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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 -
Kardiologia Polska 2015According to the current guidelines, atrioventricular (DDD) pacing is superior to atrial pacing (AAI) in the treatment of sick sinus syndrome (SSS).
BACKGROUND
According to the current guidelines, atrioventricular (DDD) pacing is superior to atrial pacing (AAI) in the treatment of sick sinus syndrome (SSS).
AIM
To compare outcomes of AAI and DDD pacing in patients with SSS during long-term follow-up.
METHODS
We studied 809 patients, including 86 patients in the AAI group (57 women, mean age 65 ± 15 years) and 723 patients in the DDD group (406 women, mean age 71.5 ± 10 years). Evaluation of outcomes of AAI and DDD pacing in SSS was based on the analysis of medical records of patients who underwent pacemaker implantation.
RESULTS
Average duration of follow-up was 52 ± 25 months. In the AAI group, 63 of 86 patients remained without intervention. In the DDD group, 661 of 723 patients did not require surgical intervention. Overall, 105 patients died, including 13 in the AAI group and 92 in the DDD group (p = 0.4516). In the AAI group, a high degree atrioventricular block occurred on average after 46.3 ± 8.8 months and its incidence was estimated at 0.85% per year. Atrial fibrillation (AF) developed in 8 patients in the AAI group and 81 patients in the DDD group (p = 0.23). Among aetiological factors of an increased risk of developing AF, only the presence of tachycardia-bradycardia syndrome (hazard ratio [HR] 11.31) and the absence of antiarrhythmic therapy (HR 4.23) significantly increased the risk of AF. Urgent reoperation was needed in 23 patients in the AAI group and 62 patients in the DDD group (p < 0.01). Log-rank test analysis showed a significant effect of the development of AF on the risk of reoperation in this group (p = 0.0420). Lead-related complications were noted in 6 patients in the AAI group and 49 patients in the DDD group (p = 0.94). After 45 months, the risk of reoperation in the AAI group increased significantly due to a need for ventricular lead implantation.
CONCLUSIONS
1. Atrial stimulation is safe in SSS but it may be associated with an increased risk of ventricular lead implantation if atrioventricular block or persistent AF with slow ventricular rate develops. 2. DDD and AAI groups did not differ significantly in terms of survival, development of persistent AF, and lead-related complications. 3. Tachycardia-bradycardia syndrome and the lack of antiarrhythmic treatment with beta-blocker and amiodarone increased the risk of persistent AF during long-term follow-up. 4. A higher rate of reoperations in patients with AAI systems, related mainly to development of persistent AF, especially after the fourth year of follow-up, may justify DDD system implantation in SSS.
Topics: Aged; Aged, 80 and over; Cardiac Pacing, Artificial; Female; Follow-Up Studies; Humans; Male; Middle Aged; Sick Sinus Syndrome; Treatment Outcome
PubMed: 25001847
DOI: 10.5603/KP.a2014.0148 -
Disease Models & Mechanisms Jun 2022Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular...
Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular syndrome (CCMS). We show that Snrpb heterozygous mouse embryos arrest shortly after implantation. Additionally, heterozygous deletion of Snrpb in the developing brain and neural crest cells models craniofacial malformations found in CCMS, and results in death shortly after birth. RNAseq analysis of mutant heads prior to morphological defects revealed increased exon skipping and intron retention in association with increased 5' splice site strength. We found increased exon skipping in negative regulators of the P53 pathway, along with increased levels of nuclear P53 and P53 target genes. However, removing Trp53 in Snrpb heterozygous mutant neural crest cells did not completely rescue craniofacial development. We also found a small but significant increase in exon skipping of several transcripts required for head and midface development, including Smad2 and Rere. Furthermore, mutant embryos exhibited ectopic or missing expression of Fgf8 and Shh, which are required to coordinate face and brain development. Thus, we propose that mis-splicing of transcripts that regulate P53 activity and craniofacial-specific genes contributes to craniofacial malformations. This article has an associated First Person interview with the first author of the paper.
Topics: Animals; Craniofacial Abnormalities; Humans; Intellectual Disability; Mice; Micrognathism; Morphogenesis; Neural Crest; Ribs; Tumor Suppressor Protein p53; snRNP Core Proteins
PubMed: 35593225
DOI: 10.1242/dmm.049544 -
EMBO Molecular Medicine Sep 2016Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial...
Mitochondria form a dynamic network that responds to physiological signals and metabolic stresses by altering the balance between fusion and fission. Mitochondrial fusion is orchestrated by conserved GTPases MFN1/2 and OPA1, a process coordinated in yeast by Ugo1, a mitochondrial metabolite carrier family protein. We uncovered a homozygous missense mutation in SLC25A46, the mammalian orthologue of Ugo1, in a subject with Leigh syndrome. SLC25A46 is an integral outer membrane protein that interacts with MFN2, OPA1, and the mitochondrial contact site and cristae organizing system (MICOS) complex. The subject mutation destabilizes the protein, leading to mitochondrial hyperfusion, alterations in endoplasmic reticulum (ER) morphology, impaired cellular respiration, and premature cellular senescence. The MICOS complex is disrupted in subject fibroblasts, resulting in strikingly abnormal mitochondrial architecture, with markedly shortened cristae. SLC25A46 also interacts with the ER membrane protein complex EMC, and phospholipid composition is altered in subject mitochondria. These results show that SLC25A46 plays a role in a mitochondrial/ER pathway that facilitates lipid transfer, and link altered mitochondrial dynamics to early-onset neurodegenerative disease and cell fate decisions.
Topics: Cells, Cultured; Endoplasmic Reticulum; Female; Homeostasis; Humans; Leigh Disease; Lipid Metabolism; Mitochondria; Mitochondrial Proteins; Mutation, Missense; Phosphate Transport Proteins
PubMed: 27390132
DOI: 10.15252/emmm.201506159 -
Cell Death & Disease Jan 2021Mutations of WD40 repeat domain 60 (WDR60) have been identified in short-rib polydactyly syndromes (SRPS I-V), a group of lethal congenital disorders characterized by...
Mutations of WD40 repeat domain 60 (WDR60) have been identified in short-rib polydactyly syndromes (SRPS I-V), a group of lethal congenital disorders characterized by short ribs, polydactyly, and a range of extraskeletal phenotypes. However, the underlying mechanism is still unclear. Here, we report that WDR60 is essential for embryonic development and plays a critical role in the multipolar-bipolar transition and migration of newborn neurons during brain development. Mechanically, we found that WDR60 was located at the microtubule-organizing center to control microtubule organization and possibly, the trafficking of cellular components. Importantly, the migration defect caused by Wdr60 knockdown could be rescued by the stable form of α-Tubulin, α-Tubulin (an acetylation-mimicking mutant). These findings identified a non-cilia function of WDR60 and provided insight into its biological function, as well as the pathogenesis of WDR60 deficiency associated with SRPS.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Movement; Female; Humans; Mice; Neurogenesis; Neurons; Rats; Short Rib-Polydactyly Syndrome
PubMed: 33436552
DOI: 10.1038/s41419-020-03363-3 -
Investigative Ophthalmology & Visual... Sep 2018Mutations in the intraflagellar transport protein 52 homolog (IFT52) gene are reported to interrupt ciliary function and cause short-rib thoracic dysplasia (SRTD), a...
PURPOSE
Mutations in the intraflagellar transport protein 52 homolog (IFT52) gene are reported to interrupt ciliary function and cause short-rib thoracic dysplasia (SRTD), a specific form of skeletal ciliopathy. However, the roles of these mutations in retinal ciliopathy are inexplicit. We herein aim to study the impact of IFT52 mutations in retinopathies.
METHODS
A patient with syndromic ciliopathy, presenting mild SRTD (skeletal ciliopathy) and Liber congenital amaurosis (LCA; retinal ciliopathy), and nine unaffected family members were recruited. Comprehensive systemic evaluations, including ophthalmic tests, were received by the patient. Whole genome sequencing (WGS) was applied for genetic annotation. An in vitro cell system was employed to study the pathogenicity of the variant.
RESULTS
WGS identified a homozygous missense variation in IFT52, c.556A>G (p.T186A), carried by the patient but absent in both unaffected siblings. In silico analysis supported the pathogenic nature of this highly conserved variant. Structural analysis suggested that this substitution could generate a novel hydrogen bond between the mutated residue 186 and proline at residue 192, thus potentially interrupting the tertiary structure and the stability of the IFT52 protein. In vitro cellular study indicated that this mutation might disturb the stability of encoded IFT52 protein and dramatically disrupt cilia elongation in hTERT-RPE1 cells in a loss-of-function manner.
CONCLUSIONS
This report expands ocular phenotypes of IFT52 mutation-caused ciliopathy to include retinal ciliopathy and demonstrates its deleterious nature in interrupting primary ciliary function. Our study hence highlights the need for screening for IFT52 mutations in LCA patients and ophthalmic reviews of patients carrying IFT52 mutations.
Topics: Animals; Carrier Proteins; Child, Preschool; Ciliopathies; Computational Biology; Female; Fluorescent Antibody Technique, Indirect; Humans; Immunoblotting; Intracellular Signaling Peptides and Proteins; Leber Congenital Amaurosis; Mice; Mice, Inbred C57BL; Mutation, Missense; Pedigree; Plasmids; Real-Time Polymerase Chain Reaction; Retinal Degeneration; Retinal Pigment Epithelium; Short Rib-Polydactyly Syndrome; Tomography, Optical Coherence; Transfection; Whole Genome Sequencing
PubMed: 30242358
DOI: 10.1167/iovs.17-23351 -
European Journal of Medical Genetics Aug 2015Lenz-Majewski syndrome (LMS) is an extremely rare syndrome characterized by osteosclerosis, intellectual disability, characteristic facies and distinct craniofacial,...
Lenz-Majewski syndrome (LMS) is an extremely rare syndrome characterized by osteosclerosis, intellectual disability, characteristic facies and distinct craniofacial, dental, cutaneous and distal - limb anomalies. Recently, mutations in PTDSS1 gene have been identified as causative in six unrelated individuals. We report the seventh mutation proven case of LMS and provide a concise review of all known patients till date.
Topics: Abnormalities, Multiple; Base Sequence; Bone Diseases, Developmental; Child, Preschool; Exons; Facies; Gene Expression; Humans; Intellectual Disability; Male; Molecular Sequence Data; Mutation; Nitrogenous Group Transferases; Radiography
PubMed: 26117586
DOI: 10.1016/j.ejmg.2015.06.002 -
JPMA. the Journal of the Pakistan... May 2018Lenz-Majewski Hyperostotic Dwarfism (LMHD) is an extremely rare congenital, sclerosing bone dysplasia that causes cranio-tubular hyperostosis, ectodermal dysplasia...
Lenz-Majewski Hyperostotic Dwarfism (LMHD) is an extremely rare congenital, sclerosing bone dysplasia that causes cranio-tubular hyperostosis, ectodermal dysplasia (cutis laxa and enamel hypoplasia), osseous dysgenesis of hands and feet with diaphyseal cortical thickening of tubular bones and intellectual disability. Only a few cases of this syndrome have been reported in the literature so far. We report another case of LMHD with cranio-tubular hyperostosis, cutis laxa, wide open anterior and posterior fontannels, hypertelorism and thickening of diaphysis of tubular bones in a six months old Pakistani female patient. Notably, some secondary phenotypic clinical features such as multiple bony deformities, multiple skin tags and a space occupying lesion in posterior cranial fossa (Lipoma) resulting in obstructive hydrocephalus were also present in this patient. These atypical features have never been previously reported with LMHD, to the best of our knowledge. This case extends the variable phenotype and associated features of this syndrome.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Bone and Bones; Brain Neoplasms; Female; Humans; Hydrocephalus; Infant; Intellectual Disability; Lipoma; Phenotype
PubMed: 29885186
DOI: No ID Found -
Cell Cycle (Georgetown, Tex.) 2015Short-rib polydactyly syndromes (SRPS) arise from mutations in genes involved in retrograde intraflagellar transport (IFT) and basal body homeostasis, which are critical...
Short-rib polydactyly syndromes (SRPS) arise from mutations in genes involved in retrograde intraflagellar transport (IFT) and basal body homeostasis, which are critical for cilia assembly and function. Recently, mutations in WDR34 or WDR60 (candidate dynein intermediate chains) were identified in SRPS. We have identified and characterized Tctex1d2, which associates with Wdr34, Wdr60 and other dynein complex 1 and 2 subunits. Tctex1d2 and Wdr60 localize to the base of the cilium and their depletion causes defects in ciliogenesis. We propose that Tctex1d2 is a novel dynein light chain important for trafficking to the cilium and potentially retrograde IFT and is a new molecular link to understanding SRPS pathology.
Topics: Adaptor Proteins, Signal Transducing; Carrier Proteins; Cilia; Cytoskeletal Proteins; Dyneins; HEK293 Cells; HeLa Cells; Humans; Microtubule-Organizing Center; Mutation; Protein Transport; Short Rib-Polydactyly Syndrome
PubMed: 25830415
DOI: 10.4161/15384101.2014.985066 -
Rheumatology International Mar 2016Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain...
Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary connective tissue disorders characterized by joint hypermobility, widespread musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial impairment are common, yet poorly characterized, findings in EDS patients. We investigated the frequency and types of psychiatric disorders and their relationship to systemic manifestations in a cohort of 106 classic and hypermobility type EDS patients. In this retrospective study, extensive medical chart review was performed for patients referred at two genetics clinics who were diagnosed with EDS. Statistical analysis was undertaken to determine the frequency of psychiatric disorders and association with systemic findings. Psychiatric disorders were found in 42.5% of the EDS cohort, with 22.7% of patients affected with 2 or more psychiatric diagnoses. Anxiety and depression were most commonly reported, with frequencies of 23.6 and 25.5%, respectively. A variety of other psychiatric diagnoses were also identified. Abdominal pain [odds ratio (OR) 7.38], neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR 2.85) and fatigue (OR 5.55) were significantly associated with the presence of a psychiatric disorder. The presence of any pain symptom was significantly associated with having a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR 5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were significantly associated with having an anxiety or mood disorder. Joint hypermobility and the classic dermatological features of EDS showed no significant association with having a psychiatric disorder. Our findings demonstrate a high frequency of psychiatric disorders and an association with pain symptoms in EDS.
Topics: Abdominal Pain; Adult; Arthralgia; Comorbidity; Ehlers-Danlos Syndrome; Female; Humans; Male; Mental Disorders; Middle Aged; Migraine Disorders; Neuralgia; Odds Ratio; Ontario; Pain Measurement; Psychiatric Status Rating Scales; Retrospective Studies; Risk Factors; Young Adult
PubMed: 26433894
DOI: 10.1007/s00296-015-3375-1