Objective: A) To find the spectrum of defects in riboflavin transporter genes; B) To ascertain the in-vitro cellular effects of SLC52A2 mutations and riboflavin on metabolism and mitochondrial function; and C) To evaluate the in-vivo consequences of the loss of the SLC52A3 homologue and thus riboflavin deficiency in the fruit fly, Drosophila melanogaster.

Background: First described in 1894, Brown-Vialetto-Van Laere (BVVL) or riboflavin transporter neuronopathy is a rare, autosomal recessive neurodegenerative disorder characterised by bilateral sensorineural hearing loss, cranial nerve palsies, respiratory insufficiency, cerebellar ataxia and severe sensorimotor neuropathy. Most infants rapidly become ventilator-dependent and die during childhood. Mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have been identified.

Methods: We used Sanger sequencing to screen 130 patients exhibiting cranial neuropathies and sensorimotor neuropathy +/- respiratory insufficiency. We then performed functional assays and measured activities of mitochondria respiratory complexes in patients with SLC52A2 mutations. We also employed an RNAi-mediated gene knockdown of the Drosophila SLC52A3 homologue to recapitulate the loss-of-function phenotype of BVVLs.

Results: We identified 18 BVVLs cases summing 5 SLC52A2 and 14 SLC52A3 pathogenic mutations, of which 4 SLC52A2 and 10 SLC52A3 variants were not previously reported. Mitochondrial respiratory complex I and complex II activity and mitochondrial membrane potential were decreased in SLC52A2 mutation patients and carrier fibroblasts as a consequence of a deficit in riboflavin, FAD and FMN status confirmed by HPLC. Global knockdown of the Drosophila riboflavin transporter homologue revealed mitochondrial deficits in complex I activity and riboflavin, FMN and FAD levels. In addition, the flies had severely reduced life span and locomotor activity, recapitulating the patients’ phenotype and pathology.

Conclusions: Overall our findings confirm the pathogenetic role of SLC52A2 and SLC52A3 in BVVL, and thus highlight the important clinical and therapeutic implications.

UK Neuromuscular Translational Research Conference 2016.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/human-fly-and-cellular-models-of-riboflavin-transporter-neuronopathy/