Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

Abstract

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2)

“…Distinguishing the two entities at the molecular level is of high importance as patients with mutations in SLC52A2 can be ameliorated by riboflavin supplementation. 3 Furthermore, these two families illustrate the concept of spinocerebellar ataxia due to distinct mildly affected metabolic pathways, 1 as we demonstrate that partial loss of function in peroxisomes or mitochondria may lead to strikingly overlapping syndromes.…”

“…Recently, two studies have reported patients with p.(Gly306Arg) homozygous mutation and having not only sensorineural deafness and muscle weakness and wasting with respiratory insufficiency but also sensory ataxia and optic atrophy suggesting that mutations in SLC52A2 may be quite specific for the SCABD phenotype. 3,16 The published segregation of the disease with the 6p21-p23 chromosome interval in family A appears to be due to chance and not to linkage, as a LOD score of 3.25 corresponds to a probability of observing a false linkage of 0.05 after Bonferoni correction for multiple testing (whole-genome analysis). Correct linkage of the disease to 8qter was missed in this early study due to the high recombination rate of telomeric regions and to the absence of 8qter polymorphic markers in the initial Linkage Mapping Set used for whole-genome analysis.…”

“…3,15,16 In order to investigate the discrepancy brought by the identification of the causative mutation by whole-exome sequencing in SLC52A2 localized in qter of chromosome 8, we verified the genotype of the four closest 8q markers from the initial ABI PRISM Linkage Mapping Set 10 (D8S285, D8S270, D8S284 and D8S272) plus one additional marker closer to SLC52A2 (D8S1836).…”

“…In the latter, ataxia was presented as one of the potential additional features. 3 Peroxisomal biogenesis disorders (PBDs; MIM 601539) are another illustration of autosomal recessive neurological diseases often associated with ataxia. PBDs are indeed characterized by large clinical heterogeneity ranging from severe neurologic dysfunction and death within the first year of life (Zellweger syndrome) to milder disorder, in which patients can survive into young adulthood, but typically exhibit multiple organ dysfunction, sensorineural hearing loss, pigmentary retinal degeneration and psychomotor impairments including ataxia.…”

Epigenetic Mechanisms Underlying the Pathogenesis of Neurogenetic Diseases

“…A salient example of how these advances can be immediately clinically relevant and affect treatment is provided by the genetics of the childhood-onset motor neuron disease, Brown-Vialetto-Van Laere syndrome. It was recently discovered via exome sequencing that mutations in riboflavin transport pathways are responsible for causing this disorder in a subset of patients [9]; this finding led to the identification of a novel mechanistic therapy (i.e., high-dose riboflavin) that seems to be effective for treating this previously intractable neurodegenerative disorder [10]. Another example of how sequencing approaches can be pertinent for an acquired disease is the recently reported use of sequencing for pathogen detection in a 14-year-old boy with severe combined immunodeficiency, who presented with meningoencephalitis [11].…”