SLC18A3 variants lead to fetal akinesia deformation sequence early in pregnancy.

Fetal akinesia deformation sequence (FADS) and lethal multiple pterygium syndrome (LMPS) are clinically overlapping syndromes manifesting with reduced or absent fetal movement, arthrogryposis, and several anomalies during fetal life. The etiology of these syndromes is heterogeneous, and in many cases it remains unknown. In order to determine the genetic etiology of FADS in two fetuses with fetal akinesia, arthrogryposis, edema, and partial cleft palate, we utilized exome sequencing.

Fetal left ventricular noncompaction cardiomyopathy and fatal outcome due to complete deficiency of mitochondrial trifunctional protein.

Unlabelled: We report a fetal case with fatal outcome having a novel mutation in the HADHB gene, coding the beta-subunit of the mitochondrial trifunctional protein. Parents had a previous pregnancy loss due to fetal heart failure and hydrops. The next pregnancy led to left ventricular noncompaction and increasing pleural effusions after 29 gestational weeks.

Periderm prevents pathological epithelial adhesions during embryogenesis.

Appropriate development of stratified, squamous, keratinizing epithelia, such as the epidermis and oral epithelia, generates an outer protective permeability barrier that prevents water loss, entry of toxins, and microbial invasion. During embryogenesis, the immature ectoderm initially consists of a single layer of undifferentiated, cuboidal epithelial cells that stratifies to produce an outer layer of flattened periderm cells of unknown function. Here, we determined that periderm cells form in a distinct pattern early in embryogenesis, exhibit highly polarized expression of adhesion complexes, and are shed from the outer surface of the embryo late in development.

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis.

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1).

Mutant CHUK and severe fetal encasement malformation.

We report an autosomal recessive lethal syndrome characterized by multiple fetal malformations, the most obvious anomalies being the defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin. We identified the molecular defect that causes this syndrome, using a combined strategy of gene-expression arrays, candidate-gene analysis, clinical studies, and genealogic investigations. A point mutation in two affected fetuses led to the loss of the conserved helix–loop–helix ubiquitous kinase (CHUK), also known as IκB kinase α.

Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study.

Context: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively.

Objective: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas.

Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions.

Purpose: Autosomal dominant CHARGE syndrome (OMIM no. 214800) is characterized by choanal atresia or cleft lip or palate, ocular colobomas, cardiovascular malformations, retardation of growth, ear anomalies, and deafness, and is caused by mutations in the CHD7 gene. Here, we describe the outcome of a molecular genetic analysis in 18 Finnish and 56 German patients referred for molecular confirmation of the clinical diagnosis of suspected CHARGE syndrome.

Genetic prediction of future type 2 diabetes.

Background: Type 2 diabetes (T2D) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. A number of common variants have been associated with T2D but our knowledge of their ability to predict T2D prospectively is limited.

Methods And Findings: By using a Cox proportional hazard model, common variants in the PPARG (P12A), CAPN10 (SNP43 and 44), KCNJ11 (E23K), UCP2 (-866G>A), and IRS1 (G972R) genes were studied for their ability to predict T2D in 2,293 individuals participating in the Botnia study in Finland.

Predictors of and longitudinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes.

Identification of individuals at high risk of developing type 2 diabetes is a prerequisite for prevention of the disease. We therefore studied risk factors predicting type 2 diabetes in the Botnia Study in Western Finland. A total of 2,115 nondiabetic individuals were prospectively followed with repeated oral glucose tolerance tests.

Associations of dietary fiber with glucose metabolism in nondiabetic relatives of subjects with type 2 diabetes: the Botnia Dietary Study.

Objective: To study cross-sectional associations of dietary fiber intake with insulin resistance, insulin secretion, and glucose tolerance in a population at high risk for type 2 diabetes.

Research Design And Methods: The subjects consisted of 248 male and 304 female adult nondiabetic relatives of patients with type 2 diabetes. Dietary intake was measured by means of two 3-day food records.

Dietary intakes and plasma concentrations of carotenoids and tocopherols in relation to glucose metabolism in subjects at high risk of type 2 diabetes: the Botnia Dietary Study.

Background: The role of antioxidants in the pathogenesis of type 2 diabetes is uncertain.

Objective: We evaluated cross-sectional relations of dietary intakes and plasma concentrations of antioxidants with glucose metabolism in a high-risk population.

Design: The subjects were 81 male and 101 female first- and second-degree, nondiabetic relatives of patients with type 2 diabetes.

Nateglinide improves early insulin secretion and controls postprandial glucose excursions in a prediabetic population.

Objective: The purpose of this study was to evaluate the metabolic effectiveness, safety, and tolerability of nateglinide in subjects with impaired glucose tolerance (IGT) and to identify a dose appropriate for use in a diabetes prevention study.

Research Design And Methods: This multicenter, double-blind, randomized, parallel-group, fixed-dose study of 8 weeks' duration was performed in a total of 288 subjects with IGT using a 2:2:2:1 randomization. Subjects received nateglinide (30, 60, and 120 mg) or placebo before each main meal.

Efficacy and safety of nateglinide in type 2 diabetic patients with modest fasting hyperglycemia.

Nateglinide is a fast-acting insulin secretion agent that specifically targets postprandial hyperglycemia in patients with type 2 diabetes. The recent reduction in the diagnostic criteria for diabetes and improved understanding of the importance of early insulin secretion served as the rationale for this multicenter, double-blind, randomized, parallel-group, 24-wk study performed in 675 patients with type 2 diabetes but only moderately elevated fasting plasma glucose (FPG) (FPG = 7.0-8.