PT  - JOURNAL ARTICLE
AU  - Andreea Manole
AU  - Zane Jaunmuktane
AU  - Iain Hargreaves
AU  - Amelie Pandraud
AU  - Vincenzo Salpietro
AU  - Simon Pope
AU  - Marthe H. R. Ludtmann
AU  - Alejandro Horga
AU  - Renata S. Scalco
AU  - Abi Li
AU  - Balasubramaniem Ashokkumar
AU  - Charles M. Lourenço
AU  - Simon Heales
AU  - Rita Horvath
AU  - Patrick F. Chinnery
AU  - Camilo Toro
AU  - Andrew B. Singleton
AU  - Thomas S. Jacques
AU  - Andrey Y. Abramov
AU  - Francesco Muntoni
AU  - Michael G. Hanna
AU  - Mary M. Reilly
AU  - Tamas Revesz
AU  - Dimitri M. Kullmann
AU  - James E.C. Jepson
AU  - Henry Houlden
TI  - Mitochondrial impairment and rescue in riboflavin responsive neuropathy
AID  - 10.1101/110890
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 110890
4099  - http://biorxiv.org/content/early/2017/02/22/110890.short
4100  - http://biorxiv.org/content/early/2017/02/22/110890.full
AB  - Brown-Vialetto-Van Laere syndrome (BVVLS) 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 (RFVT) genes, SLC52A2 and SLC52A3, have recently been linked to BVVLS. However, the genetic frequency, neuropathology and downstream consequences of RFVT mutations have previously been undefined. 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 RFVT mutations and BVVLS, identifying twenty-two pathogenic mutations in SLC52A2 and SLC52A3, fourteen 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 (ETC), we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. ETC complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila RFVT homologue revealed reduced levels of riboflavin, downstream metabolites, and ETC complex I activity. RFVT 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 indicate mitochondrial dysfunction as a downstream consequence of RFVT gene defects in BVVLS and validate riboflavin esters as a potential therapeutic strategy.