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De novo variants in the gene encoding cyclin‐dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of 15 individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe 2 nonsense variants and a recurrent frame‐shift variant. We demonstrate the synthesis of 2 aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice‐site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioral problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in 2 individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype‐phenotype correlation, although 2 individuals harboring a stop codons at the end of the kinase domain might have a milder phenotype. Overall, there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an à vue diagnosis of this syndrome and therefore genome‐wide or gene‐panel driven genetic testing is needed. Based on this overview, we provide suggestions for clinical work‐up and management of this recently described ID syndrome. [ABSTRACT FROM AUTHOR]

The use of whole exome sequencing (WES) for diagnostics of children with rare genetic diseases raises questions about best practices in genetic counselling. While a lot of attention is now given to pre-test counselling procedures for WES, little is known about how parents experience the (positive, negative, or inconclusive) WES results in daily life. To fill this knowledge gap, data were gathered through in-depth interviews with parents of 15 children who underwent WES analysis. WES test results, like results from other genetic tests, evoked relief as well as worries, irrespective of the type of result. Advantages of obtaining a conclusive diagnosis included becoming more accepting towards the situation, being enabled to attune care to the needs of the child, and better coping with feelings of guilt. Disadvantages experienced included a loss of hope for recovery, and a loss by parents of their social network of peers and the effort necessary to re-establish that social network. While parents with conclusive diagnoses were able to re-establish a peer community with the help of social media, parents receiving a possible diagnosis experienced hurdles in seeking peer support, as peers still needed to be identified. These types of psychosocial effects of WES test results for parents are important to take into account for the development of successful genetic counselling strategies. [ABSTRACT FROM AUTHOR]

Mitochondrial complex I is the largest multi-protein enzyme complex of the oxidative phosphorylation system. Seven subunits of this complex are encoded by the mitochondrial and the remainder by the nuclear genome. We review the natural disease course and signs and symptoms of 130 patients (four new cases and 126 from literature) with mutations in nuclear genes encoding structural complex I proteins or those involved in its assembly. Complex I deficiency caused by a nuclear gene defect is usually a non-dysmorphic syndrome, characterized by severe multi-system organ involvement and a poor prognosis. Age at presentation may vary, but is generally within the first year of life. The most prevalent symptoms include hypotonia, nystagmus, respiratory abnormalities, pyramidal signs, dystonia, psychomotor retardation or regression, failure to thrive, and feeding problems. Characteristic symptoms include brainstem involvement, optic atrophy and Leigh syndrome on MRI, either or not in combination with internal organ involvement and lactic acidemia. Virtually all children ultimately develop Leigh syndrome or leukoencephalopathy. Twenty-five percent of the patients died before the age of six months, more than half before the age of two and 75 % before the age of ten years. Some patients showed recovery of certain skills or are still alive in their thirties . No clinical, biochemical, or genetic parameters indicating longer survival were found. No clear genotype-phenotype correlations were observed, however defects in some genes seem to be associated with a better or poorer prognosis, cardiomyopathy, Leigh syndrome or brainstem lesions. [ABSTRACT FROM AUTHOR]

Willemsen MH, Beunders G, Callaghan M, de Leeuw N, Nillesen WM, Yntema HG, van Hagen JM, Nieuwint AWM, Morrison N, Keijzers-Vloet STM, Hoischen A, Brunner HG, Tolmie J, Kleefstra T. Familial Kleefstra syndrome due to maternal somatic mosaicism for interstitial 9q34.3 microdeletions. The Kleefstra syndrome (Online Mendelian Inheritance in Man 607001) is caused by a submicroscopic 9q34.3 deletion or by intragenic euchromatin histone methyl transferase 1 (EHMT1) mutations. So far only de novo occurrence of mutations has been reported, whereas 9q34.3 deletions can be either de novo or caused by complex chromosomal rearrangements or translocations. Here we give the first descriptions of affected parent-to-child transmission of Kleefstra syndrome caused by small interstitial deletions, approximately 200 kb, involving part of the EHMT1 gene. Additional genome-wide array studies in the parents showed the presence of similar deletions in both mothers who only had mild learning difficulties and minor facial characteristics suggesting either variable clinical expression or somatic mosaicism for these deletions. Further studies showed only one of the maternal deletions resulted in significantly quantitative differences in signal intensity on the array between the mother and her child. But by investigating different tissues with additional fluorescent in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) analyses, we confirmed somatic mosaicism in both mothers. Careful clinical and cytogenetic assessments of parents of an affected proband with an (interstitial) 9q34.3 microdeletion are merited for accurate estimation of recurrence risk. [ABSTRACT FROM AUTHOR]

Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29 ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3 ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Substrate deprivation therapy has been successfully applied in a number of lysosomal storage diseases, such as Gaucher disease. So far only limited experience is available in Sandhoff disease. We initiated substrate deprivation therapy in one male patient, who initially presented at the age of 3.5 years with epilepsy and regression in motor skills and speech development. Juvenile Sandhoff disease was diagnosed on the basis of a decreased hexosaminidase activity in leukocytes and a homozygous HEXB gene mutation. After the epilepsy was controlled, the clinical course remained stable for years, defined by a mild proximal myopathy and stable mental retardation. At 14 years of age the patient experienced a second episode with progressively worsening general condition with diminishing muscle power and progressive ataxia. Treatment was started with the N-alkylated imino sugar miglustat, inhibiting the glucosylceramide synthase, an essential enzyme for the synthesis of glycosphingolipids. Diarrhoea was treated with lactose restriction. We performed detailed biochemical investigations, motor and mental development analysis, brain imaging, organ function studies and quality of life score prior to and at different time points after start of the treatment. Two years after the initiation of therapy the patient has a stable neurological picture without further regression in his motor development, ataxia or intelligence. There is a subjective improvement in the fine motor skills and walking up the stairs but no change in the quality of life score. Under treatment with miglustat the clinical course in our patient with Sandhoff disease did not further deteriorate. [ABSTRACT FROM AUTHOR]

This study among 702 Dutch employees working in the health care and welfare sector examined individual and organizational factors that are related to workers' employability orientation and turnover intention. Additionally, push and pull motives were examined of employees who aimed to leave their job. Results indicated that a strong employability culture adds extra variance over and above individual factors such as career satisfaction and role breadth self-efficacy in the explanation of employability orientation, turnover intention, and push motives of employees who aim to leave their job. That is, employability culture is positively related to employability orientation, but negatively related to turnover intention and to push motives of those who aim to leave. Pull motives of employees who want to leave are explained by individual factors only, such as career dissatisfaction and role breadth self-efficacy, but not by employability culture. These findings suggest that organizations that need to adapt to changing environments should implement a strong employability culture, because such a culture stimulates employability orientations among their employees while simultaneously decreasing turnover intentions. [ABSTRACT FROM AUTHOR]

Sjögren-Larsson syndrome (SLS) is an autosomal recessive neurometabolic disorder characterized by spasticity, learning disability, and ichthyosis. To our knowledge, there is no detailed report in the literature concerning the functional consequences of SLS. Therefore, we performed a cross-sectional study of motor performance and everyday functioning in 17 patients with this rare disorder. Nine female and eight male patients with SLS (age range 1-35y) were investigated. Data were obtained by structured interview with parents and patients with SLS, a telephone-conducted questionnaire, and physical examination. Motor performance was measured by the Gross Motor Function Measure; everyday functioning was assessed using the Pediatric Evaluation of Disability Inventory and the Vineland Adaptive Behavior Scale. In most patients, spasticity was bilaterally present in hamstrings, hip adductors, and gastrocnemic muscles. All participants above 7 years had contractures in the lower extremities. Limitations were present in all gross motor dimensions, except for lying and rolling. Participants had developmental ages far below their chronological age. This study revealed that patients with SLS have limitations in gross motor performance. Although some patients can reach a certain level of independence, most have activity limitations and restrictions in their participation in society. [ABSTRACT FROM AUTHOR]

Aims We studied whether reimbursement for smoking cessation treatment (SCT) can increase prolonged abstinence from smoking up to 2 years. Setting, participants and design From the general population, we recruited smokers and assigned them randomly to a control group ( n = 634) or an intervention group ( n = 632). For 6 months, participants in the intervention group could apply for reimbursement and received information regarding the reimbursed SCT. Participants in the control group received no reimbursement or information. Measurements In this follow-up study, prolonged abstinence from smoking was defined as reported being abstinent from at least 7 days before the end of reimbursement until the follow-up assessment 6 months or 2 years later. Findings At 6 months after the end of reimbursement, 18 participants in the control group (2.8%) and 35 participants (5.5%) in the intervention group reported sustained abstinence for at least 6 months [odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.1–3.6]. Two years after the reimbursement period, 10 participants in the control group (1.6%) and 27 participants in the intervention group (4.3%) still reported sustained abstinence (OR = 4.1, 95% CI 1.7–10.2). The overall effectiveness of SCT increased with reimbursement and was 22% in the intervention group and 8% in the control group after 2 years. Conclusions Reimbursement may be an effective strategy to increase the prolonged abstinence rate even after 2 years. [ABSTRACT FROM AUTHOR]

Few smokers who try to quit smoking use smoking cessation treatment (SCT), and cost could be one factor. To increase the number of successful quitters, we assessed whether financial reimbursement for SCT would encourage the use of SCT and would as a result increase the 6-month point abstinence rate. We recruited smokers aged over 18 years from a random sample of Dutch inhabitants insured by one health insurance company. The smokers were assigned randomly to the intervention group ( n = 632) or control group ( n = 634). Respondents in the intervention group received an offer of reimbursement for nicotine replacement therapy, bupropion and behavioural counselling. No reimbursement was offered to the control group. To preclude a change of behaviour due to disappointment in the control group, we used a randomized consent design. During the reimbursement period, 10.8% smokers in the intervention group reported having used SCT compared with 4.1% in the control group (OR = 2.9, 95% CI 1.8–4.7). In the intervention group, 23.4% smokers tried to stop compared with 20.8% in the control group (OR = 1.2, 95% CI 0.9–2.4). After 6 months, the biochemically validated 7-day point prevalence abstinence rate was 5.5% in the intervention group and 2.8% in the control group (OR = 2.3, 95% CI 1.2–4.1). Reimbursement for SCT seems efficacious in increasing the use of SCT and may double the number of successful quitters. [ABSTRACT FROM AUTHOR]

The article reports on the deliberations of an expert workshop on bovine coccidiosis held at the First European Buiatrics Conference in Marseille, France in December 2009. The workshop looked at factors leading to the disease, problems relating to diagnosis, treatment intervention strategies, and the role of immunity in the prevention and control of coccidiosis. The importance of knowledge on the epidemiology of coccidial infections to the various cattle management systems across Europe is stressed.

Abstract We report a patient with recurrent symptoms of neuroglycopenia due to a defective glucose transport into brain. The potential benefit of ketosis in neuroglycopenia is discussed from the therapeutic concept of a ketogenic diet in GLUT1-deficiency syndrome. Diabet. Med. 20, 481–482 (2003). [ABSTRACT FROM AUTHOR]

Supernumerary marker chromosomes (SMC) originating from chromosome 15 are the most common SMCs. They encompass clinically irrelevant SMC(15)s containing only heterochromatin and 15p material, and clinically relevant SMC(15)s that consist of both eu- and heterochromatic 15q material. On the basis of size, the clinically relevant SMC(15)s can be subdivided into type A, "large" asymmetric and type B, "small" symmetric SMC(15)s. Type B SMC(15)s contain the triplicated 15pter to BP3 (located at 26.5 Mb) region, while type A SMC(15)s consist of 15pter --> BP4(28.5 Mb)::BP5(30.5 Mb) --> 15pter. In this study, the clinical and molecular features of 18 patients with A and B SMC(15)s and two patients with a partial trisomy 15q were reviewed. Questionnaires (including Child Behavior Check Lists) were used to assess behavior and developmental features in more detail. The marker size and parental origin were determined by multiplex ligation-dependent probe amplification (MLPA). Based on the MLPA results, the majority of patients (14/18) had type A SMC(15)s. The phenotype observed did not show significant differences between types A and B SMC(15)s. A high prevalence of autistic-like behavior, attention problems, aggressive behavior, anxiety, and sleeping problems was reported. Motor and speech development varied extensively among the patients. An association was found between positive seizure history and degree of intellectual disability., (Copyright 2010 Wiley-Liss, Inc.)