Brown-Vialetto-Van Laere and Fazio Londe syndromes: defects of riboflavin transport with biochemical similarities to multiple acyl-CoA dehydrogenation defects (MADD)

Riboflavin-responsive defects of electron transfer were firstdescribed in the 1980s as mild variant forms of MADD orglutaric acidemia type II (Gregersen et al 1982; Amendt andRhead 1986). Some of these patients were shown to havedefects in ETF and ETF dehydrogenase but a number ofpatients remained in whom the biochemical and moleculardefects remained elusive (Roettger et al 1992). It was pos-tulated that these patients may have defect(s) of riboflavintransport or abnormalities in downstream flavin metabolismto form the active FAD/FMN cofactors required for facili-tating electron transfer. Treatment of some of these patientswith high dose riboflavin tended to normalize the abnormalmetabolite profiles. Treatment with high dose riboflavin wasalso subjectively claimed to improve the clinical phenotype,a difficult judgment given the mild and intermittent natureof the phenotype. The phenotype of most of the cases ofriboflavin-responsive MADD was that of stress-inducedmyopathy (de Visser et al 1986; DiDonato et al 1989).Recently, the genetic basis for Brown-Vialetto-Van Laeresyndrome(BVVLS) wasidentified asapreviouslyunknownopen reading frame C20orf54 (Green et al 2010). This genewas subsequently shown to encode a riboflavin transporterand the gene is now renamed SLC52A3 encoding humanriboflavin transporter 2 (hRFT2). At around the same time, adominantly inherited mutation in SLC52A1encoding humanriboflavin transporter 1 (hRFT1) was identified in theclinically normal mother of a neonate with complex neuro-logical disease and a MADD metabolite profile whichresponded dramatically to riboflavin therapy. It is presumedthat the neonate was riboflavin deficient secondarily to thematernal haploinsufficiency and from increased riboflavindemand during pregnancy (Ho et al 2011). Bosch and cow-orkersandothersextendedthephenotypeofSLC52A3defectsto include patients with Fazio Londe syndrome, which waspreviouslyconsideredtobeanoverlappingclinicalphenotypebut without a molecular basis (Bosch et al 2011). Anand andcoworkers added an additional riboflavin-responsive BVVLScase to the data base (Anand et al 2012). In this volume ofJIMD, Haack et al 2012, demonstrating the power of wholeexome sequencing identified disease-causing mutations in athird riboflavin transporter in an individual with BVVLS.They identified mutations in SLC52A2 and exquisitely dem-onstrate a functional defect of hRFT3, the gene product. Thispresent case also highlights the likely mechanisms of diseasephenotype in BVVLS.The clinical phenotype of BVVLS is not what wewould immediately associate with defects of electrontransfer such as MADD. For this reason, it is importantfor investigators to recognize this phenotype as it wouldappear that these defects of riboflavin transport areeminently treatable with high dose riboflavin therapy.BVVLS is rare and has been reported in about 60patients in total but may be under diagnosed. It presentsprimarily with a severe sensorineural deafness. The ageof onset is from infancy to the third decade. During therelentless progress, lower motor neuron limb signs leadto neuropathy and are accompanied by cerebellar ataxia,optic atrophy, retinal pigmentary changes, mental retar-dation and psychiatric abnormalities. Death is usually aresult of diaphragmatic paralysis (Dipti et al 2005).