Kono, Satoshi

Miyajima, Hiroaki

Shirakawa, Kentaro

Suzuki, Hitoshi

Togawa, Akashi

Yoshida, Kenichi

HamaMed-Repository

Mutations in a thiaminetransporter gene andWernicke's-like encephalopathy言語: English出版者: 公開日: 2013-08-27キーワード (Ja): キーワード (En): 作成者: Kono, Satoshi, Miyajima, Hiroaki, Yoshida,Kenichi, Togawa, Akashi, Shirakawa, Kentaro, Suzuki,Hitoshiメールアドレス: 所属: メタデータhttp://hdl.handle.net/10271/2187URLT h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 360;17 nejm.org april 23, 20091792McAdams M, Staffa J, Dal Pan G. Estimating the extent of 1. reporting to FDA: a case study of statin-associated rhabdomyoly-sis. Pharmacoepidemiol Drug Saf 2008;17:229-39.Abraham SC, Cruz-Correa M, Lee LA, Yardley JH, Wu T-T. 2. Alendronate-associated esophageal injury: pathologic and endo-scopic features. Mod Pathol 1999;12:1152-7.Ribeiro A, DeVault KR, Wolfe JT III, Stark ME. Alendronate-3. associated esophagitis: endoscopic and pathologic features. Gastrointest Endosc 1998;47:525-8.Singh SP, Odze RD. Multinucleated epithelial giant cell 4. changes in esophagitis: a clinicopathologic study of 14 cases. Am J Surg Pathol 1998;22:93-9.Inderjeeth CA, Foo AC, Lui MM, Glendenning P. Efficacy and 5. safety of pharmacological agents in managing osteoporosis in the old old: review of the evidence. Bone 2008 December 16 (Epub ahead of print).Mutations in a Thiamine-Transporter Gene  and Wernicke’s-like EncephalopathyTo the Editor: We report on two previously healthy Japanese brothers with a newly discovered recessively inherited syndrome similar to Wer-nicke’s encephalopathy that developed in the sec-ond decade of life; this syndrome was manifested clinically as thiamine-responsive diplopia and ptosis without serum thiamine deficiency. The patients had complex partial seizures resulting in status epilepticus. The administration of high-dose thiamine (up to 600 mg) improved the sei-zures within 24 hours, although the ophthalmo-plegia, nystagmus, and ataxia continued for several weeks. There were no extrapyramidal fea-tures. Magnetic resonance imaging (MRI) of the brain showed high-intensity signals in the bilat-eral medial thalamus and periaqueductal region on fluid-attenuated inversion recovery images (Fig. 1A); these signals were characteristic of findings in Wernicke’s encephalopathy and be-came normal within 1 month after treatment. Interviews of the patients’ relatives confirmed that there was no consanguinity in their parents. Subacute ophthalmoplegia with nystagmus and ataxia occurred repeatedly within several months after the discontinuation of 100 mg of thiamine per day. There was no history of chronic alcohol-ism in either patient. Korsakoff’s psychosis did not occur even after long periods of Wernicke’s-like symptoms.The clinical and imaging features resembling Wernicke’s encephalopathy in these patients sug-gested that the syndrome was caused by a ge-netic disorder of thiamine metabolism.1 Genomic analysis of SLC19A3 encoding human thiamine transporter 2 (hTHTR2)2,3 revealed that the pa-tients were compound heterozygotes for the K44E and E320Q mutations; these mutations were not present among 192 ethnically matched control subjects (Fig. 1B and 1C). Gene-expression analy-ses of mammalian culture cells showed the ma-jority of the K44E mutant to be impaired in intra-cellular transport while remaining normal in the endoplasmic reticulum. The E320Q mutant was identical in cell-surface localization to the wild-type protein (Fig. 1D), whereas intracellular thia-mine uptake activity was decreased significantly (Fig. 1E). High expression of SLC19A3 RNA in the thalamus (Fig. 1F) may explain the selective tha-lamic lesions on MRI.Mutation of SLC19A3 causes a biotin-responsive basal-ganglia disease characterized by subacute encephalopathy with rigidity and dystonia. Biotin is effective and thiamine is ineffective in treat-ing this childhood-onset disease.4,5 The features of this process on MRI are bilateral necrotic le-sions in the caudate heads; this is markedly dif-ferent from the locus of lesions in the disease we describe.4 The absence of serum thiamine defi-ciency and the efficacy of high-dose thiamine in our patients suggest that dysfunction of hTHTR2 may induce the expression of another human thia-mine transporter 1–encoded gene called SLC19A2, thereby increasing intracellular thiamine trans-port in enterocytes and neuronal cells. The iden-tification of this syndrome provides insight into the thiamine metabolism associated with Wer-nicke’s encephalopathy in humans and suggests that the mechanism of Korsakoff’s psychosis may be independent of these thiamine pathways.Satoshi Kono, M.D., Ph.D. Hiroaki Miyajima, M.D., Ph.D. Kenichi Yoshida, M.D., Ph.D. Akashi Togawa, M.D., Ph.D. Kentaro Shirakawa, M.D. Hitoshi Suzuki, M.D.Hamamatsu University School of Medicine Hamamatsu 431-3192, Japan satokono@hama-med.ac.jpThe New England Journal of Medicine Downloaded from nejm.org on December 23, 2010. For personal use only. No other uses without permission.  Copyright © 2009 Massachusetts Medical Society. All rights reserved. correspondencen engl j med 360;17 nejm.org april 23, 2009 179336p6DAEBFC4Relative Expressionof SLC19A3 RNA 3210Frontal CortexTemporal CortexHippocampusThalamusCaudate NucleusGlobus PallidusCerebellum8003 H-Thiamine Uptake(CPM/µg of protein/30 min)6004002000ControlWild TypeK44EE320QP<0.01AUTHOR:FIGURE:JOB:4-CH/TRETAKESIZEICMCASEEMail LineH/TComboRevisedAUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.Please check carefully.REG FEnon1st2nd3rdKono1 of 104-23-09ARTIST: ts36017 ISSUE:Wild TypeWild TypeK44EC C A G A A A A A AT C   GDPE320QG G T A A AG G CC C T   CA V E ANKK44EE320Q— 330 bp— 300 bp— 237 bp— 207 bp1 2 3 4WildTypeK44EE320QV5 MergePDIPeriaqueductalRegionBilateral MedialThalamusFigure 1. Analyses of Data from Two Brothers with a Wernicke’s-like Encephalopathy.Panel A shows the brain MRI scans in the older brother on hospitalization for status epilepticus with external ophthalmoplegia at 36 years of age. The scan on the left shows high-intensity signals in the periaqueductal region, and the scan on the right shows high-inten-sity signals in the bilateral medial thalamus. Panel B shows the results of electrophoresis of directly sequenced SLC19A3 polymerase-chain-reaction products amplified from the leukocyte DNA of an older brother of the two patients. The sequence analyses showed an A→G substitution at nucleotide position 218 in exon 2 resulting in a substitution of lysine at codon 44 with glutamic acid and a G→C substitution at nucleotide position 1047 in exon 3 resulting in a substitution of glutamic acid at codon 320 with glutamine. Sequence analyses of genes associated with thiamine metabolism, including TKT, PDHA2, OGDH, DLD, and SLC19A2, showed no genetic varia-tion involving newly discovered benign polymorphisms. Panel C shows the results of the analysis of the restriction-fragment–length polymorphisms of the family. In the pedigree portion of th  figure, solid symbol  d ote affected family members and half-solid sym-bols indicate carriers of the mutation. Digestion of a mutant sequence for the K44E or E320Q mutation resulted in 300-bp and 207-bp fragments, respectively. The patients (lanes 3 and 4) had two fragments that indicated compound heterozygosity for K44E and E320Q. The father was heterozygous for E320Q (lane 1), whereas the mother was heterozygous for K44E (lane 2). Panel D shows cellular local-izations of wild-type protein and K44E and E320Q mutants by means of immunofluorescence assay. SLC19A3 complementary DNA (cDNA) was subcloned into PcDNA6.2/GW/D-TOPO (Invitrogen) with a C-terminal V5 epitope tag. Chinese hamster ovary (CHO) cells were transiently transfected with wild-type, K44E, or E320Q SLC19A3 cDNA and were processed for immunofluorescence. The cells were labeled with the use of antibodies against V5 or resident protein disulfide isomerase (PDI) in the endoplasmic reticulum. Images in the Merge column are composite overlays of the V5 and PDI images. Panel E shows intracellular [3H]-thiamine uptake by CHO cell lines sta-bly expressing wild-type protein or K44E or E320Q mutants. The results are expressed in counts per minute as the means of uptake val-ues obtained from three independent experiments. I bars represent standard errors. P<0.01 for the comparisons of wild-type protein with K44E and E320Q. Panel F shows the SLC19A3 RNA levels in different areas of the human brain calculated with the use of a control messenger RNA–plasmid standard curve, then normalized to glyceraldehyde-3-phosphate dehydrogenase. The results are expressed as the means from three independent experiments. I bars represent standard errors.The New England Journal of Medicine Downloaded from nejm.org on December 23, 2010. For personal use only. No other uses without permission.  Copyright © 2009 Massachusetts Medical Society. All rights reserved. n engl j med 360;17 nejm.org april 23, 20091794correspondenceSechi G, Serra A. Wernicke’s encephalopathy: new clinical 1. settings and recent advances in diagnosis and management. Lancet Neurol 2007;6:442-55.Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, 2. Finnell RH. Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes. Mol Genet Metab 2000;71:581-90.Rajgopal A, Edmondson A, Goldman ID, Zhao R. SLC19A3 3. encodes a second thiamine transporter ThTr2. Biochim Biophys Acta 2001;1537:175-8.Ozand PT, Gascon GG, Al Essa M, et al. Biotin-responsive 4. basal ganglia disease: a novel entity. Brain 1998;121:1267-79.Zeng WQ, Al-Yamani E, Acierno JS Jr, et al. Biotin-responsive 5. basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 2005;77:16-26.Correspondence Copyright © 2009 Massachusetts Medical Society.instructions for letters to the editorLetters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following: •Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article. Letters not related to a Journal article must not exceed 400 words. All letters must be submitted over the Internet at authors.NEJM.org.  •A letter can have no more than five references and one figure or table. •A letter can be signed by no more than three authors. •Financial associations or other possible conflicts of interest must be disclosed. (Such disclosures will be published with the letters. For authors of Journal articles who are responding to letters, this information appears in the published articles.) •Include your full mailing address, telephone number, fax number, and e-mail address with your letter.Our Web site: authors.NEJM.orgWe cannot acknowledge receipt of your letter, but we will notify you when we have made a decision about publication. Letters that do not adhere to these instructions will not be considered. Rejected letters and figures will not be returned. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.The New England Journal of Medicine Downloaded from nejm.org on December 23, 2010. For personal use only. No other uses without permission.  Copyright © 2009 Massachusetts Medical Society. All rights reserved. 

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Mutations in a thiaminetransporter gene and Wernicke's-like encephalopathy

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Mutations in a thiaminetransporter gene and Wernicke's-like encephalopathy

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