Mutations in SYNGAP1 Cause Intellectual Disability,Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency

De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP‐activating protein, cause nonsyndromic intellectual disability (NSID). All disease‐causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild‐type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity‐dependent phosphorylated extracellular signal‐regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.     

‘Oh my God,I can't handle this!’: trainees’ emotional responses to complex situations

Context

Dealing with emotions is critical for medical trainees’ professional development. Taking a sociocultural and narrative approach to understanding emotions, we studied complex clinical situations as a specific context in which emotions are evoked and influenced by the social environment. We sought to understand how medical trainees respond to emotions that arise in those situations.

Methods

In an international constructivist grounded theory study, 29 trainees drew two rich pictures of complex clinical situations, one exciting and one frustrating. Rich pictures are visual representations that capture participants’ perceptions about the people, situations and factors that create clinical complexity. These pictures were used to guide semi‐structured, individual interviews. We analysed visual materials and interviews in an integrated way, starting with looking at the drawings, doing a ‘gallery walk’, and using the interviews to inform the aesthetic analysis.

Results

Participants’ drawings depicted a range of personal emotions in response to complexity, and disclosed unsettling feelings and behaviours that might be considered unprofessional. When trainees felt confident, they were actively participating, engaged in creative problem‐solving strategies, and emphasised their personal involvement. When trainees felt the situation was beyond their control, they described how they were running away from the situation, hiding themselves behind others or distancing themselves from patients or families.

Conclusions

A sense of control seems to be a key factor influencing trainees’ emotional and behavioural responses to complexity. This is problematic, as complex situations are by their nature emergent and dynamic, which limits possibilities for control. Following a social performative approach to emotions, we should help students understand that feeling out of control is an inherent property of participating in complex clinical situations, and, by extension, that it is not something they will ‘grow out of’ with expertise.

     

Imaging of pediatric cardiac tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper

Cardiac tumors in children are rare and the majority are benign. The most common cardiac tumor in children is rhabdomyoma, usually associated with tuberous sclerosis complex. Other benign cardiac masses include fibromas, myxomas, hemangiomas, and teratomas. Primary malignant cardiac tumors are exceedingly rare, with the most common pathology being soft tissue sarcomas. This paper provides consensus-based imaging recommendations for the evaluation of patients with cardiac tumors at diagnosis and follow-up, including during and after therapy.     

Mood fluctuations in Parkinson's disease: a pilot study comparing the effects of intravenous and oral levodopa administration

OBJECTIVES: Parkinson's disease (PD) is associated with motor fluctuations that have been shown to improve when stable plasma levodopa levels are achieved with continuous levodopa infusions. Many patients also develop mood fluctuations. In this pilot study, we gathered preliminary information about the relationship between changing mood states and plasma levodopa levels. METHODS: Six patients with idiopathic PD and histories of motor and mood fluctuations participated in a double-blind levodopa infusion study. Subjects received active oral carbidopa/levodopa and a placebo levodopa infusion on one day and placebo oral carbidopa/levodopa and an active levodopa infusion on the other day, in a randomly determined order. Evaluations included serial plasma levodopa levels and assessments of mood and motor states. RESULTS: Only 4 of the 6 subjects demonstrated mood fluctuations on at least one of the treatment days. All subjects achieved more stable plasma levodopa levels on the active infusion day. Two subjects experienced fewer mood fluctuations on the active infusion day and two experienced fewer on the oral day. Conclusions The results of this pilot study suggest that the relationship between mood state and plasma levodopa level may vary among PD patients.     

Characterization and NMR solution structure of a novel cyclic pentapeptide inhibitor of pathogenic hantaviruses

Hantavirus-induced diseases such as hantavirus cardiopulmonary syndrome and hemorrhagic fever with renal syndrome are a global health concern. Hantavirus cardiopulmonary syndrome caused by Sin Nombre virus lacks specific therapy and its high mortality makes Sin Nombre virus a potential bioweapon agent. Sin Nombre virus entry into susceptible cells requires expression of alpha(v)beta(3) integrin. We recently reported the sequence of a cyclic nonapeptide that inhibited Sin Nombre virus entry into Vero E6 cells at a level comparable to ReoPro, a Fab fragment of the anti-beta(3) antibody c7E3. Here, we refine the parental peptide, cyclo-[CPFVKTQLC], using alanine scanning and amino acid deletions, by optimizing for viral inhibition. The IC(50) of the resulting peptide, cyclo-[CPFVC], was 267 microM compared with 263 microM for the parental peptide. The solution structure of cyclo-[CPFVC] was determined by two-dimensional nuclear magnetic resonance spectroscopy, revealing the Phe ring in an extended conformation stacked against the Pro ring and containing a beta-turn encompassing Val-4 through Cys-1. As an initial step in identifying interactions between cyclo-[CPFVC] and its target cellular receptor, the refined peptide structure was docked into the ReoPro binding site of integrin beta(3). This structure will provide the basis for designing more potent peptidomimetic therapeutics to prevent Sin Nombre virus entry and treat hantavirus cardiopulmonary syndrome.     

The patients’ perspective: Results of a survey assessing knowledge about and attitudes toward depression in PD

We report results of a survey assessing patients’ knowledge about and attitudes towards depression in Parkinson’s disease (PD). 345 patients from 8 tertiary care centers responded (43% response rate). Overall, patients were relatively knowledgeable about depression and its occurrence in PD. However, many patients believed that depression is a normal reaction to the illness. While many respondents would be reluctant to initiate a discussion of depression during a clinical evaluation, most would feel comfortable talking about depression with their physician if he or she asked them questions about their mood. Based on the results of this survey, we recommend the following approach for physicians: (1) inform PD patients that, although a frequent occurrence, depression need not be accepted as a “normal reaction” to PD; and (2) routinely inquire about depressive symptoms rather than waiting for the patient to spontaneously report them.     

School-related assets and youth risk behaviors: alcohol consumption and sexual activity

BACKGROUND: Two risk behaviors, alcohol consumption and early initiation of sexual intercourse (ISI), can have devastating consequences for youth. The purpose of this study was to determine the association of school connectedness and school‐related behaviors (eg, academic performance, skipping school, getting into trouble at school) with these 2 risk behaviors. METHODS: The Youth Asset Survey (YAS) was administered to 1117 youth/parent pairs in their homes using Computer‐Assisted Personal/Self‐Interviewing (CAPI/CASI). The YAS measures 17 youth assets and risk behaviors including alcohol consumption and sexual activity. RESULTS: The mean age of the sample was 14.3 years; 53% were female; and 70% were from 2‐parent homes. Five school‐related behaviors were positively associated with no ISI. Four school‐related behaviors were positively associated with reporting no alcohol consumption in the past 30 days, including the School Connectedness asset (only among 12‐ to 13‐year‐olds), not skipping school (only among non‐Hispanic Caucasians), staying out of trouble, and paying attention. CONCLUSIONS: School is very much a part of the lives of youth and therefore the relationship they have with their school experience is important and may influence their involvement in risk behaviors. Feeling connected to school is a positive asset that can protect youth from such risky behaviors as sexual initiation and alcohol consumption.