Alteration of Flavin Cofactor Homeostasis in Human Neuromuscular Pathologies

New Insights into the Neurodegeneration Mechanisms Underlying Riboflavin Transporter Deficiency (RTD): Involvement of Energy Dysmetabolism and Cytoskeletal Derangement

“…These also include intron variant, splice site, frameshift and synonymous [ 15 ]. Even dominantly acting SLC52A1 variants and gene deletions have recently been reported in clinical cases and have causally been linked to placental transport defects [ 15 , 16 ]. Specifically, SLC52A1 haploinsufficiency was identified in two asymptomatic women as the cause of biochemical abnormalities in their newborns resembling those of multiple acyl CoA dehydrogenase deficiency (MADD), a typical muscular lipid-storage disorder characterized by defects in the oxidation of fatty acids and amino acids leading to a clinically heterogeneous disease associated with metabolic acidosis, cardiomyopathy, liver disease, episodes of metabolic decompensation, weakness muscle, and respiratory failure [ 15 , 16 ].…”

“…RFVTs are predicted to have 11 transmembrane domains [ 17 ]. However, it is possible that RFVTs might exist in different isoforms due to alternative processing of each transcript [ 16 ]. These proteins are responsible for transporting RF across cell membranes and are widely distributed in tissues throughout the body, with RFVT-2 and -3 being mostly expressed in the intestines, brain, and spinal cord [ 11 , 18 ] or produced by the intestinal microbiota, to a lesser extent.…”

“…Indeed, flavin cofactors ensure the functionality of fundamental biochemical processes, namely respiratory chain, Krebs cycle, β-oxidation of fatty acyl-CoAs. Inborn errors of such metabolism, caused by disturbances of the coordinated supply of RF and its co-factors, may alter muscular and neuronal flavin-dependent pathways [ 16 ]. Besides mitochondrial energy metabolism, other metabolic pathways strongly depend on RF.…”

“…It is not surprising that the tissues primarily affected by RF homeostasis alterations are the nervous and muscular tissues, since they require higher bioenergetics demand. Even with respect to the cell type, motor neurons and skeletal and heart muscle cells are among the active-most cells, with greatest energy expenditure [ 16 ].…”

Mimicking human riboflavin responsive neuromuscular disorders by silencing flad‐1 gene in C. elegans: Alteration of vitamin transport and cholinergic transmission

“…12,13 Mutations of FLAD1 gene severely affect muscular and cardiac functionality in humans. [11][12][13]15 Other genes correlated to Rf homeostasis are causative of metabolic neuromuscular disorders (for exhaustive reviews see References 12,16 and references therein). Noteworthy is the Brown-Vialetto-Van Laere Syndrome (BVVLS, also known as Rf Transporter Deficiency, RTD), a rare neurological disease in which the functionality of either SLC52A3 (BVVLS1, OMIM #211530) or SLC52A2 (BVVLS2, OMIM #614707) is altered.…”