Abstract
Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.
Highlights
Brown-Vialetto-Van Laere (BVVL) syndrome is an autosomal recessive neurological disorder first described by Brown in 1894 and later by Vialetto and Van Laere (Brown, 1894; Vialetto, 1936; Van Laere, 1966)
Using fibroblasts derived from BVVL syndrome patients with riboflavin transporter mutations and healthy age-matched controls (Supplementary material), we found a significant reduction in the intracellular levels of FMN and FAD in patient fibroblasts when grown in low extracellular riboflavin conditions (Supplementary Fig. 7A and B)
Given the reduced electron transport chain (ETC) complex I activity in drift knockdown flies, we investigated whether loss of drift affected mitochondrial membrane potential (ÁÉm), an indicator of mitochondrial health and function
Summary
Brown-Vialetto-Van Laere (BVVL) syndrome is an autosomal recessive neurological disorder first described by Brown in 1894 and later by Vialetto and Van Laere (Brown, 1894; Vialetto, 1936; Van Laere, 1966). Previous work has revealed strong links between mutations in two genes (SLC52A2 and SLC52A3) and BVVL syndrome, both of which encode riboflavin transporters (Green et al, 2010; Johnson et al, 2012; Foley et al, 2014). The role of another riboflavin transporter-encoding gene, SLC52A1, in BVVL syndrome pathogenicity is still uncertain, as it was found to be defective in only one case (Ho et al, 2011). SLC52A2 and SLC52A3 mutations include missense, nonsense, frame-shift, and splice-site alterations, but uniformly result in loss-of-function through reduced riboflavin transporter expression and/or riboflavin uptake (Foley et al, 2014; Udhayabanu et al, 2016)
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