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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.

SUBMITTER: Foley AR 

PROVIDER: S-EPMC3891447 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.

Foley A Reghan AR   Menezes Manoj P MP   Pandraud Amelie A   Gonzalez Michael A MA   Al-Odaib Ahmad A   Abrams Alexander J AJ   Sugano Kumiko K   Yonezawa Atsushi A   Manzur Adnan Y AY   Burns Joshua J   Hughes Imelda I   McCullagh B Gary BG   Jungbluth Heinz H   Lim Ming J MJ   Lin Jean-Pierre JP   Megarbane Andre A   Urtizberea J Andoni JA   Shah Ayaz H AH   Antony Jayne J   Webster Richard R   Broomfield Alexander A   Ng Joanne J   Mathew Ann A AA   O'Byrne James J JJ   Forman Eva E   Scoto Mariacristina M   Prasad Manish M   O'Brien Katherine K   Olpin Simon S   Oppenheim Marcus M   Hargreaves Iain I   Land John M JM   Wang Min X MX   Carpenter Kevin K   Horvath Rita R   Straub Volker V   Lek Monkol M   Gold Wendy W   Farrell Michael O MO   Brandner Sebastian S   Phadke Rahul R   Matsubara Kazuo K   McGarvey Michael L ML   Scherer Steven S SS   Baxter Peter S PS   King Mary D MD   Clayton Peter P   Rahman Shamima S   Reilly Mary M MM   Ouvrier Robert A RA   Christodoulou John J   Züchner Stephan S   Muntoni Francesco F   Houlden Henry H  

Brain : a journal of neurology 20131119 Pt 1


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  ...[more]

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