Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects.

Dysfunction of motile monocilia, altering the leftward flow at the embryonic node essential for determination of left-right body asymmetry, is a major cause of laterality defects. Laterality defects are also often associated with reduced mucociliary clearance caused by defective multiple motile cilia of the airway and are responsible for destructive airway disease. Outer dynein arms (ODAs) are essential for ciliary beat generation, and human respiratory cilia contain different ODA heavy chains (HCs): the panaxonemally distributed γ-HC DNAH5, proximally located ß-HC DNAH11 (defining ODA type 1), and the distally localized ß-HC DNAH9 (defining ODA type 2). Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction. Consistent with the observed subtle respiratory phenotype, high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia. DNAH9-deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2. Yeast two-hybrid and co-immunoprecipitation analyses indicate interaction of DNAH9 with the ODA components DNAH5 and DNAI2 as well as the ODA-docking complex component CCDC114. We further show that during ciliogenesis of respiratory cilia, first proximally located DNAH11 and then distally located DNAH9 is assembled in the axoneme. We propose that the ß-HC paralogs DNAH9 and DNAH11 achieved specific functional roles for the distinct axonemal compartments during evolution with human DNAH9 function matching that of ancient ß-HCs such as that of the unicellular Chlamydomonas reinhardtii.

Holter electrocardiography findings and P-wave dispersion in pediatric patients with transcatheter closure of atrial septal defects.

BACKGROUND: This study aimed to determine the frequency of postintervention arrhythmia and factors associated with the development of arrhythmia, including the correlation between arrhythmia and P-wave dispersion, and the effects of the latter on transcatheter closure of atrial septal defects (ASDs). METHODS: Holter ECG recordings were performed before and after the intervention and 6 and 12 months later in 47 of the 59 patients who had undergone transcatheter ASD closure and once in the healthy control subjects. RESULTS: A statistically significant correlation was identified between the patients' arrhythmia grade according to Lown's system and each of the following: the number of defects, the size of the atrioventricular valve rim, the presence of an atrial septal aneurysm. CONCLUSION: The frequency of arrhythmia increases after transcatheter ASD closure, gradually decreases within the next year, and is most frequently of a benign nature. Lown's arrhythmia grading of patients occluded with either the Amplatzer septal occluder (ASO) or the Cardio-O-Fix septal occluder (CSO) were compared, and the arrhythmia frequency was higher with the latter. One day after the intervention, the P maximum (Pmax ) and the P dispersion(Pdis ) values were not increased but in fact slightly reduced in patients occluded with either ASO or CSO. An improvement in the electrical system resulting from early anatomical and mechanical healing following transcatheter ASD occlusion may explain the reduction in the Pmax and Pdis values.

Extracorporeal life support experiences of a new congenital heart center in Turkey.

Extracorporeal life support (ECLS) provides mechanical support following cardiac surgery when respiratory and cardiac failure occurs. We retrospectively reviewed medical records of patients who needed ECLS at a new congenital heart center in Turkey. Between December 2009 and February 2012, 616 congenital heart operations were performed. A total of 13 patients (seven female) underwent ECLS. The ages of the patients ranged between 16 days and 33 years. There were two neonatal, seven infant, three pediatric, and one adult congenital cases. Medos DPII ECLS system was used in all patients. Mean duration of ECLS was 6.2 ± 5.8 days (ranged from 29 h to 24 days). While central vascular access with aorta and right atrial cannulation was used in 11 patients, neck vessels were used in the other patients. Four patients (30.7%) weaned successfully from ECLS (two infant, two pediatric cases). Three of them had ECLS intraoperatively. In all patients, two (15.4%) were discharged from the hospital. One of them had mild neurologic deficit. Bleeding from the surgical and cannulation sites was the most common complication. Thrombus was detected in pump head and changed uneventfully in three patients. Arterial pH and lactate levels at the beginning of ECLS were significantly lower in patients who were successfully weaned from ECLS than nonsurvivors (P = 0.04 and P = 0.02, respectively). ECLS can be a lifesaving modality in the perioperative period. It may be more beneficial if ECLS is used before the development of severe acidosis and high lactate levels.

Ferritin and iron levels in children with autistic disorder.

UNLABELLED: Iron has an important role on cognitive, behavioral, and motor development. High prevalence of iron deficiency has been reported in autism. The aim of this study was to investigate iron status in a group of children with autistic disorder. The sample was composed of 116 children between 3 and 16 years with a diagnosis of autistic disorder according to DSM-IV criteria. Serum ferritin, iron, hemoglobin, hematocrit, mean corpuscular volume, and red cell distribution width values were measured. We found that 24.1% of subjects had iron deficiency, and 15.5% had anemia. There was a significant positive correlation between age and ferritin and hematological measures. Results of this study confirmed that iron deficiency and anemia are common in children with autistic disorder. CONCLUSION: These findings suggest that ferritin levels should be measured in subjects with autism as a part of routine investigation.

Mutation spectrum of congenital heart disease in a consanguineous Turkish population.

BACKGROUNDS: While many studies agree that consanguinity increases the rate of congenital heart disease (CHD), few genome analyses have been conducted with consanguineous CHD cohorts. METHODS: We recruited 73 CHD probands from consanguineous families in Turkey and used whole-exome sequencing (WES) to identify genetic lesions in these patients. RESULTS: On average, each patient had 6.95 rare damaging homozygous variants, 0.68 of which are loss-of-function (LoF) variants. Seven patients (9.6%) carried damaging homozygous variants in five causal CHD genes. Six of those patients exhibited laterality defects (six HTX and one D-TGA). Three additional patients (4.1%) harbored other types of CHD-associated genomic alterations, which overall explained 13.7% (10/73) of the cohort. The contribution from recessive variants in our cohort is higher than 1.8% reported from a cohort of 2871 CHD subjects where 5.6% of subjects met the criteria for consanguinity. CONCLUSIONS: Our WES screen of a Turkish consanguineous population with structural CHD revealed its unique genetic architecture. Six of seven damaging homozygous variants in CHD causal genes occur in the setting of laterality defects implies a strong contribution from consanguinity to these defects specifically. Our study thus provided valuable information about the genetic landscape of CHD in consanguineous families in Turkey.

The significance of transesophageal echocardiography in assessing congenital heart disease: our experience.

BACKGROUND: The rapid expansion of pediatric cardiovascular surgery, along with the increase in the number of centers and operations, has also increased the use of intraoperative transesophageal echocardiography (TEE). Preoperative TEE allows for the confirmation of diagnoses established by transthoracic echocardiography and angiography, and also identifies possible additional pathologic conditions. TEE is also used to follow up on surgical repairs, determine the need for reintervention, and evaluate myocardial performance and the need for inotropic treatment. Our intention is to share the TEE findings before and after intervention for congenital heart disease in patients who received operations at our center, and the conclusions reached. PATIENTS AND METHOD: From October 2009 to February 2013, 1008 patients underwent surgery for congenital heart disease. Of these, 265 were subjected to TEE in the operating room. Each patient entering the operating room with TEE planned had the echocardiography probe placed while intubated under general anesthesia. TEE studies used a GE Vivid S5. Different investigations, according to the patients' particular pathologic conditions, were also performed in addition to standard TEE studies. RESULTS: Of the 265 patients for whom surgery was indicated by transthoracic echocardiography and other appropriate examinations, 260 had the diagnosis confirmed by preoperative TEE and the indicated intervention was performed. For the remaining 5 patients (1.8%), the intervention plan was changed following preoperative TEE. Cardiopulmonary bypass was reinitiated in 12 (4.5%) patients because of residual defects identified by postoperative TEE. Thus, the preoperative plan was changed in 17 (6.4%) patients out of a total of 265 owing to preoperative and postoperative TEE findings. CONCLUSION: The use of intraoperative TEE in surgical centers for congenital heart disease allows for a significant reduction in mortality and morbidity. Intraoperative TEE performed by experienced pediatric cardiologists is therefore an absolute necessity.

Twisted wire stent technique for delayed sternal closure after congenital heart operations.

After congenital heart operations, keeping the sternal edges wide open may require sternal stenting in some extreme cases in which delayed sternal closure is necessary after operation, because sternal edges may compromise cardiac function as a result of the elasticity of the thoracic cage. We describe an easy and safe way for sternal stenting using conventional sternal steel wires.

The response to hepatitis B vaccine: does it differ in celiac disease?

OBJECTIVES: There is a relationship between nonresponsiveness to hepatitis B virus (HBV) vaccine and certain human leukocyte antigen (HLA) genotypes. In healthy population, 4-10% vaccine recipients fail to produce protective levels of antibodies to the HBV vaccine after standard immunization depending upon age and the presence of various underlying diseases. Celiac disease (CD) is an HLA-associated immunological disease. It has been suggested that certain HLA haplotypes which are linked to CD are associated with nonresponse to HBV vaccine as well. The aim of this study is to assess the response to HBV vaccine prospectively in a group of CD and to explore the potential link between CD and HBV vaccine nonresponse by studying shared HLA haplotypes. PATIENTS AND METHODS: Sixty-three previously diagnosed celiac patients who were on a strict gluten-free diet (GFD) and 54 healthy children were evaluated serologically for anti-HBs status. Celiac children who were anti-HBs negative at baseline were fully vaccinated prospectively, and reevaluated for the response to HBV vaccine. To estimate the role of HLA type in HBV vaccine response in celiac patients, a subgroup of both patients and control participants had HLA genotypes performed. RESULTS: At enrollment, 27 (67.5%) children with CD and 48 (85.2%) healthy children were anti-HBs positive, and the difference between patients and controls was statistically significant (P<0.05). However, failure to respond to HBV vaccine was only 3.6% (response rate 96.4%) in prospectively vaccinated celiac patients. There was no relationship between HLA type and vaccine nonresponse in our study group. CONCLUSION: The response to HBV vaccine in celiac children who were compliant to GFD is not different from a healthy population. CD may be one of the immune diseases associated with a high rate of HBV vaccine nonresponse but it might not be permanent and treatment with GFD and compliance to the treatment may ameliorate the immune response to HBV vaccine in celiac children.