Clinical characteristics

The age of onset of BVVL is typically between infancy and the third decade.2 ,3 Our patient presented in her fourth decade, much older than the reported mean age of presentation (4.1–8.2 years).3 ,4 The clinical presentation is highly variable and, as well as the characteristic features of lower cranial nerve involvement (nerves VIII—XII), can include lower and upper motor neurone limb signs, respiratory compromise, facial weakness, sensory ataxia and optic atrophy.2 ,4 Half of the cases are familial, arising with an autosomal recessive pattern of inheritance with homozygous or compound heterozygous mutations.

The riboflavin transporter genes

The underlying genetic cause of BVVL was identified in 2010. The first report described seven patients with homozygous mutations and one compound heterozygote affecting exons 2, 3 and 5 of the riboflavin transporter gene SLC52A3 (aka C20orf54 or RFVT3).1 A novel homozygous pathogenic mutation in a related riboflavin transporter gene SLC52A2 (aka RFVT2) was found in a Lebanese kindred.5 Further mutations in this gene have subsequently been described in 18 child-onset cases.6 Bosch et al 4 have summarised the published mutations in SLC52A2 and SLC52A3 up until 2012.

SLC52A2 and SLC52A3 genes code for the human riboflavin transporters (RFVT) 2 and 3, respectively. A third member of the family, SLC52A1 (coding for RFVT1), has not yet been shown to harbour pathogenic mutations in BVVL itself, but was abnormal in a case of maternal riboflavin deficiency.7

Our patient was compound heterozygous for the SLC52A3 gene (V413A/D461Y). This evolutionarily conserved gene contains five exons and eleven predicted transmembrane helices.1 The V413A mutation has previously been reported in a compound heterozygous pattern. This patient had a milder phenotype, manifested by disease onset in the second decade, an initial presentation of peripheral neuropathy and untreated survival into the sixth decade.

The D461Y mutation has been reported in 36 European ExAC samples in a heterozygous manner, but has not been previously reported to cause BVVL. Its pathogenicity is endorsed by its absence in 900 of our screened controls and predicted ‘damaging’ effect using FATHMM prediction software (see table 1). Thus, the D461Y mutation, similar to other pathological SLC52A3 mutations (eg, F457L, N21S), occurs at low frequencies in the general European population in the heterozygous state. We suggest that it causes BVVL when either homozygous or, as in this case, compound heterozygous with another known pathogenic variant.

Genotype–phenotype relationship

The clinical phenotypes related to SLC52A2 and SLC52A3 mutations are distinguishable. The SLC52A2 mutation phenotype is associated with an ataxic gait as the presenting symptom, with a higher likelihood of sensorimotor neuropathy, optic atrophy, weakness of the upper limbs and neck and late-onset deafness.6 In contrast, people with SLC52A3 mutations typically present with sensorineural deafness, followed by pontobulbar palsy, respiratory compromise and generalised limb weakness.4 It has been suggested that the umbrella term of BVVL syndrome be renamed ‘riboflavin transporter deficiency, types 2 and 3’, to reflect better the underlying patho-aetiology and distinct clinical phenotypes in this condition.4 ,6

Nutritional trigger

The metabolic hallmark of BVVL is abnormal mitochondrial fatty acid oxidation and branched-chain amino acid catabolism. This stems from an acquired functional riboflavin deficiency, owing to defective riboflavin transporter activity in the gut and/or the brain. It is possible to detect the biochemical defect by a reduction in plasma riboflavin, flavin mononucleotide or flavin adenine dinucleotide concentration, with an abnormal plasma acylcarnitine profile (selective increase in short- and medium-chain fatty acid plasma concentrations).8 However, a recent report suggests only 58% of genetically confirmed patients with BVVL had abnormal acylcarnitine profiles.3 Additionally, urinary organic acid profiles can resemble those seen in the multiple acyl-CoA dehydrogenation defect.

Our patient developed symptoms after an abrupt change in the quality of her diet 8 weeks before admission. This very likely triggered motor neuronal dysfunction and degeneration, as her genetic defect left her vulnerable to a low dietary intake of riboflavin.

Riboflavin therapy in BVVL

The general management of patients with BVVL includes supportive measures, such as nasogastric tube or gastrostomy insertion to ensure adequate nutrition, and non-invasive ventilation to overcome any neurogenic respiratory compromise. Corticosteroids and immunoglobulins do not help.2

Riboflavin treatment (reported dose range 7–60 mg/kg/day) can normalise the metabolic abnormalities detected in BVVL and lead to clinical stabilisation and improvement in most people.3 ,4 ,9 ,10 Currently there is no recommended metabolic biomarker to assess response to treatment. Early treatment is encouraged as soon as the diagnosis is considered, as some neurological deficits, in particular diaphragmatic paralysis, may be irreversible. Once our patient started oral riboflavin, she made a remarkable recovery in motor function (see online supplementary file/video). Her clinical improvement has been sustained for 3 years with regular dietician input and a weaning dose of maintenance riboflavin supplementation (minimum 200 mg daily).