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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2
Brain, Volume 137, No. 1, Year 2014
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Description
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. © 2013 The Author.
Authors & Co-Authors
Foley, A. Reghan
Unknown Affiliation
Menezes, Manoj P.
Unknown Affiliation
Pandraud, Amelie
Unknown Affiliation
González, Michael Anthony
Unknown Affiliation
Al-Odaib, Ahmad
Unknown Affiliation
Abrams, Alexander J.
Unknown Affiliation
Sugano, Kumiko
Unknown Affiliation
Yonezawa, Atsushi
Unknown Affiliation
Manzur, Adnan Y.
Unknown Affiliation
Burns, Joshua M.
Unknown Affiliation
Hughes, Imelda
Unknown Affiliation
McCullagh, B. Gary
Unknown Affiliation
Jungbluth, Heinz J.
Unknown Affiliation
Lim, Ming
Unknown Affiliation
Lin, J. P.
Unknown Affiliation
Megarbane, Andre
Unknown Affiliation
Urtizberea, Jean Andoni M.
Unknown Affiliation
Shah, Ayaz H.
Unknown Affiliation
Antony, Jayne Henly
Unknown Affiliation
Webster, R.
Unknown Affiliation
Broomfield, Alexander
Unknown Affiliation
Ng, Joanne
Unknown Affiliation
Mathew, Ann A.
Unknown Affiliation
O'Byrne, James Joseph
Unknown Affiliation
Forman, Eva
Unknown Affiliation
Scoto, Mariacristina
Unknown Affiliation
Prasad, Manish
Unknown Affiliation
O'Brien, Katherine
Unknown Affiliation
Olpin, Simon E.
Unknown Affiliation
Oppenheim, Marcus
Unknown Affiliation
Hargreaves, Iain Parry
Unknown Affiliation
Land, John M.
Unknown Affiliation
Wang, Min X.
Unknown Affiliation
Carpenter, Kevin
Unknown Affiliation
Horvàth, Rita
Unknown Affiliation
Straub, V. W.
Unknown Affiliation
Lek, Monkol
Unknown Affiliation
Gold, Wendy
Unknown Affiliation
Farrell, Michael
Unknown Affiliation
Brandner, Sebastian G.P.
Unknown Affiliation
Phadke, Rahul
Unknown Affiliation
Matsubara, Kazuo
Unknown Affiliation
McGarvey, Michael L.
Unknown Affiliation
Scherer, Steven S.
Unknown Affiliation
Baxter, P.
Unknown Affiliation
King, Mary Dolores
Unknown Affiliation
Clayton, Peter T.
Unknown Affiliation
Rahman, Shamima
Unknown Affiliation
Reilly, Mary M.
Unknown Affiliation
Ouvrier, Robert A.
Unknown Affiliation
Christodoulou, John
Unknown Affiliation
Züchner, Stephan L.
Unknown Affiliation
Muntoni, Francesco M.
Unknown Affiliation
Houlden, Henry H.
Unknown Affiliation
Statistics
Citations: 149
Authors: 54
Affiliations: 23
Identifiers
Doi:
10.1093/brain/awt315
e-ISSN:
14602156
Research Areas
Disability
Genetics And Genomics
Health System And Policy
Maternal And Child Health
Study Design
Cohort Study