Deficiency | #252011 | SDHAF1 (612848) | Riboflavin treatment resulted in a clinical improvement in 3 patients | Plasma lactate, pyruvate and alanine remained within the control range in two patients. In a third patient, plasma lactate was elevated and normalized after riboflavin treatment | [92,94,95] |
| Ethylmalonic Encephalopathy (EE) | #602473 | ETHE1 (23474) | Riboflavin treatment, in combination with other vitamins and CoQ10, has in a few cases been seen to slightly reduce symptoms. A single study has reported a partial effect of riboflavin alone | Clear biochemical improvement of blood acylcarnitines has been reported using riboflavin in combination with other vitamins, CoQ10, and NAC. A single study has showed some improvements upon treatment with riboflavin alone | [109,111,112,121] |
| Brown-Vialetto-Van Laere Syndrome 1 and 2 (BVVLS1; BVVLS2), Fazio-Londe Disease |
#211530 #614707 #615026 |
SLC52A3 (113278) SLC52A2 (79581) |
Several studies; clinical improvement or stabilization of symptoms observed in almost all patients treated with riboflavin | Some patients have shown abnormalities in blood acylcarnitines, urine organic acids, and plasma flavin content that were improved by riboflavin treatment | [128,129,145] |
| Transient MADD or Riboflavin Deficiency | #615026 | SLC52A1 (607883) | Two cases; clear clinical improvement of both neonates | Biochemical normalization of blood acyl-carnitines and/or urine organic acids in both mothers and neonates | [130,131,132] |
| Mitochondrial Folate Transporter Deficiency or Riboflavin-Responsive Exercise Intolerance (RREI) | #616839 | SLC25A32 (81034) | Clinical improvement in 2/2 patients | NR | [133,134] |
| Lipid Storage Myopathy due to Flavin Adenine Dinucleotide Synthetase Deficiency (LSMFLAD) | #255100 | FLAD1 (80308) | Several cases; clinical improvement in patients harboring missense variants. Patients with biallelic LOF variants have shown only a transient clinical improvement or an alleviation of symptoms | Some decreases in acylcarnitine species and normalization of urine organic acids in patients harboring missense variants | [9,88,137,139,141,144] |
Abbreviations: CoQ10, Coenzyme Q10; LOF, loss of function; NAC, N-acetylcysteine; NR, not reported.