Partial response to biotin therapy in a patient with holocarboxylase synthetase deficiency: clinical,biochemical, and molecular genetic aspects

We report the clinical course and biochemical findings of a 10-year-old, mentally retarded girl with late-onset holocarboxylase synthetase (HCS, gene symbol HLCS) deficiency and only partial response to biotin. On treatment, even with an unusually high dose of 200mg/day, activities of the biotin-dependent mitochondrial carboxylases in lymphocytes remained below 50% of the mean control values. Not only urinary 3-hydroxyisovaleric acid excretion has been persistently elevated, but also plasma and, with even higher concentrations, cerebrospinal fluid 3-hydroxyisovaleric acid have not normalized. The unusual and insufficient response of this patient to biotin treatment can be explained by the effect of the combination of the common HLCS allele IVS10 +5 g>a on one chromosome and a truncating mutation on the other. This case illustrates mechanisms involved in the genotype-phenotype correlation that unequivocally exists in HCS deficiency.     

Structural genomic variation in childhood epilepsies with complex phenotypes

A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.     

Prediction of tamoxifen outcome by genetic variation of CYP2D6 in post-menopausal women with early breast cancer

The question of whether genetic polymorphisms of CYP2D6 can affect treatment outcome in patients with early post-menopausal oestrogen receptor (ER)-positive breast cancer has been a matter of debate over the past few years. In this article we revisit the hypothesis of CYP2D6 being a potential tamoxifen outcome predictor and provide detailed insight into the ongoing controversy that prevented the CYP2D6 marker from being accepted by the scientific and clinical community. We summarize the available pharmacokinetic, pharmacodynamic and pharmacogenetic evidence and resolve the controversy based on the recognized methodological and statistical issues. The cumulative evidence suggests that genotyping for CYP2D6 is clinically relevant in post-menopausal women. This is important, because the clarification of this issue has the potential to resolve a clinical management question that is relevant to hundreds of thousands of women diagnosed with ER-positive breast cancer each year, who should not be denied effective endocrine therapy.     

Prevalence of thrombophilia and catheter-related thrombosis in cystic fibrosis

Venous thrombosis in children and young adults is frequently associated with predisposing conditions and with an indwelling catheter or totally implantable venous access device (TIVAD). These systems are commonly used for the delivery of antibiotic therapy in patients with cystic fibrosis (CF). We reviewed our CF center's history of catheter-related events over 13 years and prospectively investigated the presence of risk factors for thrombosis in 66 children and adults with CF (age, 3-38 years; 32 females). Five thrombotic events had occurred in 4 patients, 2 of whom carried the factor V Leiden mutation. Five asymptomatic patients were diagnosed with heterozygous mutations of the factor V or prothrombin gene. Functional activity of protein C was decreased in 13 subjects, with a correlation to impaired liver function. Protein S activity was abnormal in 20 patients and was related to CF genotype. Anti-phospholipid antibodies (APA) were present in 6 asymptomatic patients. A reinvestigation after 3 years confirmed protein S deficiency in 12 of 14 patients, while most abnormalities for protein C or APA were inconsistent. In conclusion, a thrombophilic state was detected in 53% of patients, and 2 out of 4 subjects with TIVAD-related thrombosis carried a genetic defect. It may thus be helpful to include a hemostatic evaluation in the clinical decision process for or against TIVAD insertion in eligible CF patients.     

Metabolic responses of the heart in acute myocardial infarction in man

Acute myocardial infarction evokes a characteristic neurohumoral response: Catecholamine release is increased, plasma contents of free fatty acids and glucose are elevated and glucose tolerance is diminished. To what degree the myocardium participates in this stress response was evaluated by sampling coronary sinus and arterial blood in 50 patients with acute transmural infarction. Studies were initiated an average of 8 hours after the clinical onset of infarction and were continued for up to 60 hours. A total of 173 separate metabolic studies were analyzed. Forty-one percent exhibited a pattern of predominant myocardial free fatty acid uptake (mean extraction ratio 24 percent) in the presence of elevated plasma free fatty acid and glucose contents (respective means 1,181 μmol/liter and 210 mg/100 ml). Myocardial extraction ratios for glucose, lactate and pyruvate were low (respective means 1.1, 4 and 11 percent). Twenty-one percent of the studies revealed normal myocardial metabolism and 18 percent showed enhanced carbohydrate uptake, as evidenced by increased myocardial extractions of lactate and pyruvate (respective means 42 percent) and of glucose (mean 5 percent). Plasma contents of glucose and free fatty acids were lower than in the predominant free fatty acid group (respective means 156 mg/100 ml and 743 μmol/liter). The remaining 20 percent of studies showed high plasma substrate contents and low myocardial substrate uptake suggesting metabolic breakdown. The free fatty acid metabolic pattern was observed in more than 50 percent of the studies performed at the time of or close to the occurrence of important clinical complications. Propranolol, 0.1 mg/kg intravenously, shifted myocardial substrate utilization from free fatty acids toward carbohydrates. The myocardial respiratory quotient increased from an average of 0.79 to 0.88 (P < 0.01).The study demonstrates that the metabolic patterns of the myocardium are influenced by the systemic response to stress. Beta adrenergic blockade changed substrate utilization of the myocardium, supporting the hypothesis that adrenergic activation plays an important role in these metabolic responses.     

An in vitro study of the effects of isoflurane on oxygen transfer

A common anesthetic technique utilized during cardiopulmonary bypass (CPB) includes the use of various inhalation agents, such as isoflurane. The purpose of this study was to evaluate the effects of this agent on oxygen transfer during CPB. An in vitro model was designed using bovine blood. Blood flow was held constant at 2 l/min, while gas flow was manipulated at 1 and 3 l/min. The percentage of inspired oxygen (FiO2) was set at 50 and 100%, and isoflurane was manipulated to 1.0, 3.0 and 5.0%. Blood gas analysis, oxygen transfer, and inlet and outlet isoflurane concentrations were measured at each of the given conditions. A total of 12 trials with four oxygenators were conducted. In the four oxygenators used in our study, no significant differences in oxygenator performance were found. At conditions of 1 I/min gas flow, 50% FiO2 and 1% isoflurane, there were no significant changes in O2 transfer between baseline and measurements taken during isoflurane administration (100.18 +/- 12.49 vs 102.35 +/- 10.99 ml O2/min, p=0.8031). At 3 I/min gas flow, 100% FiO2 and 5% isoflurane, no significant differences were found (142.35 +/- 10.76 vs 154.04 +/- 8.95 ml O2/min, p=0.1459). The only significant differences found for oxygen transfer were between 50 and 100% FiO2, all other conditions being set equal (102.35 +/- 10.99 vs 137.68 +/- 8.62 ml O2/min, p=0.0023). In conclusion, increasing concentrations of isoflurane up to 5% does not affect the efficiency of oxygen transfer in an in vitro circuit. Further studies are necessary to evaluate the effects in an in vivo setting.     

Effects of supraphysiological doses of L-thyroxine on cognitive function in healthy individuals

Cognitive disturbance is commonly associated with disorders of the thyroid gland, particularly hypothyroidism, and usually subsides following thyroid hormone replacement therapy. In contrast, the effects of thyroid hormones on cognitive functions in healthy individuals have rarely been studied. The goal of this open-label study was to investigate the short-term effects (duration of administration 45 days on average) of supraphysiological doses of L-thyroxine (L-T(4)) on cognitive performance in young, euthyroid, healthy subjects. Eleven subjects performed a comprehensive neuropsychological test battery, once without and once during administration of supraphysiological doses of L-T(4). There were no significant differences in any of the cognitive test results between the two test sessions. The results of this study do not support our working hypothesis that thyroid hormone can change cognitive performance in young, euthyroid, healthy individuals.