Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Late-onset urea cycle disorder in a 20-month-old boy is unusually associated with Klinefelter syndrome with a 47XXY karyotype. We record the typical clinical and biochemical findings of ornithine transcarbamylase (OTC) deficiency in a young boy with a short history of recurrent vomiting, self mutilating behaviour, lethargy, ataxia and seizures. Laboratory studies showed hyperammonaemia and orotic aciduria, with normal citrulline and other urea cycle amino acids. Unfortunately, a liver biopsy for OTC activity measurement was refused by the parents. A rapid reversal of phenotype was seen on the introduction of a low-protein diet with accompanying benzoate and phenylbutyrate administration. Linkage studies suggested the inheritance of two X chromosomes, which was confirmed by karyotype analysis. Sequencing of all exons and immediate splice site regions revealed no sequence alterations in these sections of the OTC gene. A search for skewing of X-inactivation in the liver was not possible but we did show a random pattern of X-inactivation in leukocytes. The possibility of maternal X chromosome iso-disomy in our patient was discounted by microsatellite analysis, which revealed the inheritance of two independent X chromosomes. Mutation analysis in the OTC gene has shown that approximately 20% of patients with liver biopsy confirmed OTC deficiency do not have mutations in the coding or immediate splice-site sequences of this gene. Their classification as OTC phenocopies remains speculative, awaiting clarification of the underlying DNA alteration. We report on the novel association of OTC deficiency and Klinefelter syndrome with the additional interest of a probable unusual genetic defect underlying the OTC abnormality.
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PMID:An OTC deficiency 'phenocopy' in association with Klinefelter syndrome. 1718 14

A 41-year-old man was diagnosed with hypogonadotropic hypogonadism managed with gonadotropins after routine fertility review. Eight months later he presented with new polydipsia and polyuria, lethargy and easy bruising. A full blood count showed 28% circulating blasts. A bone marrow biopsy confirmed a diagnosis of acute myeloid leukaemia with inv(3)(q21.3q26.2) with additional monosomy 7. Central diabetes insipidus (DI) was diagnosed following a water deprivation test. Pituitary magnetic resonance imaging showed a slightly thickened pituitary stalk, stable Rathke's cyst, and new absence of the pituitary bright spot. The patient was commenced on desmopressin and induction chemotherapy, subsequently requiring a bone marrow transplant. Bone marrow examination at 100 days post-transplant revealed cytogenetic remission. All symptoms of DI resolved and magnetic resonance imaging showed return of the posterior bright spot and a pituitary stalk of normal thickness. Biochemical hypogonadotropic hypogonadism persisted but was uninterpretable in the context of systemic illness and recent chemotherapy. DI is a rare complication of haematological malignancies, and the prevalence and pathophysiology of DI in this context are poorly understood. Pathogenic mechanisms proposed include leukaemic infiltration of the pituitary, interference with antidiuretic hormone synthesis, and abnormal thrombopoiesis influencing hormone levels. Particular cytogenetic abnormalities such as inv(3)(q21.3q26.2) and monosomy 7 appear to be more commonly associated with DI and also appear to confer worse outcomes. Aetiologies in the literature remain elusive but as DI is a recognised association of haematological malignancies it should be considered in a patient presenting with polydipsia and polyuria.
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PMID:Acute myeloid leukaemia presenting with diabetes insipidus. 3243 Oct 29