Brugada ECG pattern: a physiopathological prospective study based on clinical, electrophysiological, angiographic, and genetic findings.

INTRODUCTION: Brugada syndrome (BrS) is considered a primary electrical disease. However, morphological abnormalities have been reported and localized arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) may mimic its phenotype, raising the question of an overlap between these two conditions and making difficult the therapeutic management of patients with borderline forms. The main objective of this study was to assess prospectively the prevalence of BrS and ARVD/C on the basis of international criteria, in patients with BrS-ECG and normal echocardiography, looking for a potential overlap between the two pathologies. The secondary objectives were to describe and quantify angiographic structural alterations, hemodynamics, electrophysiology, and genetics in the setting of BrS-ECG. MATERIALS AND METHODS: Hundred and fourteen consecutive patients matched in age underwent prospectively cardiac catheterization and quantitative biventricular contrast angiography to rule out a structural heart disease. Fifty-one patients with a BrS-ECG (BrS group, 7 F, 44 M, 43 ± 11 y) had a spontaneous or ajmaline-induced BrS coved type ECG. For angiographic comparison, 49 patients with localized ARVD/C but without ST segment elevation in the right precordial leads (14 F, 35 M, 39 ± 13 y) were also studied. They fulfilled international ESC/WHF 2000 criteria and presented angiographic localized forms, mainly confined to hypokinetic anteroapical zone (characterized by trabecular dysarray and hypertrophy), and/or diaphragmatic wall, thus resulting in RV normal volumes and preserved systolic function. These two populations were also compared with 14 control patients (7 F, 7 M, 38 ± 16 y). Among BrS group, we identified three main angiographic phenotypes: BrS group I = patients with normal RV (n = 15, 29%); BrS group II = patients with segmental RV wall motion abnormalities but no structural arguments for ARVD/C (n = 26, 51%); BrS group III = patients with localized abnormalities suggestive of focal ARVD/C (n = 10, 20%). RESULTS: Among BrS group, 34/51 patients (67%) fulfilled BrS HRS/EHRA 2005 criteria. Nineteen (37%) were symptomatic for aborted sudden death, agonal nocturnal respiration or syncope. Ventricular stimulation was positive in 14 patients (28%). Angiography showed RV abnormalities in 36/51 patients (71%) of BrS group (BrS groups II and III). Late potentials were present in 73% (100% sensitivity and NPV for an angiographic ARVD/C, but poor specificity and PPV, both 37%). In BrS group III, 8/10 patients (16% of BrS patients) finally fulfilled international ESC/WHF 2000 ARVD/C criteria and 5/10 (10% of BrS patients) fulfilled BrS diagnostic criteria. An overlap was observed in 4 patients (8% of BrS patients) who fulfilled both ARVD/C and BrS criteria. Among the 45 genotyped patients, only one presented a SCN5A mutation, whereas a TRPM4 mutation was found in another patient. Both belonged to BrS group II. MOG1 gene analysis was negative for all patients, as were PKP2, DSP, DSG2, and DSC2 analyzes performed in BrS group III. CONCLUSIONS: Seventy-one percent of patients with a BrS-ECG had abnormal RV wall motion and 16 had structural alterations corresponding to localized (anteroapical and/or diaphragmatic) ARVD/C. Moreover, 8% of BrS-ECG patients fulfilled both BrS and ARVD/C criteria. Our results support the hypothesis of an overlap between BrS and localized forms of ARVD/C. Conversely, genetic screening was poorly contributive for both diseases in the present series.

Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene. METHODS: As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). RESULTS: The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations. CONCLUSIONS: This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

MOG1: a new susceptibility gene for Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Na(v)1.5. However, ≈ 20% of probands have SCN5A mutations, suggesting the implication of other genes. MOG1 recently was described as a new partner of Na(v)1.5, playing a potential role in the regulation of its expression and trafficking. We investigated whether mutations in MOG1 could cause BrS. METHODS AND RESULTS: MOG1 was screened by direct sequencing in patients with BrS and idiopathic ventricular fibrillation. A missense mutation p.Glu83Asp (E83D) was detected in a symptomatic female patient with a type-1 BrS ECG but not in 281 controls. Wild type (WT)- and mutant E83D-MOG1 were expressed in HEK Na(v)1.5 stable cells and studied using patch-clamp assays. Overexpression of WT-MOG1 alone doubled sodium current (I(Na)) density compared to control conditions (P<0.01). In contrast, overexpression of mutant E83D alone or E83D+WT failed to increase I(Na) (P<0.05), demonstrating the dominant-negative effect of the mutant. Microscopy revealed that Na(v)1.5 channels failed to properly traffic to the cell membrane in the presence of the mutant. Silencing endogenous MOG1 demonstrated a 54% decrease in I(Na) density. CONCLUSIONS: Our results support the hypothesis that dominant-negative mutations in MOG1 can impair the trafficking of Na(v)1.5 to the membrane, leading to I(Na) reduction and clinical manifestation of BrS. Moreover, silencing MOG1 reduced I(Na), demonstrating that MOG1 is likely to be important in the surface expression of Na(v)1.5 channels. All together, our data support MOG1 as a new susceptibility gene for BrS.

Population pharmacokinetics and pharmacogenetics of imatinib in children and adults.

PURPOSE: The aim of this study was to explore the effect of several demographic, biological, and pharmacogenetic covariates on the disposition of imatinib and its main metabolite (CGP74588) in both adults and children. EXPERIMENTAL DESIGN: Thirty-three children with solid malignancies included in a phase II exploratory study and 34 adults with gastrointestinal stromal tumors received 340 mg/m(2) and 400 mg imatinib, respectively. Plasma imatinib and CGP74588 concentrations observed on day 1 and at steady-state were analyzed by a population pharmacokinetic method (NONMEM) to evaluate the effect of age, body weight, age, sex, albuminemia, plasma alpha1-acid glycoprotein (AGP), and eight polymorphisms corresponding to ABCB1, ABCG2, CYP3A4, CYP3A5, and AGP (pharmacogenetic data available for 46 of 67 patients). RESULTS: Analysis of the whole data set in 67 patients showed that apparent clearance (CL/F) of imatinib was positively correlated with body weight and albuminemia and negatively with AGP. By considering these three covariates, the interindividual variability on CL/F decreased from 47% to 19%. The apparent clearance of CGP74588 was similarly dependent on both body weight and AGP and significantly lower (30% reduction) at steady-state. By adding genotype status to the final covariate imatinib model, a 22% reduction in CL/F was observed in heterozygous compared with wild-type patients corresponding to ABCG2 c.421C>A (P<0.05). CONCLUSIONS: By considering morphologic and biological covariates, a unique covariate model could be used to accurately describe imatinib pharmacokinetics in patients ages 2 to 84 years. Morphologic and biological characteristics have a stronger influence than pharmacogenetics on imatinib pharmacokinetics.