Sum m a r yThyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using wholeexome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.T hyroid hormones have diverse actions, which include regulation of skeletal growth, maturation of the central nervous system, cardiac and gastrointestinal function, and energy homeostasis. In addition, thyroid hormones control their own production by feedback inhibition of hypothalamic thyrotropinreleasing hormone and pituitary thyroid-stimulating hormone, which direct their synthesis or release. These physiological effects are principally mediated by hormone action through nuclear receptor proteins that act as ligand-inducible transcription factors and either positively or negatively regulate the expression of target genes in different tissues in a hormone-dependent manner.The receptors are encoded by two genes (THRA and THRB), each of which undergoes alternate splicing to generate receptor subtypes (TRα1, TRβ1, and TRβ2), with differing tissue distributions. TRα1 is the predominant subtype in bone, the gastrointestinal tract, cardiac and skeletal muscle, and the central nervous system; TRβ1 is most abundant in the liver and kidney; and TRβ2 is more discretely expressed in the hypothalamus, pituitary, cochlea, and retina. 1 In the absence of hormone, thyroid receptors that are not bound to ligands repress or silence targetgene transcription by recruiting multiprotein complexes containing corepressors (e.g., nuclear receptor corepressor and silencing mediator of retinoic acid and thyroid hormone receptor), with histone deacetylase activity; triiodothyronine occupancyThe New England Journal of Medicine Downloaded from nejm.org on May 10, 2018. For personal use only. No other uses without permission.

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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...