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 Webster & 34 others Alexander 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 journalArticle

    78 Citations (Scopus)
    5 Downloads (Pure)

    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.

    Original languageEnglish
    Pages (from-to)44-56
    Number of pages13
    JournalBrain
    Volume137
    Issue number1
    Early online date19 Nov 2013
    DOIs
    Publication statusPublished - Jan 2014

    Keywords

    • 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

    Cite this

    Foley, A. R., Menezes, M. P., Pandraud, A., Gonzalez, M. A., Al-Odaib, A., Abrams, A. J., ... Houlden, H. (2014). Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain, 137(1), 44-56. https://doi.org/10.1093/brain/awt315

    Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. / Foley, A. Reghan; Menezes, Manoj P.; Pandraud, Amelie; Gonzalez, Michael A.; Al-Odaib, Ahmad; Abrams, Alexander J.; Sugano, Kumiko; Yonezawa, Atsushi; Manzur, Adnan Y.; Burns, Joshua; Hughes, Imelda; McCullagh, B. Gary; Jungbluth, Heinz; Lim, Ming J.; Lin, Jean-Pierre; Megarbane, Andre; Urtizberea, J. Andoni; Shah, Ayaz H.; Antony, Jayne; Webster, Richard; Broomfield, Alexander; Ng, Joanne; Mathew, Ann A.; O'Byrne, James J.; Forman, Eva; Scoto, Mariacristina; Prasad, Manish; O'Brien, Katherine; Olpin, Simon; Oppenheim, Marcus; Hargreaves, Iain; Land, John M.; Wang, Min X.; Carpenter, Kevin; Horvath, Rita; Straub, Volker; Lek, Monkol; Gold, Wendy; Farrell, Michael O.; Brandner, Sebastian; Phadke, Rahul; Matsubara, Kazuo; McGarvey, Michael L.; Scherer, Steven S.; Baxter, Peter S.; King, Mary D.; Clayton, Peter; Rahman, Shamima; Reilly, Mary M.; Ouvrier, Robert A.; Christodoulou, John; Zuechner, Stephan; Muntoni, Francesco; Houlden, Henry.

    In: Brain, Vol. 137, No. 1, 01.2014, p. 44-56.

    Research output: Contribution to journalArticle

    Foley, AR, Menezes, MP, Pandraud, A, Gonzalez, MA, Al-Odaib, A, Abrams, AJ, Sugano, K, Yonezawa, A, Manzur, AY, Burns, J, Hughes, I, McCullagh, BG, Jungbluth, H, Lim, MJ, Lin, J-P, Megarbane, A, Urtizberea, JA, Shah, AH, Antony, J, Webster, R, Broomfield, A, Ng, J, Mathew, AA, O'Byrne, JJ, Forman, E, Scoto, M, Prasad, M, O'Brien, K, Olpin, S, Oppenheim, M, Hargreaves, I, Land, JM, Wang, MX, Carpenter, K, Horvath, R, Straub, V, Lek, M, Gold, W, Farrell, MO, Brandner, S, Phadke, R, Matsubara, K, McGarvey, ML, Scherer, SS, Baxter, PS, King, MD, Clayton, P, Rahman, S, Reilly, MM, Ouvrier, RA, Christodoulou, J, Zuechner, S, Muntoni, F & Houlden, H 2014, 'Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2', Brain, vol. 137, no. 1, pp. 44-56. https://doi.org/10.1093/brain/awt315
    Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ et al. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain. 2014 Jan;137(1):44-56. https://doi.org/10.1093/brain/awt315
    Foley, A. Reghan ; Menezes, Manoj P. ; Pandraud, Amelie ; Gonzalez, Michael A. ; Al-Odaib, Ahmad ; Abrams, Alexander J. ; Sugano, Kumiko ; Yonezawa, Atsushi ; Manzur, Adnan Y. ; Burns, Joshua ; Hughes, Imelda ; McCullagh, B. Gary ; Jungbluth, Heinz ; Lim, Ming J. ; Lin, Jean-Pierre ; Megarbane, Andre ; Urtizberea, J. Andoni ; Shah, Ayaz H. ; Antony, Jayne ; Webster, Richard ; Broomfield, Alexander ; Ng, Joanne ; Mathew, Ann A. ; O'Byrne, James J. ; Forman, Eva ; Scoto, Mariacristina ; Prasad, Manish ; O'Brien, Katherine ; Olpin, Simon ; Oppenheim, Marcus ; Hargreaves, Iain ; Land, John M. ; Wang, Min X. ; Carpenter, Kevin ; Horvath, Rita ; Straub, Volker ; Lek, Monkol ; Gold, Wendy ; Farrell, Michael O. ; Brandner, Sebastian ; Phadke, Rahul ; Matsubara, Kazuo ; McGarvey, Michael L. ; Scherer, Steven S. ; Baxter, Peter S. ; King, Mary D. ; Clayton, Peter ; Rahman, Shamima ; Reilly, Mary M. ; Ouvrier, Robert A. ; Christodoulou, John ; Zuechner, Stephan ; Muntoni, Francesco ; Houlden, Henry. / Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. In: Brain. 2014 ; Vol. 137, No. 1. pp. 44-56.
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    title = "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.",
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    author = "Foley, {A. Reghan} and Menezes, {Manoj P.} and Amelie Pandraud and Gonzalez, {Michael A.} and Ahmad Al-Odaib and Abrams, {Alexander J.} and Kumiko Sugano and Atsushi Yonezawa and Manzur, {Adnan Y.} and Joshua Burns and Imelda Hughes and McCullagh, {B. Gary} and Heinz Jungbluth and Lim, {Ming J.} and Jean-Pierre Lin and Andre Megarbane and Urtizberea, {J. Andoni} and Shah, {Ayaz H.} and Jayne Antony and Richard Webster and Alexander Broomfield and Joanne Ng and Mathew, {Ann A.} and O'Byrne, {James J.} and Eva Forman and Mariacristina Scoto and Manish Prasad and Katherine O'Brien and Simon Olpin and Marcus Oppenheim and Iain Hargreaves and Land, {John M.} and Wang, {Min X.} and Kevin Carpenter and Rita Horvath and Volker Straub and Monkol Lek and Wendy Gold and Farrell, {Michael O.} and Sebastian Brandner and Rahul Phadke and Kazuo Matsubara and McGarvey, {Michael L.} and Scherer, {Steven S.} and Baxter, {Peter S.} and King, {Mary D.} and Peter Clayton and Shamima Rahman and Reilly, {Mary M.} and Ouvrier, {Robert A.} and John Christodoulou and Stephan Zuechner and Francesco Muntoni and Henry Houlden",
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    AU - Foley, A. Reghan

    AU - Menezes, Manoj P.

    AU - Pandraud, Amelie

    AU - Gonzalez, Michael A.

    AU - Al-Odaib, Ahmad

    AU - Abrams, Alexander J.

    AU - Sugano, Kumiko

    AU - Yonezawa, Atsushi

    AU - Manzur, Adnan Y.

    AU - Burns, Joshua

    AU - Hughes, Imelda

    AU - McCullagh, B. Gary

    AU - Jungbluth, Heinz

    AU - Lim, Ming J.

    AU - Lin, Jean-Pierre

    AU - Megarbane, Andre

    AU - Urtizberea, J. Andoni

    AU - Shah, Ayaz H.

    AU - Antony, Jayne

    AU - Webster, Richard

    AU - Broomfield, Alexander

    AU - Ng, Joanne

    AU - Mathew, Ann A.

    AU - O'Byrne, James J.

    AU - Forman, Eva

    AU - Scoto, Mariacristina

    AU - Prasad, Manish

    AU - O'Brien, Katherine

    AU - Olpin, Simon

    AU - Oppenheim, Marcus

    AU - Hargreaves, Iain

    AU - Land, John M.

    AU - Wang, Min X.

    AU - Carpenter, Kevin

    AU - Horvath, Rita

    AU - Straub, Volker

    AU - Lek, Monkol

    AU - Gold, Wendy

    AU - Farrell, Michael O.

    AU - Brandner, Sebastian

    AU - Phadke, Rahul

    AU - Matsubara, Kazuo

    AU - McGarvey, Michael L.

    AU - Scherer, Steven S.

    AU - Baxter, Peter S.

    AU - King, Mary D.

    AU - Clayton, Peter

    AU - Rahman, Shamima

    AU - Reilly, Mary M.

    AU - Ouvrier, Robert A.

    AU - Christodoulou, John

    AU - Zuechner, Stephan

    AU - Muntoni, Francesco

    AU - Houlden, Henry

    PY - 2014/1

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    N2 - 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.

    AB - 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.

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    KW - Brown-Vialetto-Van Laere syndrome

    KW - riboflavin therapy

    KW - RFVT2

    KW - SLC52A2

    KW - Vialetto-Van-Laere

    KW - Fazio-Londe-Disease

    KW - autosomal recessive inheritance

    KW - progressive bulbar paralysis

    KW - pontobulbar palsy

    KW - Vanlaere syndrome

    KW - deafness

    KW - overlap

    KW - family

    KW - brain

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    DO - 10.1093/brain/awt315

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