Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

A. Reghan Foley, Manoj P. Menezes, Amelie Pandraud, Michael A. Gonzalez, Ahmad Al-Odaib, Alexander J. Abrams, Kumiko Sugano, Atsushi Yonezawa, Adnan Y. Manzur, Joshua Burns, Imelda Hughes, B. Gary McCullagh, Heinz Jungbluth, Ming J. Lim, Jean-Pierre Lin, Andre Megarbane, J. Andoni Urtizberea, Ayaz H. Shah, Jayne Antony, Richard WebsterAlexander Broomfield, Joanne Ng, Ann A. Mathew, James J. O'Byrne, Eva Forman, Mariacristina Scoto, Manish Prasad, Katherine O'Brien, Simon Olpin, Marcus Oppenheim, Iain Hargreaves, John M. Land, Min X. Wang, Kevin Carpenter, Rita Horvath, Volker Straub, Monkol Lek, Wendy Gold, Michael O. Farrell, Sebastian Brandner, Rahul Phadke, Kazuo Matsubara, Michael L. McGarvey, Steven S. Scherer, Peter S. Baxter, Mary D. King, Peter Clayton, Shamima Rahman, Mary M. Reilly, Robert A. Ouvrier, John Christodoulou, Stephan Zuechner, Francesco Muntoni, Henry Houlden*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    121 Citations (Scopus)
    7 Downloads (Pure)


    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.

    Original languageEnglish
    Pages (from-to)44-56
    Number of pages13
    Issue number1
    Early online date19 Nov 2013
    Publication statusPublished - Jan 2014


    • childhood neuronopathy
    • Brown-Vialetto-Van Laere syndrome
    • riboflavin therapy
    • RFVT2
    • SLC52A2
    • Vialetto-Van-Laere
    • Fazio-Londe-Disease
    • autosomal recessive inheritance
    • progressive bulbar paralysis
    • pontobulbar palsy
    • Vanlaere syndrome
    • deafness
    • overlap
    • family
    • brain


    Dive into the research topics of 'Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2'. Together they form a unique fingerprint.

    Cite this