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Genetics in Medicine : Official Journal... Jan 2021We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool.
METHODS
In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs-personalized checklists-are used during annual wellness visits with the patient's PCP.
RESULTS
A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U.
CONCLUSIONS
DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.
Topics: Caregivers; Child; Down Syndrome; Health Personnel; Humans; Personal Satisfaction
PubMed: 32879436
DOI: 10.1038/s41436-020-00952-7 -
Brain Sciences Jul 2020Since the end of 2019, the whole world has been struggling with the pandemic of the new Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Available evidence...
Since the end of 2019, the whole world has been struggling with the pandemic of the new Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Available evidence suggests that pain is a common symptom during Coronavirus Disease 2019 (COVID-19). According to the World Health Organization, many patients suffer from muscle pain (myalgia) and/or joint pain (arthralgia), sore throat and headache. The exact mechanisms of headache and myalgia during viral infection are still unknown. Moreover, many patients with respiratory failure get admitted to the intensive care unit (ICU) for ventilatory support. Pain in ICU patients can be associated with viral disease itself (myalgia, arthralgia, peripheral neuropathies), may be caused by continuous pain and discomfort associated with ICU treatment, intermittent procedural pain and chronic pain present before admission to the ICU. Undertreatment of pain, especially when sedation and neuromuscular blocking agents are used, prone positioning during mechanical ventilation or extracorporeal membrane oxygenation (ECMO) may trigger delirium and cause peripheral neuropathies. This narrative review summarizes current knowledge regarding challenges associated with pain assessment and management in COVID-19 patients. A structured prospective evaluation should be undertaken to analyze the probability, severity, sources and adequate treatment of pain in patients with COVID-19 infection.
PubMed: 32698378
DOI: 10.3390/brainsci10070465 -
Scientific Reports Jul 2020Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and...
Weill-Marchesani syndrome (WMS) is a rare disorder displaying short stature, brachydactyly and joint stiffness, and ocular features including microspherophakia and ectopia lentis. Brachydactyly and joint stiffness appear less commonly in patients with WMS4 caused by pathogenic ADAMTS17 variants. Here, we investigated a large family with WMS from Newfoundland, Canada. These patients displayed core WMS features, but with proportionate hands that were clinically equivocal for brachydactyly. Whole exome sequencing and autozygosity mapping unveiled a novel pathogenic missense ADAMTS17 variant (c.3068 G > A, p.C1023Y). Sanger sequencing demonstrated variant co-segregation with WMS, and absence in 150 population matched controls. Given ADAMTS17 involvement, we performed deep phenotyping of the patients' hands. Anthropometrics applied to hand roentgenograms showed that metacarpophalangeal measurements of affected patients were smaller than expected for their age and sex, and when compared to their unaffected sibling. Furthermore, we found a possible sub-clinical phenotype involving markedly shortened metacarpophalangeal bones with intrafamilial variability. Transfection of the variant ADAMTS17 into HEK293T cells revealed significantly reduced secretion into the extracellular medium compared to wild-type. This work expands understanding of the molecular pathogenesis of ADAMTS17, clarifies the variable hand phenotype, and underscores a role for anthropometrics in characterizing sub-clinical brachydactyly in these patients.
Topics: ADAMTS Proteins; Anthropometry; Bodily Secretions; Brachydactyly; Canada; Female; Fingers; HEK293 Cells; Humans; Male; Mutation, Missense; Phenotype; Weill-Marchesani Syndrome; Exome Sequencing
PubMed: 32616716
DOI: 10.1038/s41598-020-66978-8 -
Medicine Feb 2020KIAA0586 variants have been associated to short-rib thoracic dysplasia, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax, short limbs, and...
INTRODUCTION
KIAA0586 variants have been associated to short-rib thoracic dysplasia, an autosomal recessive skeletal ciliopathy characterized by a narrow thorax, short limbs, and radiological skeletal abnormalities.
PATIENT CONCERNS
Patients 1 and 2 were two Roma Gypsy siblings presenting thoracic dysplasia and a combination of oral cavity anomalies.
DIAGNOSIS
A custom NGS gene panel, including genes associated to skeletal ciliopathies, identified the homozygous KIAA0586 splicing variant c.1815G>A (p.Gln605Gln) in both siblings, confirming the clinical diagnosis of short-rib-polydactyly.
INTERVENTION
Patients were transferred to neonatal intensive care unit and received life-support treatment.
OUTCOMES
Patients 1 and 2 died after few hours and 1 month of birth, respectively, because of respiratory failure related with the disease.
CONCLUSION
We report two patients affected by short-rib polydactyly syndrome and overlapping phenotype with oral-facial-digital syndrome associated with the c.1815G>A variant in KIAA0586, suggesting a quite peculiar genotype-phenotype correlation.
Topics: Cell Cycle Proteins; Ciliopathies; Humans; Infant, Newborn; Italy; Male; Orofaciodigital Syndromes; Phenotype; Roma; Short Rib-Polydactyly Syndrome; Siblings
PubMed: 32080096
DOI: 10.1097/MD.0000000000019169 -
Tremor and Other Hyperkinetic Movements... 2019Detection of defective deep brain stimulation (DBS) contacts/electrodes is sometimes challenging.
BACKGROUND
Detection of defective deep brain stimulation (DBS) contacts/electrodes is sometimes challenging.
CASE REPORT
We report a patient with Tourette syndrome (TS), who presented with abrupt tic increase and mild generalized headache 9 years after DBS implantation. On the suspicion of a hardware defect, a fracture of the DBS electrode and extension lead was ruled out by radiography and standard implantable pulse generator readouts. Further investigation revealed position-dependent modifiable therapeutic impedances, suggesting an impaired contact of the extension lead/adaptor. After replacement normal impedances were recorded, and the patient fully recovered.
DISCUSSION
In DBS dysfunction with inconspicuous hardware check, position-dependent defects might be suspected.
Topics: Adult; Deep Brain Stimulation; Electrodes, Implanted; Humans; Male; Postoperative Complications; Tourette Syndrome
PubMed: 31709126
DOI: 10.7916/tohm.v0.713 -
Molecular Genetics & Genomic Medicine Jan 2020This study reports the genetic features of four Caucasian males from the Saguenay-Lac-St-Jean region affected by partial agenesis of the corpus callosum (ACC) with...
BACKGROUND
This study reports the genetic features of four Caucasian males from the Saguenay-Lac-St-Jean region affected by partial agenesis of the corpus callosum (ACC) with hypotonia, epilepsy, developmental delay, microcephaly, hypoplasia, and autistic behavior.
METHODS
We performed whole exome sequencing (WES) to identify new genes involved in this pathological phenotype. The regions of interest were subsequently sequenced for family members.
RESULTS
Single-nucleotide variations (SNVs) and insertions or deletions were detected in genes potentially implicated in brain defects observed in these patients. One patient did not have mutations in genes related to ACC, but carried a de novo pathogenic mutation in Mucolipin-1 (MCOLN1) and was diagnosed with mucolipidosis type IV. Among the other probands, missense SNVs were observed in DCLK2 (Doublecortin Like Kinase 2), HERC2 (HECT And RLD Domain Containing E3 Ubiquitin Protein Ligase 2), and KCNH3 (Potassium channel, voltage-gated, subfamily H, member 3). One patient also carried a non-frameshift insertion in CACNA1A (Cav2.1(P/Q-type) calcium channels).
CONCLUSION
Although no common genetic defect was observed in this study, we provide evidence for new avenues of investigation for ACC, such as molecular pathways involving HERC2, CACNA1A, KCNH3, and more importantly DCLK2. We also allowed to diagnose an individual with mucolipidosis type IV.
Topics: Adolescent; Adult; Agenesis of Corpus Callosum; Calcium Channels; Developmental Disabilities; Doublecortin-Like Kinases; Epilepsy; Ether-A-Go-Go Potassium Channels; Exome; Humans; Male; Microcephaly; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Syndrome; Transient Receptor Potential Channels; Ubiquitin-Protein Ligases
PubMed: 31578829
DOI: 10.1002/mgg3.992 -
Nature Sep 2019Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue...
Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis. They are also implicated in human developmental disorders and cancers, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
Topics: Animals; Cell Line; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; DNA, Intergenic; Genome-Wide Association Study; Growth Disorders; Histones; Humans; Mice; Protein Binding; Protein Domains; Protein Transport; Sotos Syndrome
PubMed: 31485078
DOI: 10.1038/s41586-019-1534-3 -
Kardiologia Polska Sep 2019
Anomalous origin of the right coronary artery from the left Valsalva sinus in a patient presenting with syncope, ventricular tachycardia, and electrocardiographic early repolarization pattern.
Topics: Coronary Angiography; Coronary Vessel Anomalies; Electrocardiography; Humans; Middle Aged; Sinus of Valsalva; Syncope; Syndrome; Tachycardia, Ventricular
PubMed: 31354160
DOI: 10.33963/KP.14909 -
PloS One 2019Mutations in EFTUD2 are responsible for the autosomal dominant syndrome named MFDM (mandibulofacial dysostosis with microcephaly). However, it is not clear how reduced...
Mutations in EFTUD2 are responsible for the autosomal dominant syndrome named MFDM (mandibulofacial dysostosis with microcephaly). However, it is not clear how reduced levels of EFTUD2 cause abnormalities associated with this syndrome. To determine if the mouse can serve as a model for uncovering the etiology of abnormalities found in MFDM patients, we used in situ hybridization to characterize expression of Eftud2 during mouse development, and used CRISPR/Cas9 to generate a mutant mouse line with deletion of exon 2 of the mouse gene. We found that Eftud2 was expressed throughout embryonic development, though its expression was enriched in the developing head and craniofacial regions. Additionally, Eftud2 heterozygous mutant embryos had reduced EFTUD2 mRNA and protein levels. Moreover, Eftud2 heterozygous embryos were born at the expected Mendelian frequency, and were viable and fertile despite being developmentally delayed. In contrast, Eftud2 homozygous mutant embryos were not found post-implantation but were present at the expected Mendelian frequency at embryonic day (E) 3.5. Furthermore, only wild-type and heterozygous E3.5 embryos survived ex vivo culture. Our data indicate that Eftud2 expression is enriched in the precusor of structures affected in MFDM patients and show that heterozygous mice carrying deletion of exon 2 do not model MFDM. In addition, we uncovered a requirement for normal levels of Eftud2 for survival of pre-implantation zygotes.
Topics: Abnormalities, Multiple; Animals; Embryo Implantation; Female; Humans; Loss of Function Mutation; Male; Mandibulofacial Dysostosis; Mice; Mice, Inbred C57BL; Microcephaly; Mutation; Peptide Elongation Factors; Phenotype; Pregnancy; Ribonucleoprotein, U5 Small Nuclear; Sequence Deletion
PubMed: 31276534
DOI: 10.1371/journal.pone.0219280