Bain, MD

Bax, BE

Moran, NF

Muqit, MM

English

Moran, N. F.

Bain, M. D.

Muqit, M. M. K.

Bax, B. E.

Discovery Research Portal

Carrier erythrocyte entrapped thymidine phosphorylas etherapy for MNGIE

N. F. Moran

M. D. Bain

M.M.K. Muqit

B. E. Bax

Crossref

CARRIER ERYTHROCYTE ENTRAPPED THYMIDINE PHOSPHORYLASE THERAPY FOR MNGIE

St George's Online Research Archive

DOI: 10.1212/01.wnl.0000324602.97205.ab  2008;71;686-688 NeurologyN. F. Moran, M. D. Bain, M.M.K. Muqit and B. E. Bax  THERAPY FOR MNGIECARRIER ERYTHROCYTE ENTRAPPED THYMIDINE PHOSPHORYLASEThis information is current as of September 23, 2008  http://www.neurology.org/cgi/content/full/71/9/686located on the World Wide Web at: The online version of this article, along with updated information and services, isAll rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. since 1951, it is now a weekly with 48 issues per year. Copyright © 2008 by AAN Enterprises, Inc. ® is the official journal of the American Academy of Neurology. Published continuouslyNeurology at SWETS SUB SERVICE on September 23, 2008 www.neurology.orgDownloaded from At the time of reporting there were no reports ofsignificant hepatotoxicity involving levetiracetam inclinical trials. There has been one reported case of afatal fulminant hepatic failure in a patient with re-fractory epilepsy treated with combination carbam-azepine and levetiracetam. Autopsy findings revealedcomplete hepatocyte necrosis5 but it was unclear iflevetiracetam was the only or primary culprit incausality.5In our patient careful consideration has beengiven toward other potential etiologies of hepatotox-icity. Phenytoin was deemed unlikely to be the causedue to preexisting deranged LFTs prior to commenc-ing it and was still administered in the postoperativeperiod when his LFTs were improving. Azathioprinecan cause hepatotoxicity but the timing of its com-mencement did not correlate with the recurrence ofabnormal LFTs. This very same reason applies to allhis other posttransplant medications which werecontinued safely upon discharge. Oxcarbazepine andalbendazole were already ceased prior to the develop-ment of documented hepatotoxicity making themvery unlikely culprits. None of the antimicrobialswere ceased when the patient’s LFTs deterioratedposttransplant and its improvement thereafter wasnot related to their withdrawal.Exclusion of other possible etiologies has left leve-tiracetam as the most likely cause of fulminant he-patic failure in our patient. This link was furtherstrengthened by the inadvertent rechallenge with thedrug after post liver transplant resulting in deteriora-tion of the LFTs and biopsy findings suggestive of atoxic cause.From the Department of Gastroenterology and Hepatology(T.C.H.T., L.A.A., G.P.J., G.M.), WA Liver and Kidney Trans-plant Service (A.M., L.D., G.P.J.), Sir Charles Gairdner Hospital,Western Australia; Division of Tissue Pathology (B.W.d.B.), Path-West, Queen Elizabeth II Medical Centre, Western Australia; andDepartment of Medicine (L.A.A., G.M.), University of WesternAustralia.Disclosure: The authors report no disclosures.Received August 3, 2007. Accepted in final form March 19, 2008.Address correspondence and reprint requests to Dr. TerrenceC.H. Tan, Department of Gastroenterology and Hepatology, SirCharles Gairdner Hospital, Nedlands, Western Australia 6008Australia; perthfracp@gmail.comCopyright © 2008 by AAN Enterprises, Inc.1. Ben-Menachem E, Gilland E. Efficacy and tolerability oflevetiracetam during 1-year follow up in patients with re-fractory epilepsy. Seizure 2003;12:131–135.2. Radtke RA. Pharmacokinetics of levetiracetam. Epilepsia2001;42 suppl 4:24–27.3. Patsalos PN. Clinical pharmacokinetics of levetiracetam.Clin Pharmacokinet 2004;43:707–724.4. Patsalos PN. Pharmacokinetic profile of levetiracetam:toward ideal characteristics. Pharmacol Ther 2000;85:77–85.5. Skopp G, Schmitt HP, Pedal I. Fulminant liver failure in apatient on carbamazepine and levetiracetam associatedwith status epilepticus. Archiv Kriminologie 2006;217:161–175.CARRIER ERYTHROCYTE ENTRAPPED THYMIDINEPHOSPHORYLASETHERAPYFORMNGIEMitochondrial neurogastrointestinal encephalomy-opathy (MNGIE) is an autosomal recessive condi-tion caused by mutations in the nuclear gene ECGF1coding for thymidine phosphorylase (TP).1,2 Clinicalfeatures include gastrointestinal dysmotility, periph-eral sensorimotor polyneuropathy, progressive exter-nal ophthalmoplegia, and hepatopathy. In vitroevidence and the improvement following stem celltransplantation (alloSCT) in one patient suggest thepathogenesis centers on elevated systemic levels ofthe TP substrates, thymidine (Thd) and deoxyuri-dine (dUrd).3,4Case report. In September 2005, a 21-year-oldwoman presented after a 4-week history of pro-gressive bilateral distal lower limb numbness andfoot drop. She had bouts of unexplained gastroin-testinal symptoms and weight loss since age 6 yearsand at 19 developed an acute abdomen leading toa laparotomy that revealed gross small bowel dis-tension (thought to be caused by an elevated liga-ment of Treitz) and hepatosplenomegaly. Agastrojejunostomy was performed.On neurologic examination, the positive findingswere subtle pigmentary retinopathy, partial ptosis,slight reduction of eye abduction, markedly slowhorizontal saccades, severe weakness of ankle move-ments, absent muscle stretch reflexes and plantar re-flexes, and stocking diminution for light touch andpain (all findings bilateral and symmetric). Of noteon systemic examination: underweight, gross hepato-splenomegaly, tachycardia, and hyperdynamic car-diac apex.Her parents were not related. She left higher edu-cation in autumn 2005 due to her illness.After the laparotomy, investigations includinghepatitis serology and serum copper were normal; aliver biopsy revealed steatohepatitis. A brain MRIwas normal except equivocal diffuse high T2 signalin the centrum semiovale bilaterally.Following the initial presentation, abnormal re-sults included normochromic normocytic anemia;serum lactate 3.72 mmol/L; CSF protein 1.95 g/L;N.F. Moran, MBChB,MRCP, MScM.D. Bain, MDM.M.K. Muqit, MRCPB.E. Bax, PhD686 Neurology 71 August 26, 2008 at SWETS SUB SERVICE on September 23, 2008 www.neurology.orgDownloaded from CSF lactate 5.6 mmol/L; plasma Thd 13 mol/Land dUrd 16 mol/L (normal: both 0.05 mol/L); urine Thd and dUrd 1.94 mmol/L and dUrd1.95 mmol/L (normal: both undetectable); TP activ-ity measured by HPLC was undetectable in leuko-cytes and platelets (ranges for controls expressed asnmol/hour/mg prot: leukocytes 321–1,341; platelets377–1,078). Mitochondrial DNA analysis of bloodcells for 3243G and 8993TC/G was negative.Nerve conduction studies confirmed a generalizedsensorimotor polyneuropathy. Abdomen CT showedgross hepatosplenomegaly with marked hepatic ste-atosis and nodularity.Analysis of ECGF1 in blood cells demonstrated ahomozygous mutation of the conserved AG nucleo-tide of the 3=-splice site of intron 2 corresponding toIVS3-1GC.Through 2006, she was increasingly unwell, withneuropathic upper limb involvement and worseningabdominal symptoms. She required TPN and subse-quently a nasojejunal tube due to gastroparesis. Bloodresults showed albumin 27 g/L, INR 1.16, bilirubin 8mmol/L, ALP 135IU/L, AST 92IU/L, and GGT129IU/L. She required recurrent paracentesis for mas-sive ascites and developed hematemesis from esophagealvarices which were banded.Treatment. Approval for a trial of carrier erythro-cyte entrapped thymidine phosphorylase therapy(CEETP) was given by the local New Clinical Proce-dures Committee, local Ethics Committee, and Ad-ministration of Radioactive Substances AdvisoryCommittee, UK. A patient information sheet wasprovided and written informed consent obtained.On day one, 140 mL of whole blood was collectedaseptically and the erythrocytes were loaded with TPusing the previously described hypo-osmotic dialysisprocedure.5 The washed and packed TP-loaded car-rier erythrocytes were resuspended in an equal vol-ume of retained plasma and returned to the patientby slow IV infusion. The administered dose of TPwas 1,020 units encapsulated within 20.25  1010erythrocytes (where 1 unit of TP is definedas the activity required to convert 1.0 mol ofThd and phosphate to thymine and 2-deoxyribose1-phosphate per minute at 25°C).Pretreatment and serial postinfusion blood sam-ples and 24-hour urine collections were made.Results. Three days postinfusion (figure), the uri-nary excretion of Thd was 6% and that of dUrd 13%of the pretherapy values. The plasma concentrationsdecreased in parallel. Unfortunately, the patient’sclinical condition remained poor and she died ofpneumonia 21 days after CEETP.Discussion. CEETP was associated with marked re-duction of plasma and urine Thd and dUrd. Al-though these metabolites can fluctuate widely inpatients with MNGIE, the consistency of the fallwould suggest a causal relationship with the adminis-tered CEETP. The results are encouraging, particu-larly as a low dose was administered. An observedclinical effect was unlikely given advanced diseaseand the use of a single treatment.We had discounted alloSCT and liver transplantbecause of an unacceptable mortality risk due to thepatient’s severe clinical state. Autologous erythro-cytes encapsulated adenosine deaminase has beenused successfully in a patient with adenosine deami-nase deficiency.6,7 The approach is applicable to dis-orders where the erythrocyte membrane is permeableto target plasma metabolites. Encapsulation preventsthe formation of neutralizing antibodies and main-tains enzyme activity for the erythrocyte life span.We hypothesize that a reduction of Thd and dUrd inthe plasma would lead to similar reductions in theintracellular compartment, as observed in other con-ditions, thus translating into clinical improvement.Our previous in vivo survival studies demon-strated an initial splenic sequestration of carriererythrocytes, followed by a reflux into the circulationFigure Plasma and urine metabolite valuesbefore and after CEETP infusionNormal ranges: plasma deoxyuridine0.05 mol/L; plasmathymidine 0.05 mol/L; urine deoxyuridine undetectable;urine thymidine undetectable.Neurology 71 August 26, 2008 687 at SWETS SUB SERVICE on September 23, 2008 www.neurology.orgDownloaded from 24 to 144 hours postinfusion; this may contribute tothe fluctuations observed in plasma metabolite con-centrations.5 The disjunction of the plasma metabo-lites at day 14 is based on a single observation; thismight be explained by saturation of the erythrocytemembrane nucleoside transporter.The main safety consideration was of an immuno-logic reaction to bacterial TP or endotoxins. Endotoxinlevels were within pharmaceutical safe levels. Our previ-ous experience with adenosine deaminase indicates im-munologic protection with encapsulation within carriererythrocytes, but we cannot exclude the possibility fol-lowing repeated administrations.CEETPmay be a promising treatment forMNGIE.However, repeated administration, probably two tofour weekly and potentially lifelong, would be required,with costs not too dissimilar to other enzyme replace-ment therapies ($200,000 per year). The frequency ofadministration is likely to be influenced by many fac-tors, particularly the severity of TP dysfunction anderythrocyte half life. The latter was satisfactory in thecurrent case despite massive splenomegaly. The clinicalutility of reducing Thd and dUrd concentrations re-mains largely theoretical. Carrier erythrocyte entrappedTP enzyme therapy offers the opportunity to impose aperiod of lowered Thd and dUrd concentrations duringwhich any clinical benefit can be assessed before consid-ering alloSCT.From Kent & Canterbury Hospital (N.F.M), Canterbury; KingsCollege Hospital (N.F.M.), London; Department of Child Health(M.D.B., B.E.B.), Division of Clinical and Developmental Sci-ences, St George’s, University of London; and Institute of MolecularNeuroscience (M.M.K.M.), Institute of Neurology, London.Disclosure: The authors report no disclosures.Received August 28, 2007. Accepted in final form April 2, 2008.Address correspondence and reprint requests to Dr. Nicholas Freder-ick Moran, Neurology, Kent & Canterbury Hospital, EthelbertRoad, Canterbury, CT1 3NG, UK; nfm10@aol.comCopyright © 2008 by AAN Enterprises, Inc.ACKNOWLEDGMENTThe authors posthumously acknowledge the subject of this paper, Rosie,as well as her family, who supported her through her protracted illness.The treatment was administered in the hope of ameliorating her condi-tion, but Rosie was fully aware of its experimental nature and was hopefulthat other patients with MNGIE might ultimately be successfully treated.The authors acknowledge Dr. Lynette Fairbanks of the Purine ResearchLaboratory, St. Thomas’ Hospital, London, for the biochemical analysis;and Dr. Michio Hirano, Columbia University College of Physiciansand Surgeons, New York, for his input into the clinical managementof this patient.1. Hirano M, Silvestri G, Blake DM, et al. Mitochondrialneurogastrointestinal encephalomyopathy (MNGIE):clinical, biochemical, and genetic features of an autoso-mal recessive mitochondrial disorder. Neurology 1994;44:721–727.2. Nishino I, Spinazzola A, Hirano M. Thymidine phosphor-ylase gene mutations in MNGIE, a human mitochondrialdisorder. Science 1999;283:689–692.3. Marti R, Nishigaki Y, Hirano M. Elevated plasma de-oxyuridine in patients with thymidine phosphorylasedeficiency. Biochem Biophys Res Commun 2003;303:14–18.4. Hirano M, Marti R, Casaali C, et al. Allogenic stem celltransplantation corrects biochemical derangements inMNGIE. Neurology 2006;67:1458–1460.5. Bax BE, Bain MD, Talbot PJ, Parker-Williams EJ, Chalm-ers RA. Survival of human carrier erythrocytes in vivo.Clin Sci 1999;96:171–178.6. Bax BE, Bain MD, Fairbanks LD, Simmonds HA, Web-ster AD, Chalmers RA. Carrier erythrocyte entrappedadenosine deaminase therapy in adenosine deaminase defi-ciency. Adv Exp Med Biol 2000;486:47–50.7. Bax BE, Bain MD, Fairbanks LD, Webster ADB. A nineyear evaluation of carrier erythrocyte encapsulated adeno-sine deaminase therapy in a patient with adult-type adeno-sine deaminase deficiency Eur J Haematol 2007;79:338–348.688 Neurology 71 August 26, 2008 at SWETS SUB SERVICE on September 23, 2008 www.neurology.orgDownloaded from DOI: 10.1212/01.wnl.0000324602.97205.ab  2008;71;686-688 NeurologyN. F. Moran, M. D. Bain, M.M.K. Muqit and B. E. Bax  THERAPY FOR MNGIECARRIER ERYTHROCYTE ENTRAPPED THYMIDINE PHOSPHORYLASEThis information is current as of September 23, 2008  & ServicesUpdated Information http://www.neurology.org/cgi/content/full/71/9/686including high-resolution figures, can be found at:  Subspecialty Collections http://www.neurology.org/cgi/collection/generalized_seizures Generalized seizures http://www.neurology.org/cgi/collection/antiepileptic_drugs Antiepileptic drugs http://www.neurology.org/cgi/collection/all_epilepsy_seizures Epilepsy/SeizuresAll http://www.neurology.org/cgi/collection/all_toxicology ToxicologyAll http://www.neurology.org/cgi/collection/all_clinical_neurology All Clinical Neurologyfollowing collection(s): This article, along with others on similar topics, appears in the Permissions & Licensing http://www.neurology.org/misc/Permissions.shtmlor in its entirety can be found online at: Information about reproducing this article in parts (figures, tables) Reprints http://www.neurology.org/misc/reprints.shtmlInformation about ordering reprints can be found online:  at SWETS SUB SERVICE on September 23, 2008 www.neurology.orgDownloaded from 

A nine year evaluation of carrier erythrocyte encapsulated adenosine deaminase therapy in a patient with adult-type adenosine deaminase deficiency

Address correspondence and reprint requests to Dr. Nicholas Frederick Moran, Neurology, Kent & Canterbury Hospital, Ethelbert Road, Canterbury,

Allogenic stem cell transplantation corrects biochemical derangements in MNGIE.

Carrier erythrocyte entrapped adenosine deaminase therapy in adenosine deaminase deficiency. Adv Exp Med Biol

Elevated plasma deoxyuridine in patients with thymidine phosphorylase deficiency.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): clinical, biochemical, and genetic features of an autosomal recessive mitochondrial disorder. Neurology

Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder.

www.neurology.orgDownloaded from DOI:

Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE

http://openaccess.sgul.ac.uk/100448/1/MNGIE.pdf

Carrier erythrocyte entrapped thymidine phosphorylase therapy for MNGIE

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