Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations.

NODAL and its signaling pathway are known to play a key role in specification and patterning of vertebrate embryos. Mutations in several genes encoding components of the NODAL signaling pathway have previously been implicated in the pathogenesis of human left-right (LR) patterning defects. Therefore, NODAL, a member of TGF-beta superfamily of developmental regulators, is a strong candidate to be functionally involved in congenital LR axis patterning defects or heterotaxy. Here we have investigated whether variants in NODAL are present in patients with heterotaxy and/or isolated cardiovascular malformations (CVM) thought to be caused by abnormal heart tube looping. Analysis of a large cohort of cases (n = 269) affected with either classic heterotaxy or looping CVM revealed four different missense variants, one in-frame insertion/deletion and two conserved splice site variants in 14 unrelated subjects (14/269, 5.2%). Although similar with regard to other associated defects, individuals with the NODAL mutations had a significantly higher occurrence of pulmonary valve atresia (P = 0.001) compared with cases without a detectable NODAL mutation. Functional analyses demonstrate that the missense variant forms of NODAL exhibit significant impairment of signaling as measured by decreased Cripto (TDGF-1) co-receptor-mediated activation of artificial reporters. Expression of these NODAL proteins also led to reduced induction of Smad2 phosphorylation and impaired Smad2 nuclear import. Taken together, these results support a role for mutations and rare deleterious variants in NODAL as a cause for sporadic human LR patterning defects.

Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children.

BACKGROUND: Some patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy also present with skeletal myopathy and Wolff-Parkinson-White (WPW) syndrome; mutations in the gene encoding the lysosome-associated protein-2 (LAMP-2) have been identified in these patients, suggesting that some of these patients have Danon disease. In this study we investigated the frequency of LAMP2 mutations in an unselected pediatric HCM population. METHODS AND RESULTS: LAMP2 was amplified from genomic DNA isolated from peripheral lymphocytes of 50 patients diagnosed with HCM and analyzed by direct DNA sequencing. In 2 of the 50 probands (4%), nonsense mutations were identified. In 1 family the proband initially presented with HCM as a teenager, which progressed to dilated cardiomyopathy (DCM) and heart failure. Skeletal myopathy and WPW were also noted. The teenage sister of the proband is a carrier of the same LAMP2 mutation and has HCM without skeletal myopathy or WPW. The other proband presented with HCM, WPW, and skeletal myopathy as a teenager, whereas his carrier mother developed DCM during her 40s. Skeletal and cardiac muscle sections revealed the absence of LAMP-2 on immunohistochemical staining. CONCLUSIONS: LAMP2 mutations may account for a significant proportion of cases of HCM in children, especially when skeletal myopathy and/or WPW is present, suggesting that Danon disease is an underrecognized entity in the pediatric cardiology community.

Advancing the discussion about systematic classroom behavioral observation, a product review of Tenny, J. (2010). eCOVE observation software. Pacific City, OR: eCOVE Software, LLC.

Applied child psychologists and behavioral consultants often use systematic behavioral observations to inform the psychological assessment and intervention development process for children referred for attention and hyperactivity problems. This article provides a review of the 2010 version of the eCOVE classroom observation software in terms of its utility in tracking the progress of children with attention and hyperactive behaviors and its use in evaluating teacher behaviors that may impede or promote children's attention and positive behavior. The eCOVE shows promise as an efficient tool for psychologists and behavioral consultants who want to evaluate the effects of interventions for children with symptoms of ADHD, ODD, mood disorders and learning disorders; however, some research-based improvements for future models are suggested. The reviewers also share their firsthand experience in using eCOVE to evaluate teacher and student behavior exhibited on a television show about teaching urban high school students and during a movie about an eccentric new kindergarten teacher. Rich examples are provided of using strategic behavioral observations to reveal how to improve the classroom environment so as to facilitate attention, motivation and positive behavior among youth. Broader implications for enhancing the use of systematic behavioral observations in the assessment of children and adolescents with attention disorders and related behavioral problems are discussed. Key issues are examined such as the use of behavioral observations during psychological consultation to prevent the previously found gender bias in referrals for ADHD. Using behavioral observations to enhance differential diagnosis is also discussed.