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X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/−mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1Ain patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1Amutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1Atruncating mutations (P=0.00851) and an excess of de novomutations (P=2.53 × 10-10) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1Adefine a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophilaknockout models.

To investigate body fluids of patients with undiagnosed leukodystrophies using in vitro 1H-NMR spectroscopy (H-NMRS).

To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype–phenotype relationship for mutations in the ATMgene.

Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a severe and progressive autosomal recessive polyneuropathy. Mutations in the potassium-chloride cotransporter 3 gene (KCC3) were identified as responsible for HMSN/ACC in the French Canadian (FC) population. In the present study, the authors were interested in finding new mutations in non-FC populations, assessing the activity of mutant proteins and refining genotype-phenotype correlations.

1H magnetic resonance (MR) spectroscopy is a useful tool to obtain metabolic information from the brain in paediatric patients. To detect signals of metabolites at low concentrations or from small volumes, the signal-to-noise ratio (SNR) has to be optimized. The SNR can be increased by going to higher field strengths. However, this leads to higher spectral bandwidths, which increases the chemical shift artefact. Here we present a transmit/receive headcoil which is adapted to the dimensions of the paediatric head and enables PRESS localization with high radio-frequency (RF) bandwidths that minimize the chemical shift displacement to only 5%. In addition, since the pulse lengths are shorter with higher RF bandwidths, the echo time can be reduced to 10 ms improving SNR as well.

Sjögren-Larsson syndrome (SLS) is an autosomal recessively inherited neurocutaneous disorder caused by a deficiency of the microsomal enzyme fatty aldehyde dehydrogenase (FALDH). We report the clinical characteristics and the results of molecular studies in 19 SLS patients. Patients 1-17 show the classical triad of severe clinical abnormalities including ichthyosis, mental retardation and spasticity. Most patients were born preterm, and all patients exhibit ocular abnormalities and pruritus. Electro-encephalography shows a slow background activity, without other abnormalities. MRI of the brain shows an arrest of myelination, periventricular signal abnormalities of white matter and mild ventricular enlargement. Cerebral (1)H-MR spectroscopy reveals a characteristic, abnormal lipid peak. The degree of white matter abnormality in the MRIs and the height of the lipid peak in (1)H-MR spectra do not correlate with the severity of the neurological signs. The clinical presentation and the clinical course is strikingly similar in these patients. Patient 18 shows a mild phenotype that essentially contains the same, but less severe, clinical features. Patient 19 exhibits the typical, but very mild, dermatological and ocular abnormalities, without any clinical neurological involvement. The diagnosis of SLS was confirmed by demonstration of the enzyme defect in cultured skin fibroblasts. Furthermore, as might be predicted from the essential role of FALDH in leucotriene B(4) (LTB(4)) metabolism, elevated urinary concentrations of LTB(4) and 20-OH-LTB(4) were found in all patients studied. Molecular studies of the FALDH gene revealed eight different mutations, including three new ones: a large 26-base pair deletion (21-46del), a missense mutation (80C-->T) and an insertion mutation (487-488insA). The vast majority of SLS patients seem to be severely affected independent of their genotype.

To determine the spectrum of clinical and MRI/1H MRS features of patients with fatty aldehyde dehydrogenase (FALDH) deficiency.

OBJECTIVE: To collect descriptive data on annoyance from environmental tobacco smoke (ETS), attitudes toward smoking at the workplace, and support for a no-smoking policy. DESIGN: Survey of eight large companies in four sectors of Dutch industry. SUBJECTS: A representative sample of smoking and non-smoking employees (n = 1480). RESULTS: Thirty-five per cent of non-smoking employees felt it was "annoying" to "very annoying" when their colleagues smoked during worktime, and 78% thought a smoky work environment was harmful to their health. About two-thirds of non-smokers "sometimes" to "often" experienced annoyance from ETS at their workplace. The individual solution approach (no explicit policy) is not only rejected by most nonsmokers but also by many smokers. In three sectors of industry, there was much support among employees for a smoking ban except for work areas designated for smoking. CONCLUSIONS: These results could encourage more companies to implement smoking restrictions and they may be used as reference data by companies wanting to develop effective no-smoking policies.

Introduction. An increasing number of parents use both e-cigarettes and cigarettes (dual users). Previous studies have shown that dual users may have higher rates of contemplating smoking cessation than parents who only smoke cigarettes. This study was aimed to assess the delivery of tobacco cessation treatment (prescription for nicotine replacement therapy and referral to the quitline) among parents who report being dual users vs. cigarette-only smokers. Methods. A secondary analysis of parent survey data collected between April and October 2017 at 10 pediatric primary care practices participating in a cluster-randomized controlled trial of the Clinical Effort Against Secondhand Smoke Exposure (CEASE) intervention was conducted. Parents were considered to be dual users of cigarettes and e-cigarettes if they reported smoking a cigarette, even a puff, in the past seven days and using an e-cigarette within the past 30 days. Parents were asked if they received a prescription for nicotine replacement therapy and referral to the quitline to help them quit from their child’s clinician. Multivariable logistic regression examined factors (dual use, insurance status, relationship to the child, race, and education status of the parent) associated with delivery of smoking cessation treatment (receiving prescriptions and/or enrollment in quitline) to smoking parents. Further, we compared the rates of tobacco cessation treatment delivery to dual users in the usual-care control practices vs. intervention practices. Results. Of 1007 smokers or recent quitters surveyed in the five intervention practices, 722 parents reported current use of cigarettes-only and 111 used e-cigarettes. Of these 111 parents, 82 (73.9%) reported smoking cigarettes. Parents were more likely to report receiving any treatment if they were dual users vs. cigarette-only smokers (OR 2.43, 95% CI 1.38, 4.29). Child’s insurance status, parents’ sex, education, and race were not associated with parental receipt of tobacco cessation treatment in the model. No dual users in the usual-care control practices reported receiving treatment. Discussion. Dual users who visited CEASE intervention practices were more likely to receive treatment than cigarette-only smokers when treatments were discussed. An increased uptake of tobacco cessation treatments among dual users reinforces the importance of discussing treatment options with this group, while also recognizing that cigarette-only smokers may require additional intervention to increase the acceptance rate of cessation assistance. This trial is registered with ClinicalTrials.gov, Identifier: NCT01882348.

Abstract: In a 4-year-old girl supravalvular aortic stenosis was diagnosed by echocardiography. Her younger brother was operated on for the same heart disease one year before.