Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience

Abstract

IntroductionRiboflavin (vitamin B2) is absorbed in the small intestine by the human riboflavin transporters RFVT1 and RFVT3. A third riboflavin transporter (RFVT2) is expressed in the brain. In 2010 it was demonstrated that mutations in the riboflavin transporter genes SLC52A2 (coding for RFVT2) and SLC52A3 (coding for RFVT3) cause a neurodegenerative disorder formerly known as Brown-Vialetto-Van Laere (BVVL) syndrome, now renamed to riboflavin transporter deficiency. Five years after the diagnosis of the first patient we performed a review of the literature to study the presentation, treatment and outcome of patients with a molecularly confirmed diagnosis of a riboflavin transporter deficiency.MethodA search was performed in Medline, Pubmed using the search terms ‘Brown-Vialetto-Van Laere syndrome’ and ‘riboflavin transporter’ and articles were screened for case reports of patients with a molecular diagnosis of a riboflavin transporter deficiency.ResultsReports on a total of 70 patients with a molecular diagnosis of a RFVT2 or RTVT3 deficiency were retrieved. The riboflavin transporter deficiencies present with weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia, feeding difficulties and respiratory difficulties which are caused by a sensorimotor axonal neuropathy and cranial neuropathy. Biochemical abnormalities may be absent and the diagnosis can only be made or rejected by molecular analysis of all genes. Treatment with oral supplementation of riboflavin is lifesaving. Therefore, if a riboflavin transporter deficiency is suspected, treatment must be started immediately without first awaiting the results of molecular diagnostics.

Genome-wide RNA-seq of iPSC-derived motor neurons indicates selective cytoskeletal perturbation in Brown–Vialetto disease that is partially rescued by riboflavin

“…BVVL and FL are rare genetic MN diseases caused by mutations in RFVT2 / 3 genes; however, the mechanisms by which mutant RFVT proteins induce MN degeneration are largely unknown1. Riboflavin (B2) supplementation seems to ameliorate the clinical phenotype even if the exact mechanisms of action on MNs have not yet clarified1.…”

“…Riboflavin (7,8-dimethyl-10-ribityl-isoalloxazine; vitamin B2) is a water-soluble group B vitamin and the precursor of the coenzymes flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)1. They are essential cofactors in different metabolic processes, including carbohydrate, amino acid, and lipid metabolism and the electron transport chain2.…”

“…The principal cause of death is respiratory failure due to diaphragm denervation910111216171819, and the FL clinical presentation is similar to BVVL, without the hearing loss. Therapy with high-dose oral riboflavin (B2) was efficacious in BVVL cases with significant clinical improvement1. Despite this advancement in the knowledge of riboflavin deficiency disorders, the causal relationship between riboflavin transporter mutations and neural/MN degeneration remains unknown.…”

Advances in Research on the Relationship between Vitamins and Neuropathy

“…In addition, the clinical symptoms of riboflavin transport protein deficiency mainly involve central nervous system lesions, including cranial nerve damage (II (optic atrophy), VIII (hearing loss) and XII (tongue muscle atrophy)), sensory ataxia, eating Difficulty and breathing effort [9], but studies have shown that intake of high doses of riboflavin can improve riboflavin transport protein deficiency caused by symptoms, and the degree of improvement may be related to riboflavin dose [10].…”

Brown-Vialetto-Van Laere syndrome: a novel diagnosis to a common presentation

“…To date, 34 patients with molecular diagnosis of BVVLS caused by mutations in the SLC52A3 gene have been reported 4. The age of onset extends from infancy to adolescence with an average age in the second decade.…”