Copper deficiency presenting as metabolic bone disease in extremely low birth weight, short-gut infants.

Copper deficiency can cause bone lesions in infants, which might be confused with child abuse. Two extremely low birth weight preterm infants had complicated medical courses requiring prolonged parenteral nutrition for short-gut syndrome, which led to the development of cholestasis. Both had spent their entire lives in the hospital. They had been on prolonged ventilator support for chronic lung disease. They developed signs of copper deficiency between 5 and 6 months of age, initially raising child abuse concerns. Musculoskeletal discomfort led to the recognition of radiographic findings of metabolic bone disease. Included were osteoporosis, metaphyseal changes, and physeal disruptions. Copper levels were low; both low copper parenteral nutrition and gut losses from refeeding diarrhea likely contributed to their deficiency. Therapeutic supplementation with copper corrected their deficits and clinical and radiologic findings. The information from these cases, in particular, their radiologic findings, indicate the need to monitor copper status in at-risk premature infants. These findings may aid prevention and earlier recognition of copper deficiency. Their specific radiologic and clinical findings should aid differentiation of such children from abused infants.

Electrocardiographic changes and arrhythmias following percutaneous atrial septal defect and patent foramen ovale device closure.

OBJECTIVES: To compare pre- and post-procedure electrocardiograms (ECGs) in a large cohort of patients after percutaneous closure of atrial septal defect (ASD) and patent foramen ovale (PFO). BACKGROUND: Percutaneous device closure of ASD or PFO is commonplace. Conduction and rhythm anomalies associated with percutaneous device placement have been reported. METHODS: We reviewed records for all patients who underwent percutaneous device closure of ASD or PFO at our institution from 1999 to 2008. Pre-procedure ECG and Holter studies were compared to available short term (<2 months after placement) and intermediate follow-up (>2 months) ECG or Holter. RESULTS: Pre- and post-procedural ECGs were available in 610 patients (305 females, average age 50 ± 18.1 years, range 1-91 years, 384 PFO, 184 ASD, 42 with multiple defects, mean device size 16 mm, range 5-38 mm). We report an incidence of 5.2% (32/610) of arrhythmias in the 4 months following device placement, including 29 patients with atrial tachyarrhythmias (ATs, 22 fibrillation, 7 flutter), 1 with junctional tachycardia, and 2 with heart block. Among other findings, the average P-wave duration was increased on intermediate follow-up as compared to early follow-up (P < 0.001). Development of new-onset 1st degree AV Block after the procedure was associated with an increased risk of ATs post-procedure (P < 0.0001). CONCLUSION: We report a low risk of clinically significant post-procedure arrhythmias after device placement. Clinically significant heart block occurred in only two patients (0.3%). Changes in several markers of atrial conduction were found, suggesting an effect of device closure on intra-atrial conduction.

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.

Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these mutations appear to affect the functional properties of cardiac troponin C (cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of HCM, yet surprisingly, prior to this report, cTnC had not been classified as a HCM-susceptibility gene. In this study, we show that mutations occurring in the human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well established HCM-susceptibility genes that encode other sarcomeric proteins. Comprehensive open reading frame/splice site mutation analysis of TNNC1 performed on 1025 unrelated HCM patients enrolled over the last 10 years revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. Functional studies with these recombinant HcTnC HCM mutations showed increased Ca(2+) sensitivity of force development (A8V, C84Y and D145E) and force recovery (A8V and D145E). These results are consistent with the HCM functional phenotypes seen with other sarcomeric-HCM mutations (E134D showed no changes in these parameters). This is the largest cohort analysis of TNNC1 in HCM that details the discovery of at least three novel HCM-associated mutations and more strongly links TNNC1 to HCM along with functional evidence that supports a central role for its involvement in the disease. This study may help to further define TNNC1 as an HCM-susceptibility gene, a classification that has already been established for the other members of the troponin complex.

Mutation of an A-kinase-anchoring protein causes long-QT syndrome.

A-kinase anchoring proteins (AKAPs) recruit signaling molecules and present them to downstream targets to achieve efficient spatial and temporal control of their phosphorylation state. In the heart, sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD), mediated by beta-adrenergic receptor (betaAR) activation, requires assembly of AKAP9 (Yotiao) with the I(Ks) potassium channel alpha subunit (KCNQ1). KCNQ1 mutations that disrupt this complex cause type 1 long-QT syndrome (LQT1), one of the potentially lethal heritable arrhythmia syndromes. Here, we report identification of (i) regions on Yotiao critical to its binding to KCNQ1 and (ii) a single putative LQTS-causing mutation (S1570L) in AKAP9 (Yotiao) localized to the KCNQ1 binding domain in 1/50 (2%) subjects with a clinically robust phenotype for LQTS but absent in 1,320 reference alleles. The inherited S1570L mutation reduces the interaction between KCNQ1 and Yotiao, reduces the cAMP-induced phosphorylation of the channel, eliminates the functional response of the I(Ks) channel to cAMP, and prolongs the action potential in a computational model of the ventricular cardiocyte. These reconstituted cellular consequences of the inherited S1570L-Yotiao mutation are consistent with delayed repolarization of the ventricular action potential observed in the affected siblings. Thus, we have demonstrated a link between genetic perturbations in AKAP and human disease in general and AKAP9 and LQTS in particular.