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.
Highlights
Brown-Vialetto-Van Laere syndrome (OMIM 211530) is a neurodegenerative disorder first reported in 1894 by Charles Brown as an ‘infantile’ form of amyotrophic lateral sclerosis with associated hearing loss (Brown, 1894)
We have described 18 patients with mutations in the riboflavin transporter gene SLC52A2 who demonstrate a striking clinical phenotype of sensory ataxia and upper limb, axial and respiratory weakness as a result of an axonal sensorimotor peripheral neuropathy; and a cranial neuropathy affecting cranial nerves II, VIII and XII
We report the consistent neurophysiological profile and sural nerve pathology associated with mutations in RFVT2 and demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression
Summary
Brown-Vialetto-Van Laere syndrome (OMIM 211530) is a neurodegenerative disorder first reported in 1894 by Charles Brown as an ‘infantile’ form of amyotrophic lateral sclerosis with associated hearing loss (Brown, 1894). The report of three siblings with pontobulbar paralysis and associated hearing loss by Ernesto Vialetto in 1936 followed by the report of three sisters with these clinical features by M.J. Van Laere in 1966 resulted in the term Brown-Vialetto-Van Laere syndrome (Vialetto, 1936; Van Laere, 1966). Van Laere in 1966 resulted in the term Brown-Vialetto-Van Laere syndrome (Vialetto, 1936; Van Laere, 1966) These reports described markedly similar phenotypes, the term Brown-Vialetto-Van Laere syndrome subsequently has been assigned to a heterogeneous group of conditions, some with clear involvement of cranial nerves VII–XII and others with only minimal bulbar involvement but prominent limb weakness (Bosch et al, 2012). Sensorineural deafness is a common feature of Brown-Vialetto-Van Laere syndrome and had been used to distinguish this condition from other motor neuron diseases such as Fazio-Londe disease (OMIM 211500) (McShane et al, 1992), before the observation that Brown-Vialetto-Van Laere disease and Fazio-Londe disease seem to be allelic conditions that present along a phenotypic spectrum (Dipti et al, 2005; Bosch et al, 2011)
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