SCIENTIFIC COMMENTARIES Promising riboflavin treatment for motor neuron disorder

Many genes in which mutations cause motor neuron disorders have been identified, helping to provide early diagnosis or prognosis to patients; but there is still no cure for any of these pathologies. Only symptomatic and supportive therapies can provide better quality of life and may extend survival in the most severe cases, such as amyotrophic lateral sclerosis. In this issue of Brain, Foley and colleagues present a multicentre study on a promising and potentially life-saving treatment for Brown-VialettoVan Laere syndrome documented with genetic and clinical studies (Foley et al., 2013). This severe neurodegenerative disorder was first described as familial amyotrophic lateral sclerosis with onset in infancy (Brown, 1894). After Vialetto (1936) and Van Laere (1966) reported on this rare disorder, the disease became generally known as Brown–Vialetto–Van Laere syndrome (BVVL). With an increasing number of patients with BVVL being reported in the literature (Bosch et al., 2012), it became clear that the main clinical feature of this syndrome is progressive bulbar palsy often preceded by sensorineural deafness, with facial weakness and respiratory failure. The condition is genetically heterogeneous with mainly autosomal recessive inheritance, but dominant forms also occur. The female to male prevalence is 3:1, with boys being more severely affected than girls. Patients have variable age at onset (first to third decade), and those with early-onset tend to have rapid disease progression but survival can be prolonged with active management of respiration and weakness. The first genetic studies were performed in a consanguineous family in which patients were excluded for mutations in the survival of motor neuron (SMN1) and neuronal apoptosis inhibitory protein (NAIP) genes associated with spinal muscular atrophy (Mégarbané et al., 2000). More recently, 44 patients were screened and excluded for SMN1 deletions, superoxide dismutase 1 (SOD1) gene mutations, and for common mitochondrial mutations and deletions (Johnson et al., 2012). Mégarbané and colleagues (2000) indicated that ‘the identification of the BVVL gene by a whole genome screening is likely to provide more information about the pathogenesis, and that pooling such families worldwide is the only chance to achieve it’. Indeed, homozygosity mapping assigned a first locus on chromosome 20p13 and a second one on 8q24.3 (Green et al., 2010; Johnson et al., 2012). Subsequent Sanger sequencing of positional candidate genes or exome sequencing identified homozygous or compound heterozygous mutations in SLC52A3 (C20orf54, RFT2) and SLC52A2 (RFT3), respectively, genes coding for riboflavin transporters (Green et al., 2010; Johnson et al., 2012). In these genetic studies no mutations were reported in another riboflavin transporter gene, SLC52A1 (RFT1); however, a deletion was previously reported in a single patient presenting with clinical and biochemical features of multiple acyl-CoA dehydrogenase deficiency (Ho et al., 2011). The patient’s clinical condition dramatically improved within 24 h of commencement of therapy including oral riboflavin (Ho et al., 2011). Foley et al. (2013) summarize the molecular findings of 78 familial and isolated patients with BVVL from 18 countries worldwide. In 18 patients, recessive mutations were found in the SLC52A2 riboflavin transporter, suggesting that SLC52A2 mutations are a frequent cause for this childhood neuronopathy. These patients share the core BVVL phenotype with a rapidly progressive axonal sensory and motor neuropathy, hearing loss, optic atrophy and respiratory insufficiency (Foley et al., 2013). In this study no mutations were found in SLC52A1 and SLC52A3. The SLC52A1, -A2 and -A3 genes are members of the solute carrier family 52, encoding human riboflavin transporters (RTF1, RTF3 and RTF2, respectively), and are localized within the cytoplasm and endosomal vesicles. The SLC52A1 and SLC52A3 proteins are highly expressed in the small intestine, testis and placenta. The SLC52A2 protein is also present in the small intestine, however, its expression is more pronounced in foetal brain and spinal cord (Yao et al., 2010). Biochemical and cellular studies in BVVL patient skin fibroblasts with mutant SLC52A2 revealed concomitant reduction of SLC52A1 and SLC52A3 protein levels. This reduction was also detected in leucocytes and fibroblasts obtained from the patient’s parents who were heterozygous for a mutant SLC52A2 allele. This finding suggests functional cooperation between the riboflavin transporters (Ciccolella et al., 2013). Brain 2014: 137; 2–11 | 2