Review New insights into the nutritional genomics of adult-onset riboflavin-responsive diseases 2023 Murgia et al

[Andy]

Abstract

Riboflavin, or vitamin B2, is an essential nutrient that serves as a precursor to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). The binding of the FAD and/or FMN cofactors to flavoproteins is critical for regulating their assembly and activity. There are over 90 proteins in the human flavoproteome that regulate a diverse array of biochemical pathways including mitochondrial metabolism, riboflavin transport, ubiquinone and FAD synthesis, antioxidant signalling, one-carbon metabolism, nitric oxide signalling and peroxisome oxidative metabolism. The identification of patients with genetic variants in flavoprotein genes that lead to adult-onset pathologies remains a major diagnostic challenge. However, once identified, many patients with adult-onset inborn errors of metabolism demonstrate remarkable responses to riboflavin therapy.

We review the structure:function relationships of mutant flavoproteins and propose new mechanistic insights into adult-onset riboflavin-responsive pathologies and metabolic dysregulations that apply to multiple biochemical pathways. We further address the vexing issue of how the inheritance of genetic variants in flavoprotein genes leads to an adult-onset disease with complex symptomologies and varying severities. We also propose a broad clinical framework that may not only improve the current diagnostic rates, but also facilitate a personalized approach to riboflavin therapy that is low cost, safe and lead to transformative outcomes in many patients.

Open access, https://nutritionandmetabolism.biomedcentral.com/articles/10.1186/s12986-023-00764-x

 

[Hoopoe]

Do you think that there is phenotype overlap between this group of diseases and ME/CFS?

 

[Andy]

Selected quotes from the paper.

Inadequate dietary intake of riboflavin, known as ariboflavinosis, is manifested by a range of diverse clinical presentations that can include peripheral neuropathy, fatigue, exercise intolerance, defects in lipid oxidation, anaemia and dermatological symptoms

Genetic disorders that involve in-born errors of flavoprotein metabolism that are characterized by early-onset multiple acyl-CoA dehydrogenase deficiency (MADD; OMIM #231680) have long been recognized principally for their severe neonatal phenotypes and high mortality rates. In particular, early-onset MADD can arise from loss-of-function variants in the electron transfer flavoprotein A (ETFA), electron transfer flavoprotein B (ETFB) or the electron transfer flavoprotein dehydrogenase (ETFDH) genes. The expression of such variants results in defects in the transfer of electrons from acyl-CoA dehydrogenase to the respiratory chain leading to impaired mitochondrial beta oxidation and ATP production [45].

While the autosomal recessive mutations in ETFA, ETFB and ETFDH that give rise to such neonatal-onset MADD have been widely described [46], late-onset MADD has received less attention. Affected individuals can develop a spectrum of symptoms in adolescence or adulthood that can include exercise intolerance, myalgia, chronic fatigue, metabolic acidosis, cognitive impairment and post-exercise pain [47]. Diagnosis of late-onset MADD can be challenging and requires the investigation of multiple biochemical biomarkers that may include urine organic acids as well as blood acyl-carnitines and lactate.