Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

被引：123

作者：

Foley, A. Reghan ^{[1
,2
,3
]}

Menezes, Manoj P. ^{[4
,5
]}

Pandraud, Amelie ^{[6
,7
,8
]}

Gonzalez, Michael A. ^{[9
,10
]}

Al-Odaib, Ahmad ^{[5
,11
,12
]}

Abrams, Alexander J. ^{[9
,10
]}

Sugano, Kumiko ^{[13
]}

Yonezawa, Atsushi ^{[13
]}

Manzur, Adnan Y. ^{[1
,2
,3
]}

Burns, Joshua ^{[4
,5
]}

Hughes, Imelda ^{[14
]}

McCullagh, B. Gary ^{[14
]}

Jungbluth, Heinz ^{[15
,16
,17
]}

Lim, Ming J. ^{[15
]}

Lin, Jean-Pierre ^{[15
]}

Megarbane, Andre ^{[18
,19
]}

Urtizberea, J. Andoni ^{[20
]}

Shah, Ayaz H. ^{[21
]}

Antony, Jayne ^{[4
]}

Webster, Richard ^{[4
]}

Broomfield, Alexander ^{[22
]}

Ng, Joanne ^{[23
]}

Mathew, Ann A. ^{[23
]}

O'Byrne, James J. ^{[24
]}

Forman, Eva ^{[24
]}

Scoto, Mariacristina ^{[1
,2
,3
]}

Prasad, Manish ^{[25
]}

O'Brien, Katherine ^{[26
]}

Olpin, Simon ^{[27
]}

Oppenheim, Marcus ^{[6
,7
,8
]}

Hargreaves, Iain ^{[6
,7
,8
]}

Land, John M. ^{[6
,7
,8
]}

Wang, Min X. ^{[28
]}

Carpenter, Kevin ^{[5
,29
]}

Horvath, Rita ^{[30
]}

Straub, Volker ^{[30
]}

Lek, Monkol ^{[4
]}

Gold, Wendy ^{[5
,11
]}

Farrell, Michael O. ^{[31
]}

Brandner, Sebastian ^{[32
]}

Phadke, Rahul ^{[1
,2
,3
,32
]}

Matsubara, Kazuo ^{[13
]}

McGarvey, Michael L. ^{[33
]}

Scherer, Steven S. ^{[33
]}

Baxter, Peter S. ^{[25
]}

King, Mary D. ^{[24
]}

Clayton, Peter ^{[34
,35
]}

Rahman, Shamima ^{[6
,7
,8
,22
,34
,35
]}

Reilly, Mary M. ^{[6
,7
,8
]}

Ouvrier, Robert A. ^{[4
,5
]}

机构：

[1] UCL, Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England

[2] UCL, Inst Child Hlth, MRC Ctr Neuromuscular Disorders, London WC1N 1EH, England

[3] Ormond St Hosp Children, London WC1N 1EH, England

[4] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia

[5] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia

[6] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[7] UCL, Inst Neurol, MRC, Ctr Neuromuscular Dis, London WC1N 3BG, England

[8] Natl Hosp Neurol & Neurosurg, Neurometab Unit, London WC1N 3BG, England

[9] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn Dept Human Genet, Miami, FL 33136 USA

[10] Univ Miami, Miller Sch Med, Hussman Inst Human Genom, Miami, FL 33136 USA

[11] Childrens Hosp Westmead, Western Sydney Genet Program, Sydney, NSW 2145, Australia

[12] King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 12713, Saudi Arabia

[13] Kyoto Univ Hosp, Dept Clin Pharmacol & Therapeut, Sakyo Ku, Kyoto 6068507, Japan

[14] Royal Manchester Childrens Hosp, Dept Paediat Neurol, Manchester M13 9WL, Lancs, England

[15] St Thomas Hosp, Evelina Childrens Hosp, Dept Paediat Neurol, London SE1 7EH, England

[16] Kings Coll London, Muscle Signalling Sect, Randall Div Cell & Mol Biophys, London WC2R 2LS, England

[17] Kings Coll London, Inst Psychiat, Clin Neurosci Div, London WC2R 2LS, England

[18] Univ St Joseph, Fac Med, Unite Genet Med, Beirut 11042020, Lebanon

[19] Univ St Joseph, Fac Med, Lab Associe INSERM UMR S 910, Beirut 11042020, Lebanon

[20] Hop Marin de Hendaye, AP HP, F-64700 Hendaye, France

[21] Royal Aberdeen Childrens Hosp, Aberdeen AB15 6XS, Scotland

[22] Great Ormond St Hosp Sick Children, Metab Med Unit, London WC1N 3JH, England

[23] Great Ormond St Hosp Sick Children, Dept Neurol, London WC1N 3JH, England

[24] Childrens Univ Hosp, Dept Paediat Neurol, Dublin 2, Ireland

[25] Sheffield Childrens Hosp, Dept Paediat Neurol, Sheffield S10 2TH, S Yorkshire, England

[26] Childrens Hosp, Dept Audiol, Westmead, NSW 2145, Australia

[27] Sheffield Childrens Hosp, Sheffield S10 2TH, S Yorkshire, England

[28] Royal Prince Alfred Hosp, Inst Clin Neurosci, Sydney, NSW 2050, Australia

[29] Univ Sydney, Discipline Genet Med, Sydney, NSW 2006, Australia

[30] Univ Newcastle, Int Ctr Life, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England

[31] Beaumont Hosp, Dept Pathol, Dublin 9, Ireland

[32] Natl Hosp Neurol & Neurosurg, UCL Inst Neurol, Div Neuropathol, London WC1N 3BG, England

[33] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA

[34] UCL, Inst Child Hlth, Clin & Mol Genet Unit, London WC1N 1EH, England

[35] Great Ormond St Hosp Sick Children, London WC1N 1EH, England

来源：

BRAIN | 2014年 / 137卷

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

childhood neuronopathy; Brown-Vialetto-Van Laere syndrome; riboflavin therapy; RFVT2; SLC52A2; VIALETTO-VAN-LAERE; PROGRESSIVE BULBAR PARALYSIS; PONTOBULBAR PALSY; VANLAERE SYNDROME; DEAFNESS; OVERLAP; DISEASE; FAMILY;

D O I：

10.1093/brain/awt315

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：44 / 56

页数：13

共 34 条

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