Yavuz Ayhan

Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor-α Mutations

CONTEXT Recently several patients with resistance to thyroid hormone (RTH)-α due to T3 receptor-α (TRα) mutations were identified. The phenotype of these patients consists of varying degrees of growth impairment, delayed bone, mental and motor development, constipation, macrocephaly, and near-normal thyroid function tests. OBJECTIVE The objective of the study was to describe the clinical phenotype of three new families with RTHα and thereby gain more detailed knowledge on this novel syndrome. DESIGN, SETTING, AND PARTICIPANTS RTHα was suspected in three index patients from different families. Detailed clinical and biochemical assessment and imaging and genetic analyses were performed in the patients and their relatives. In addition, functional consequences of TRα mutations were investigated in vitro. RESULTS We studied 22 individuals from three families and identified 10 patients with heterozygous TRα mutations: C380fs387X, R384H, and A263S, respectively. The frame-shift mutation completely inactivated TRα, whereas the missense mutations produced milder defects. These mutations were associated with decreasing severity of the clinical phenotype: the patient in family 1 showed severe defects in growth, mental, and motor development, whereas the seven patients in family 3 had only mild clinical features. The most frequent abnormalities were anemia, constipation, and a delay in at least one of the developmental milestones. Serum free T3 ranged from high-normal to high and serum free T4 and rT3 from normal to low. TSH levels were normal in all patients. CONCLUSIONS This large case series underlines the variation in the clinical phenotype of RTHα patients. RTHα should be suspected in subjects when even mild clinical and laboratory features of hypothyroidism are present along with high/high-normal free T3, low/normal free T4, and normal TSH.

Relation of the Allelic Variants of Multidrug Resistance Gene to Agranulocytosis Associated With Clozapine.

Abstract Clozapine use is associated with leukopenia and more rarely agranulocytosis, which may be lethal. The drug and its metabolites are proposed to interact with the multidrug resistance transporter (ABCB1/MDR1) gene product, P-glycoprotein (P-gp). Among various P-glycoprotein genetic polymorphisms, nucleotide changes in exons 26 (C3435T), 21 (G2677T), and 12 (C1236T) have been implicated for changes in pharmacokinetics and pharmacodynamics of many substrate drugs. In this study, we aimed to investigate the association between these specific ABCB1 polymorphisms and clozapine-associated agranulocytosis (CAA). Ten patients with a history of CAA and 91 control patients without a history of CAA, despite 10 years of continuous clozapine use, were included. Patient recruitment and blood sample collection were conducted at the Hacettepe University Faculty of Medicine, Department of Psychiatry, in collaboration with the members of the Schizophrenia and Other Psychotic Disorders Section of the Psychiatric Association of Turkey, working in various psychiatry clinics. After DNA extraction from peripheral blood lymphocytes, genotyping was performed using polymerase chain reaction and endonuclease digestion. Patients with CAA had shorter duration of clozapine use but did not show any significant difference in other clinical, sociodemographic characteristics and in genotypic or allelic distributions of ABCB1 variants and haplotypes compared with control patients. Among the 10 patients with CAA, none carried the ABCB1 all-variant haplotype (TT-TT-TT), whereas the frequency of this haplotype was approximately 12% among the controls. Larger sample size studies and thorough genetic analyses may reveal both genetic risk and protective factors for this serious adverse event.

Serotonin syndrome with a combination of aripiprazole and fluoxetine: a case report

Serotonin syndrome (SS) is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. SS is characterized by a triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities [Boyer and Shannon, 2005]. The syndrome is, for some authors, a loose term to define the clinical picture at the moderate to severe end of a spectrum of serotonin toxicity, mild symptoms of which include tremor, hyperreflexia, and occasional myoclonus [Gillman and Whyte, 2004]. In the severe forms of toxicity, generalized myoclonus, sustained ankle clonus, and hyperreflexia may occur along with hyperthermia, which is associated with increased mortality [Gillman, 2013]. SS is classically associated with the high doses of a single selective serotonin reuptake inhibitor (SSRI) use, or with a combination of two or more serotonergic agents [Mason et al. 2000]. Fluoxetine is metabolized in the liver by the isoenzymes of the cytochrome P450 system, including CYP2D6 [Blazquez et al. 2012]. The role of CYP2D6 in the metabolism of fluoxetine may be clinically important, as there is a great genetic variability in the function of this enzyme [Gaedigk, 2013]. Aripiprazole, an atypical antipsychotic, which is a partial agonist at the 5-HT1A receptors, is equally metabolized via both CYP3A4 and CYP2D6 isoenzymes [Molden et al. 2006]. Therefore, coadministration with fluoxetine (a potent inhibitor of CYP450 2D6) may significantly increase the plasma concentrations of aripiprazole. On the other hand, aripiprazole has no known effect on fluoxetine metabolism [Boulton et al. 2010]. Here, we describe a case in which increased plasma concentration of aripiprazole due to a drug interaction with fluoxetine led to SS.

Association between ADH1C and ALDH2 polymorphisms and alcoholism in a Turkish sample.

Abstract Background: Polymorphisms in the genes encoding alcohol metabolizing enzymes are associated with alcohol dependence. Aim: To evaluate the association between the alcohol dehydrogenase 1C (ADH1C) Ile350Val and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys polymorphisms and alcohol dependence in a Turkish sample. Methods: 235 individuals (115 alcohol-dependent patients and 120 controls) were genotyped for ADH1C and ALDH2 with PCR–RFLP (polymerase chain reaction–restriction fragment length polymorphism). Association between the polymorphisms and family history, daily and maximum amount of alcohol consumed was investigated. The associations between alcohol dependence, severity of consumption and family history and the polymorphisms were analyzed by chi-square or Fishers exact test where necessary. Relationship between genotypes and dependence related features was evaluated using analysis of variance (ANOVA). Results: The -350Val allele for ADH1C (ADH1C*2) was increased in alcohol-dependent patients (P = 0.05). In individuals with a positive family history, the genotype distribution differed significantly (P = 0.031) and more patients carried the Val allele compared with controls (P = 0.025). Genotyping of 162 participants did not reveal the -504Lys allele in ALDH2. Conclusions: These findings suggest that ADH1C*2 is associated with alcohol dependence in the Turkish population displaying a dominant inheritance model. ADH1C*2 allele may contribute to the variance in heritability of alcohol dependence. The ALDH2 -504Lys/Lys or Glu/Lys genotypes were not present in alcohol-dependent patients, similar to that seen in European populations and in contrast to the findings in the Asian populations.

Etomidate is associated with longer seizure duration, lower stimulus intensity, and lower number of failed trials in electroconvulsive therapy compared with thiopental.

Objective Induction agents used for electroconvulsive therapy (ECT) may alter seizure parameters. In this study, we aimed to investigate the effects of etomidate and thiopental on seizure-related variables. Methods Registries of patients who received ECT between 2010 and 2013 in a tertiary psychiatry clinic were evaluated retrospectively. The information of patients who were on the same induction agent and muscle relaxant during the whole treatment course was assessed. Primary outcome measures were total number of ECT sessions, mean peripheral and central seizure duration, cumulative stimulus intensity, and the number of adequate seizures per total number of stimuli. Secondary measures were maximum systolic-diastolic and mean blood pressure, peak heart rate, and the frequency of antihypertensive drug use during the sessions. Results Although the total number of ECT sessions is similar between the etomidate (n = 43) and thiopenthal (n = 31) groups, the mean seizure duration per stimuli was significantly longer whereas the cumulative stimulus intensity was lower in the etomidate group. The number of adequate seizures obtained in relation with the number of stimuli was also significantly higher, indicating increased probability of eliciting an adequate seizure with etomidate. During threshold determination, the number of stimuli needed to provide an adequate seizure was marginally less with etomidate. No group difference was observed in hemodynamic changes and the frequency of antihypertensive use. Conclusions Etomidate use, compared with thiopental as an induction agent, is associated with longer seizure duration with less cumulative intensity. The use of etomidate reduces the number of failed trials and may prevent the application of unnecessary electrical stimuli with a possibly safe hemodynamic profile.

A case of clozapine intoxication presenting with atypical NMS symptoms

Clozapine is an antipsychotic drug indicated for treatment-resistant schizophrenia. Clozapine at toxic doses may cause hyperthermia, alterations in consciousness, seizures, cardiac arrhythmias, excessive mucus production in bronchi, hypersalivation, miosis, blood dyscrasias, pancreatitis and hepatitis (Sartorius et al., 2002). Clozapine blood levels are influenced by age, gender, ethnicity, physical illnesses like liver failure, changes in the activity of the cytochrome oxidase enzymes due to genetic variability, concurrent medication use, smoking or caffeine consumption (Greenwood-Smith et al., 2003). Generally, plasma levels of over 1000 ng/ml are associated with central nervous system adverse effects (Varma et al., 2011). One potentially lethal side effect of antipsychotics including clozapine is neuroleptic malignant syndrome (NMS). Neuroleptic malignant syndrome is typically characterized by fever, altered mental status, leukocytosis, autonomic dysfunction and rigidity. Atypical antipsychotics including clozapine are associated less with NMS than typical antipsychotics, and when NMS occurs during treatment with atypical antipsychotics, associated symptoms are less typical (Trollor et al., 2012). In this case report, we present a patient using clozapine for treatment of schizophrenia who was admitted to the Emergency Room with NMS-like symptoms. We present a 53 yr old, female patient diagnosed with schizophrenia, who was on clozapine 500 mg/d for the past 3 yr. She had hyperlipidemia and chronic obstructive pulmonary disease (COPD) and was using rosuvastatin 20 mg/d. She was admitted to the Emergency Room (ER) with acute onset-confusion, shivering, meaningless talk and urinary incontinence. Her body temperature was 39.2°C, blood pressure 90/50 mmHg, pulse rate 117/min, RR: 17/min, SaO2:%96. Electrocardiogram (ECG) was normal. Her Glasgow Coma Score was 15. Blood tests showed hyponatremia (133.2 mEq/l), increased levels of creatinine (1.52 mg/dl), BUN (23.68 mg/dl), uric acid (7.07 mg/dl) and decreased levels of phosphorus (2.50 mg/dl). Liver and thyroid function tests and potassium, chloride and calcium levels were within normal range. Complete …