Citations

Deletion of 15q11.2‐q13 results in either Prader–Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region (PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent‐of‐origin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem triplication. Only one patient had a paternal duplication; this patient does not have features typical of patients with maternal duplication of the PWASCR. Three of the mothers had a tandem duplication (two were paternal and one was maternal origin). While one of the two mothers with paternal duplication was noted not to have autism, the other was noted to have learning disability and depression. Based on our data, we conclude that SMC15 are almost exclusively maternal in origin and result in an abnormal phenotype. Tandem duplications/triplications are generally of maternal origin when ascertained on the basis of abnormal phenotype; however, tandem duplications of paternal origin have also been identified. Therefore, we suggest that methylation testing be performed for cases of tandem duplications/triplications since the pathogenicity of paternal gains is uncertain. © 2014 Wiley Periodicals, Inc.

Rationale : Semaphorin 3A ( SEMA3A )-encoded semaphorin is a chemorepellent that disrupts neural patterning in the nervous and cardiac systems. In addition, SEMA3A has an amino acid motif that is analogous to hanatoxin, an inhibitor of voltage-gated K + channels. SEMA3A -knockout mice exhibit an abnormal ECG pattern and are prone to ventricular arrhythmias and sudden cardiac death. Objective : Our aim was to determine whether SEMA3A is a naturally occurring protein inhibitor of K v 4.3 (I to ) channels and its potential contribution to Brugada syndrome. Methods and Results : K v 4.3, Na v 1.5, Ca v 1.2, or K v 4.2 were coexpressed or perfused with SEMA3A in HEK293 cells, and electrophysiological properties were examined via whole-cell patch clamp technique. SEMA3A selectively altered K v 4.3 by significantly reducing peak current density without perturbing K v 4.3 cell surface protein expression. SEMA3A also reduced I to current density in cardiomyocytes derived from human-induced pluripotent stem cells. Disruption of a putative toxin binding domain on K v 4.3 was used to assess physical interactions between SEMA3A and K v 4.3. These findings in combination with coimmunoprecipitations of SEMA3A and K v 4.3 revealed a potential direct binding interaction between these proteins. Comprehensive mutational analysis of SEMA3A was performed on 198 unrelated SCN5A genotype–negative patients with Brugada syndrome, and 2 rare SEMA3A missense mutations were identified. The SEMA3A mutations disrupted SEMA3A’s ability to inhibit K v 4.3 channels, resulting in a significant gain of K v 4.3 current compared with wild-type SEMA3A. Conclusions : This study is the first to demonstrate SEMA3A as a naturally occurring protein that selectively inhibits K v 4.3 and SEMA3A as a possible Brugada syndrome susceptibility gene through a K v 4.3 gain-of-function mechanism.

ABSTRACTIntroductionWe used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome.MethodsAll subjects had brain imaging using 18F‐6‐fluoro‐l‐dopa (FDOPA, dopamine synthesis and storage), (+)‐11C‐dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C‐raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C‐3‐amino‐4‐(2‐dimethylaminomethyl‐phenylsulfanyl)‐benzonitrile (DASB, serotonin transporter).ResultsFDOPA‐PET and DTBZ‐PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC‐PET showed higher uptake in these area. DASB‐PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum.ConclusionsOur data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. © 2014 International Parkinson and Movement Disorder Society

Osteoporosis, defined as low bone mass leading to increased fracture risk, is a major health problem that affects approximately 10 million Americans. The aging U.S. population is predicted to contribute to as much as a 50% increase in prevalence by 2025. Although common, osteoporosis can be clinically silent, and without prevention and screening, the costs of osteoporotic fracture–related morbidity and mortality will burden the U.S. healthcare system. This is a particularly relevant concern in the context of diminishing health care resources. Dual-energy X-ray absorptiometry is the most widely used, validated technique for measuring bone mineral density (BMD) and diagnosing osteoporosis. Cost-effectiveness analyses support early detection and treatment of high-risk patients with antiresorptive medications such as bisphosphonates. Moreover, optimization of bone health throughout life can help prevent osteoporosis. Current guidelines recommend screening women by age 65 years, but because no guidelines for screening intervals exist, decisions are made on the basis of clinical judgment alone. Although the recent literature provides some guidance, this review further explores current recommendations in light of newer evidence to provide more clarity on prevention, screening, and management strategies for patients with osteoporosis in the primary care setting.

A 23-year-old woman presented with an 8-month history of asymptomatic thickening of the central areola bilaterally and oily nipple discharge. On examination, there were yellowish-pink papules coalescing into plaques bilaterally. Biopsy showed ectopic sebaceous glands (Montgomery tubercles), known as bilateral areolar sebaceous hyperplasia.