Hypomyelination Caused by Scap Deletion is Slowly Rescued by Extracellular Lipids that Alter Myelin Structure

Myelination requires a massive increase in glial cell membrane synthesis. Here we demonstrate that the acute phase of myelin lipid synthesis is regulated by SREBP cleavage activation protein (SCAP), an activator of sterol regulatory element-binding proteins (SREBPs). Deletion of SCAP in Schwann cells led to a loss of SREBP-mediated gene expression, congenital hypomyelination and abnormal gait. Interestingly, aging SCAP mutant mice showed partial regain of function; they exhibited improved gait and produced small amounts of myelin indicating a slow SCAP-independent uptake of external lipids. Accordingly, extracellular lipoproteins promoted myelination by SCAP mutant Schwann cells. However, SCAP mutant myelin never reached normal thickness and had biophysical abnormalities concordant with abnormal lipid composition. These data demonstrate that SCAP mediated regulation of glial lipogenesis is key to the proper synthesis of myelin membrane. The described defects in SCAP mutant myelination provide new insights into the pathogenesis, and open new avenues for treatment strategies, of peripheral neuropathies associated with lipid metabolic disorders.

Recent decrease in the prevalence of congenital heart defects in europe.

OBJECTIVES: To examine trends in the prevalence of congenital heart defects (CHDs) in Europe and to compare these trends with the recent decrease in the prevalence of CHDs in Canada (Quebec) that was attributed to the policy of mandatory folic acid fortification. STUDY DESIGN: We used data for the period 1990-2007 for 47 508 cases of CHD not associated with a chromosomal anomaly from 29 population-based European Surveillance of Congenital Anomalies registries in 16 countries covering 7.3 million births. We estimated trends for all CHDs combined and separately for 3 severity groups using random-effects Poisson regression models with splines. RESULTS: We found that the total prevalence of CHDs increased during the 1990s and the early 2000s until 2004 and decreased thereafter. We found essentially no trend in total prevalence of the most severe group (group I), whereas the prevalence of severity group II increased until about 2000 and decreased thereafter. Trends for severity group III (the most prevalent group) paralleled those for all CHDs combined. CONCLUSIONS: The prevalence of CHDs decreased in recent years in Europe in the absence of a policy for mandatory folic acid fortification. One possible explanation for this decrease may be an as-yet-undocumented increase in folic acid intake of women in Europe following recommendations for folic acid supplementation and/or voluntary fortification. However, alternative hypotheses, including reductions in risk factors of CHDs (eg, maternal smoking) and improved management of maternal chronic health conditions (eg, diabetes), must also be considered for explaining the observed decrease in the prevalence of CHDs in Europe or elsewhere.

Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients.

ABSTRACT: BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.

Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 Are Identified in Individuals with Congenital Hypogonadotropic Hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) and its anosmia-associated form (Kallmann syndrome [KS]) are genetically heterogeneous. Among the >15 genes implicated in these conditions, mutations in FGF8 and FGFR1 account for ∼12% of cases; notably, KAL1 and HS6ST1 are also involved in FGFR1 signaling and can be mutated in CHH. We therefore hypothesized that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CHH as causal or modifier mutations. Thus, we aimed to (1) investigate whether CHH individuals harbor mutations in members of the so-called "FGF8 synexpression" group and (2) validate the ability of a bioinformatics algorithm on the basis of protein-protein interactome data (interactome-based affiliation scoring [IBAS]) to identify high-quality candidate genes. On the basis of sequence homology, expression, and structural and functional data, seven genes were selected and sequenced in 386 unrelated CHH individuals and 155 controls. Except for FGF18 and SPRY2, all other genes were found to be mutated in CHH individuals: FGF17 (n = 3 individuals), IL17RD (n = 8), DUSP6 (n = 5), SPRY4 (n = 14), and FLRT3 (n = 3). Independently, IBAS predicted FGF17 and IL17RD as the two top candidates in the entire proteome on the basis of a statistical test of their protein-protein interaction patterns to proteins known to be altered in CHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (6/8 individuals). Mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.

Successful Transapical Aortic Valve Implantation in a Congenital Bicuspid Aortic Valve.

Transcatheter stent-valve implantation in stenosed congenital bicuspid aortic valves is under debate. Heavily calcified elliptic bicuspid valves represent a contraindication to catheter-based valve therapies because of a risk of stent-valve displacement, distortion, or malfunctioning after the implantation. In this case report we illustrate our experience with a patient suffering from stenosed congenital bicuspid aortic valve who successfully underwent a transapical 26-mm Edwards Sapien stent-valve (Edwards Lifesciences Inc, Irvine, CA) implantation. Postoperative distortion, malfunctioning, and paravalvular leaks were not detected.

Complete bilateral facial cleft (Tessier 4) with corneal staphyloma: a rare association.

The oro-ocular cleft no. 4 according to the Tessier classification is one of the rarest facial cleft, and to this day, few cases have been reported in the literature. We describe the case of a 9-month-old girl with a complete bilateral facial cleft. On the right cornea protruded a hard lesion, a corneal staphyloma. We describe the 3 primary surgical steps used to restore the possibility of satisfactory feeding, to promote language acquisition, and to protect vision in the nonaffected eye. The psychological and social aspects of severe facial deformities in developing countries are also tackled.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

Multiples hyperplasies nodulaires focales hépatiques associées à une agénésie congénitale de la veine porte [Multiple focal nodular hyperplasia of the liver associated with congenital absence of the portal vein]

We report the 32nd case of congenital absence of portal vein in an 18-year-old female adult associated with multiple focal nodular hyperplasia of the liver. The association of various hepatic tumors has been observed in half of the publications about congenital absence of portal vein. Hepatic tumors seem to result from systemic diversion of portal vein flow with a resultant increase of arterial flow causing important vascular and nutritif changes the liver and consequent parenchymal transformation.

Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification.

BACKGROUND: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. METHODS: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. RESULTS: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P=0.04). A significant correlation (P=0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS=46% vs 75%, P=0.023; OS=66.8% vs 100%, P=0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P=0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P=0.018). CONCLUSIONS: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.

Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.

PURPOSE: Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved. PATIENTS AND METHODS: Cytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction. RESULTS: 3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3). CONCLUSION: Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.

Congenital diaphragmatic hernia: evaluation of prenatal diagnosis in 20 European regions.

OBJECTIVE: To evaluate prenatal diagnosis of congenital diaphragmatic hernia by ultrasound in well-defined European populations. DESIGN: Data from 20 registries of congenital malformations in 12 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to three ultrasound investigations per patient being routinely performed. RESULTS: There were 187 cases with congenital diaphragmatic hernia, with an overall prenatal detection rate of 59% (110/187). There was considerable variation in prenatal detection rate between regions. There was a significant difference in the detection rate of isolated congenital diaphragmatic hernia (59/116, 51%) compared with congenital diaphragmatic hernia associated with multiple malformations, karyotype anomalies or syndromes (51/71, 72%) (P = 0.01). Termination of pregnancy was performed in 39 cases (21%) of which 14 cases were isolated congenital diaphragmatic hernia. Mean gestational age at discovery was 24.2 weeks (range, 11-38 weeks). CONCLUSIONS: The overall prenatal detection rate of congenital diaphragmatic hernia is high (59%) but varies significantly between European regions. The gestational age at discovery was greater than 24 weeks in half of the prenatally diagnosed cases.

Spirometric abnormalities in patients with Fabry disease and effect of enzyme replacement therapy

Aim: Fabry disease is an X-linked genetic disorder due to deficiency of the lysosomal enzyme a-galactosidase A, which leads to the accumulation of neutral glycosphingolipids within the lysosomes of almost all tissues. Clinical manifestations usually include acroparaesthesia, renal insufficiency and cardiomyopathy. Recently, pulmonary manifestations consisting of progressive obstructive airway disease have been reported. The aim of this study was to analyse the cross-sectional prevalence of airflow obstruction in a Swiss cohort of patients, and in selected cases, to evaluate the impact of enzyme replacement therapy (ERT) with agalsidase alfa (ReplagalTM; TKT - 5S). Methods: Forty-four patients (27 men, 17 women) were included in the study and received pulmonary function testing. Fifteen patients underwent spirometry after ERT. Results: Twelve patients (nine men) had chronic obstructive pulmonary disease according to the Global Obstructive Lung Disease (GOLD) initiative criteria: forced expiratory volume (FEV1)/forced vital capacity (FVC) 50.7), but only one was an active smoker and one a previous smoker. FEV1/ FVC as percentage predicted was weakly correlated with age (r=0.42, p=0.005, calculated by Pearson product-moment correlation), demonstrating that airway obstruction occurs in the late stages of the disease. Median FEV1 in patients with obstruction was 67% of predicted (range, 45-90%). Reversibility of FEV1 after b2-agonist inhalation never exceeded 8% of predicted. Diffusing capacity of the lung for carbon monoxide (DLCO) was measured in 13 individuals with a median of 88% of predicted (range, 39-125%). After 15+9 months of ERT, spirometry measurements were recorded in 15 patients. Decline in FEV1 was -2+5% of predicted. (p40.05, measured by the Wilcoxon signed-rank test). Median change in DLCO was -10% of predicted (-40 to +25%, p40.05). High resolution computed tomography scans demonstrated a moderate thickening of the bronchial wall in affected individuals, without evidence of emphysema. Conclusion: We conclude that Fabry disease can be complicated by significant airway obstruction, particularly in patients in the advanced stages of the disease, and that in the period studied, ERT had no demonstrable impact on pulmonary function.

Cardiac re-synchronization therapy in a patient with isolated ventricular non-compaction: a case report.

Isolated ventricular non-compaction (IVNC) is a rare, congenital, unclassified cardiomyopathy characterized by prominent trabecular meshwork and deep recesses. Major clinical manifestations of IVNC are heart failure, atrial and ventricular arrhythmias, and thrombo-embolic events. We describe a case of a 69-year-old woman in whom the diagnosis of IVNC was discovered late, whereas former echocardiographic examinations were considered normal. She was known for systolic left ventricular dysfunction for 3 years and then became symptomatic (NYHA III). In the past, she suffered from multiple episodes of deep vein thrombosis and pulmonary embolism. Electrocardiogram revealed a wide QRS complex, and transthoracic echocardiography showed typical apical thickening of the left and right ventricular myocardial wall with two distinct layers. The ratio of non-compacted to compacted myocardium was >2:1. Cardiac MRI confirmed the echocardiographic images. Cerebral MRI revealed multiple ischaemic sequellae. In view of the persistent refractory, heart failure in medical treatment of patients with classical criteria for cardiac re-synchronization therapy, as well as the ventricular arrhythmias, a biventricular automatic intracardiac defibrillator (biventricular ICD) was implanted. The 2-year follow-up period was characterized by improvement of NYHA functional class from III to I and increasing in left ventricular function. We hereby present a case of IVNC with favourable outcome after biventricular ICD implantation. Cardiac re-synchronization therapy could be considered in the management of this pathology.

Evaluation of prenatal diagnosis of congenital heart diseases by ultrasound: experience from 20 European registries.

OBJECTIVES: To evaluate prenatal diagnosis of congenital heart diseases by ultrasound investigation in well-defined European populations. DESIGN: Data from 20 registries of congenital malformations in 12 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to three ultrasound investigations per patient routinely performed. RESULTS: There were 2454 cases with congenital heart disease with an overall prenatal detection rate of 25%. Termination of pregnancy was performed in 293 cases (12%). There was considerable variation in prenatal detection rate between regions, with the lowest detection rates being in countries without ultrasound screening (11%) and in Eastern European countries (Croatia, Lithuania and Ukraine; 8%). In Western European countries with ultrasound screening, detection rate ranged from 19-48%. There was a significant difference in prenatal detection rate and proportion of induced abortions between isolated congenital heart disease and congenital heart disease associated with chromosome anomalies, multiple malformations and syndromes (P < 0.0001). There were 1694 cases with isolated congenital heart disease of which 16% were diagnosed prenatally. Malformations affecting the size of the ventricles were detected prenatally in half of the cases. CONCLUSIONS: Prenatal detection rate of congenital heart disease varies significantly between countries even with the same screening recommendations. The presence of associated malformations significantly increases the prenatal detection rate.