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American Journal of Veterinary Research Sep 2016OBJECTIVE To characterize a population of Brazilian minipigs with naturally occurring syndactyly by use of plain radiographs and CT images and to evaluate kinetic and...
OBJECTIVE To characterize a population of Brazilian minipigs with naturally occurring syndactyly by use of plain radiographs and CT images and to evaluate kinetic and temporospatial variables by use of a pressure-sensing walkway. ANIMALS 10 Brazilian minipigs from 6 to 8 months of age (group 1, 5 healthy pigs [body weight, 10.5 to 18.5 kg]; group 2, 5 pigs with syndactyly [body weight, 7.5 to 18.0 kg]). PROCEDURES Forelimbs and hind limbs of all pigs were assessed by use of radiography and CT. Gait was analyzed by use of a pressure-sensing walkway. RESULTS All limbs of all pigs of group 2 had syndactyly. Two forelimbs had complex-1 syndactyly, and 8 forelimbs had complex-2 syndactyly. Four hind limbs had simple syndactyly, 1 hind limb had complex-1 syndactyly, and 5 hind limbs had complex-2 syndactyly. Kinetic and temporospatial values and symmetry indices did not differ between groups. Plantar and palmar surfaces of healthy pigs had 2 areas of maximum pressure, whereas plantar and palmar surfaces of pigs with syndactyly had only 1 area of maximum pressure. CONCLUSIONS AND CLINICAL RELEVANCE In this population of pigs, the most common type of syndactyly was complex-2, and comparison with the healthy group revealed no alteration in kinetic and temporospatial variables. Therefore, results suggested that syndactyly in young minipigs did not cause locomotor disturbances.
Topics: Animals; Body Weight; Extremities; Foot; Gait; Kinetics; Radiography; Swine; Swine Diseases; Swine, Miniature; Syndactyly; Tomography, X-Ray Computed; Walking
PubMed: 27580109
DOI: 10.2460/ajvr.77.9.976 -
Nature Apr 2024Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is...
Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.
Topics: Animals; Female; Humans; Male; Mice; Alternative Splicing; Autistic Disorder; Calcium; Calcium Channels, L-Type; Cell Movement; Dendrites; Exons; Long QT Syndrome; Neurons; Oligonucleotides, Antisense; Organoids; Prosencephalon; Syndactyly; Interneurons
PubMed: 38658687
DOI: 10.1038/s41586-024-07310-6 -
The Pan African Medical Journal 2015
Topics: Abnormalities, Multiple; Child, Preschool; Humans; Male; Poland Syndrome
PubMed: 26889305
DOI: 10.11604/pamj.2015.22.124.7972 -
Pflugers Archiv : European Journal of... Jul 2020Cav1.2 L-type calcium channels play key roles in long-term synaptic plasticity, sensory transduction, muscle contraction, and hormone release. De novo mutations in the... (Review)
Review
Cav1.2 L-type calcium channels play key roles in long-term synaptic plasticity, sensory transduction, muscle contraction, and hormone release. De novo mutations in the gene encoding Cav1.2 (CACNA1C) causes two forms of Timothy syndrome (TS1, TS2), characterized by a multisystem disorder inclusive of cardiac arrhythmias, long QT, autism, and adrenal gland dysfunction. In both TS1 and TS2, the missense mutation G406R is on the alternatively spliced exon 8 and 8A coding for the IS6-helix of Cav1.2 and is responsible for the penetrant form of autism in most TS individuals. The mutation causes specific gain-of-function changes to Cav1.2 channel gating: a "leftward shift" of voltage-dependent activation, reduced voltage-dependent inactivation, and a "leftward shift" of steady-state inactivation. How this occurs and how Cav1.2 gating changes alter neuronal firing and synaptic plasticity is still largely unexplained. Trying to better understanding the molecular basis of Cav1.2 gating dysfunctions leading to autism, here, we will present and discuss the properties of recently reported typical and atypical TS phenotypes and the effective gating changes exhibited by missense mutations associated with long QTs without extracardiac symptoms, unrelated to TS. We will also discuss new emerging views achieved from using iPSCs-derived neurons and the newly available autistic TS2-neo mouse model, both appearing promising for understanding neuronal mistuning in autistic TS patients. We will also analyze and describe recent proposals of molecular pathways that might explain mistuned Ca-mediated and Ca-independent excitation-transcription signals to the nucleus. Briefly, we will also discuss possible pharmacological approaches to treat autism associated with L-type channelopathies.
Topics: Animals; Autistic Disorder; Calcium Channels, L-Type; Channelopathies; Humans; Long QT Syndrome; Mutation, Missense; Syndactyly
PubMed: 32621084
DOI: 10.1007/s00424-020-02430-0 -
Hand (New York, N.Y.) Sep 2020Being one of the most common congenital hand malformations, syndactyly is repaired by orthopedic, plastic, and fellowship-trained general surgeons. Limited... (Review)
Review
Being one of the most common congenital hand malformations, syndactyly is repaired by orthopedic, plastic, and fellowship-trained general surgeons. Limited multi-institutional outcomes analyses regarding incidence, timing, and type of repair exist. All syndactyly cases performed over a 5-year period from 2012-2016 were isolated from the National Surgical Quality Improvement Program Pediatric database. Patient demographics, surgical factors, perioperative outcomes, and risk factors were analyzed using χ, Fisher exact, and -test analysis. A total of 956 patients who underwent syndactyly repair were identified. Most cases were simple syndactyly with nearly even case distribution among plastic and orthopedic surgeons. Most patients were men and Caucasian. Mean age at the time of surgery was 2.6 years. Most cases were performed as outpatient surgery. Patients of plastic surgeons had significantly more airway abnormalities and shorter operative times. Patients with complex syndactyly had significantly more ventilator dependence, tracheostomy, and comorbidities when compared with those with simple syndactyly. Cases with complex syndactyly also had longer operative times and a higher rate of superficial surgical site infections. Syndactyly repair is a safe procedure with few major or minor reconstructive complications regardless of the surgical specialty or syndactyly type. Patients with complex syndactyly have significantly more preoperative comorbidities with comparable outcomes. orthopedic surgeons have significantly longer operative times than plastic surgeons, likely due to caring for increased number of patients with complex syndactyly.
Topics: Child; Humans; Male; Quality Improvement; Plastic Surgery Procedures; Risk Factors; Surgeons; Syndactyly
PubMed: 30770023
DOI: 10.1177/1558944719828003 -
FEBS Letters Apr 2014There are now at least 14 distinct diseases linked to germ line mutations in the 21 genes that encode the connexin (Cx) family of gap junction proteins. This review... (Review)
Review
There are now at least 14 distinct diseases linked to germ line mutations in the 21 genes that encode the connexin (Cx) family of gap junction proteins. This review focuses on the links between germ-line mutations in the gene encoding Cx43 (GJA1) and the human disease termed oculodentodigital dysplasia (ODDD). This disease is clinically characterized by soft tissue fusion of the digits, abnormal craniofacial bone development, small eyes and loss of tooth enamel. However, the disease is considerably more complex and somewhat degenerative as patients often suffer from other syndromic effects that include incontinence, glaucoma, skin diseases and neuropathies that become more pronounced during aging. The challenge continues to be understanding how distinct Cx43 gene mutations cause such a diverse range of tissue phenotypes and pathophysiological changes while other Cx43-rich organs are relatively unaffected. This review will provide an overview of many of these studies and distill some themes and outstanding questions that need to be addressed in the coming years.
Topics: Animals; Connexin 43; Craniofacial Abnormalities; Eye Abnormalities; Foot Deformities, Congenital; Gap Junctions; Germ-Line Mutation; Humans; Phenotype; Syndactyly; Tooth Abnormalities
PubMed: 24434540
DOI: 10.1016/j.febslet.2013.12.022 -
BioMed Research International 2019Embryology of normal web space creation and the genetics of syndactyly in humans and experimental animals are well described in the literature. In this review, the... (Review)
Review
Embryology of normal web space creation and the genetics of syndactyly in humans and experimental animals are well described in the literature. In this review, the author offers a 3-step pathway of pathogenesis for syndactyly. The first step is initiated either by the overactivation of the WNT canonical pathway or the suppression of the Bone Morphogenetic Protein (BMP) canonical pathway. This leads to an overexpression of Fibroblast Growth Factor 8 (FGF8). The final step is the suppression of retinoic acid in the interdigital mesenchyme leading to suppression of both apoptosis and extracellular matrix (ECM) degradation, resulting in syndactyly.
Topics: Animals; Apoptosis; Bone Morphogenetic Proteins; Extracellular Matrix; Fibroblast Growth Factor 8; Humans; Mesoderm; Models, Animal; Syndactyly; Tretinoin; Wnt Signaling Pathway
PubMed: 31637260
DOI: 10.1155/2019/9652649 -
The Ulster Medical Journal Jan 2021Syndactyly is a common congenital condition that can present sporadically or in relation to an underlying genetic condition. Little contemporary published data exists... (Review)
Review
BACKGROUND
Syndactyly is a common congenital condition that can present sporadically or in relation to an underlying genetic condition. Little contemporary published data exists detailing specific rates of presentation and surgical intervention, especially in Western European population. This is the first published review of operative intervention rates for the condition over time in Northern Ireland.
METHODS
A ten-year retrospective review of electronic operative records from January 2007 - October 2017 was carried out within Northern Ireland's regional tertiary centre Royal Belfast Hospital for Sick Children (RBHSC). All congenital hand surgery in the country was performed here during the period reviewed, by a single surgeon. Patient age at surgical intervention, their sex, digits involved and clinical grade of syndactyly was recorded.
RESULTS
One hundred and twenty four cases were returned following the review. On individual analysis 22 cases were excluded as they were not primary congenital syndactyly. The remaining 102 cases were all Caucasian. Six cases were toe syndactyly while 96 cases involved the upper limb digits. The group consisted of 70 males and 32 female infants. Age range at time of surgical intervention was 8 months to 14 years with a median age of 26 months. For clinical grade of upper limb syndactyly; 35 cases in the data set were classed as simple incomplete, 34 cases as simple complete, 17 as complex and 5 cases as complicated syndactyly. The remaining 5 cases lacked clear documentation. The most common site of syndactyly was between the ring and middle finger (40/102). Annual frequency of operative intervention has trended upwards in the period studied.
CONCLUSION
This case review adds epidemiological data on the operative incidence of syndactyly cases in Northern Ireland - a relatively isolated genetic population. Overall rates of incidence have increased over the past 10 years. It remains unclear if this is due to new environmental influences on the developing population or increased referral for surgical intervention over time..
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Incidence; Infant; Male; Northern Ireland; Patient Acuity; Retrospective Studies; Surgical Procedures, Operative; Syndactyly
PubMed: 33642625
DOI: No ID Found -
Frontiers in Endocrinology 2020Current genetic studies of monogenic and complex bone diseases have broadened our understanding of disease pathophysiology, highlighting the need for medical... (Review)
Review
Current genetic studies of monogenic and complex bone diseases have broadened our understanding of disease pathophysiology, highlighting the need for medical interventions and treatments tailored to the characteristics of patients. As genomic research progresses, novel insights into the molecular mechanisms are starting to provide support to clinical decision-making; now offering ample opportunities for disease screening, diagnosis, prognosis and treatment. Drug targets holding mechanisms with genetic support are more likely to be successful. Therefore, implementing genetic information to the drug development process and a molecular redefinition of skeletal disease can help overcoming current shortcomings in pharmaceutical research, including failed attempts and appalling costs. This review summarizes the achievements of genetic studies in the bone field and their application to clinical care, illustrating the imminent advent of the genomic medicine era.
Topics: Bone Diseases, Developmental; Drug Discovery; Gene Editing; Humans; Hyperostosis; Mendelian Randomization Analysis; Osteochondrodysplasias; Osteogenesis Imperfecta; Osteopetrosis; Osteoporosis; Syndactyly
PubMed: 33162933
DOI: 10.3389/fendo.2020.556610 -
Journal of Medical Genetics May 1994
Review
Topics: Acrocephalosyndactylia; Chromosomes, Human, Pair 7; Diagnosis, Differential; Humans; Syndrome
PubMed: 8064818
DOI: 10.1136/jmg.31.5.393