Carrier Erythrocyte Entrapped Thymidine Phosphorylase Therapy for Mngie

Abstract

at SWETS SUB SERVICE on September 23, 2008 www.neurology.org Downloaded fromAt the time of reporting there were no reports of significant hepatotoxicity involving levetiracetam in clinical trials. There has been one reported case of a fatal fulminant hepatic failure in a patient with refractory epilepsy treated with combination carbamazepine and levetiracetam. Autopsy findings revealed complete hepatocyte necrosis 5 but it was unclear if levetiracetam was the only or primary culprit in causality. 5 In our patient careful consideration has been given toward other potential etiologies of hepatotoxicity. Phenytoin was deemed unlikely to be the cause due to preexisting deranged LFTs prior to commencing it and was still administered in the postoperative period when his LFTs were improving. Azathioprine can cause hepatotoxicity but the timing of its commencement did not correlate with the recurrence of abnormal LFTs. This very same reason applies to all his other posttransplant medications which were continued safely upon discharge. Oxcarbazepine and albendazole were already ceased prior to the development of documented hepatotoxicity making them very unlikely culprits. None of the antimicrobials were ceased when the patient's LFTs deteriorated posttransplant and its improvement thereafter was not related to their withdrawal.Exclusion of other possible etiologies has left levetiracetam as the most likely cause of fulminant hepatic failure in our patient. This link was further strengthened by the inadvertent rechallenge with the drug after post liver transplant resulting in deterioration of the LFTs and biopsy findings suggestive of a toxic cause. Gastroenterology and Hepatology (T.C.H.T., L.A.A., G.P.J., G.M.), WA Liver and Kidney Transplant Service (A.M., L.D., G.P.J.) From the Department of CARRIER ERYTHROCYTE ENTRAPPED THYMIDINE PHOSPHORYLASE THERAPY FOR MNGIEMitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive condition caused by mutations in the nuclear gene ECGF1 coding for thymidine phosphorylase (TP). 1,2 Clinical features include gastrointestinal dysmotility, peripheral sensorimotor polyneuropathy, progressive external ophthalmoplegia, and hepatopathy. In vitro evidence and the improvement following stem cell transplantation (alloSCT) in one patient suggest the pathogenesis centers on elevated systemic levels of the TP substrates, thymidine (Thd) and deoxyuridine (dUrd). 3,4Case report. In September 2005, a 21-year-old woman presented after a 4-week history of progressive bilateral distal lower limb numbness and foot drop. She had bouts of unexplained gastrointestinal symptoms and weight loss since age 6 years and at 19 developed an acute abdomen leading to a laparotomy that revealed gross small bowel distension (thought to be caused by an elevated ligament of Treitz) and hepatosplenomegaly. A gastrojejunostomy was performed.On neurologic examination, the positive findings were subtle pigmentary retinopathy, partial ptosis, slight reduction of eye abduction, markedly sl...

Hematopoietic gene therapy restores thymidine phosphorylase activity in a cell culture and a murine model of MNGIE

“…All therapeutic strategies have been aimed at normalizing the accumulation of the toxic metabolites dThd and dUrd in patients. 7,13,14 The observation that platelet transfusions transiently reduced the levels of dThd and dUrd in MNGIE patients, 18 suggested that HSCT from healthy donors could provide a permanent source of TP at levels, producing a significant clinical benefit. Patients undergoing a successful allogeneic HSCT show permanent restoration of TP activity with correction of biochemical abnormalities and progressive improvements in clinical parameters.…”

“…9,10 Therapeutic approaches have so far focused on reducing the systemic overload of these nucleosides. 7,[11][12][13][14] In recent years, several MNGIE patients have been treated with allogeneic hematopoietic stem cell transplantation (HSCT). 4,12,15,16 After successful HSCT, donorderived nucleated blood cells and platelets provided enough TP activity to reduce the dThd and dUrd concentrations to undetectable or nearly undetectable levels, and subsequent slowing of disease progression or mild clinical improvement.…”

Clinical and biochemical improvements in a patient with MNGIE following enzyme replacement

“…In this approach, a predetermined volume of the patient's blood is removed and subjected to reversible hypo-osmotic dialysis to enable encapsulation of TP within the erythrocytes, which are then returned to the patient. 5,6 EE-TP has the pharmacologic advantages of prolonging the circulatory half-life of TP and minimizing immunogenic reactions.…”

The Role of Brain MRI in Mitochondrial Neurogastrointestinal Encephalomyopathy

“…Nowadays, promising new therapeutic options, such as allogeneic haematopoietic stem cell transplantation (HSCT) 28 and CEETP therapy are available 29 . This implies that the diagnosis should be made as early as possible to prevent organ damage and to maximize the benefits of treatments [28][29][30] .…”