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Seminars in Neurology Jun 2015Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been... (Review)
Review
Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been classified into neuropathological subtypes (type Ia, Ib, IIa, IIb, and III) based on the severity of cytoarchitectural disruption--tangential or radial dispersion, or loss of laminar structure--and the presence of unique cells types such as cytomegalic neurons or balloon cells. Most focal cortical dysplasias can be identified on neuroimaging and many require resective epilepsy surgery to cure refractory seizures. The pathogenesis of focal cortical dysplasias remains to be defined, although there is recent evidence to suggest that focal cortical dysplasias arise from de novo somatic mutations occurring during brain development. Some focal cortical dysplasia subtypes show a link to the mammalian target of rapamycin signaling cascade; this has now extended to other cortical malformations, including hemimegalencephaly.
Topics: Animals; Drug Resistant Epilepsy; Humans; Malformations of Cortical Development; Neuroimaging; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 26060899
DOI: 10.1055/s-0035-1552617 -
Nutrients Mar 2015Sulphate is an obligate nutrient for healthy growth and development. Sulphate conjugation (sulphonation) of proteoglycans maintains the structure and function of... (Review)
Review
Sulphate is an obligate nutrient for healthy growth and development. Sulphate conjugation (sulphonation) of proteoglycans maintains the structure and function of tissues. Sulphonation also regulates the bioactivity of steroids, thyroid hormone, bile acids, catecholamines and cholecystokinin, and detoxifies certain xenobiotics and pharmacological drugs. In adults and children, sulphate is obtained from the diet and from the intracellular metabolism of sulphur-containing amino acids. Dietary sulphate intake can vary greatly and is dependent on the type of food consumed and source of drinking water. Once ingested, sulphate is absorbed into circulation where its level is maintained at approximately 300 μmol/L, making sulphate the fourth most abundant anion in plasma. In pregnant women, circulating sulphate concentrations increase by twofold with levels peaking in late gestation. This increased sulphataemia, which is mediated by up-regulation of sulphate reabsorption in the maternal kidneys, provides a reservoir of sulphate to meet the gestational needs of the developing foetus. The foetus has negligible capacity to generate sulphate and thereby, is completely reliant on sulphate supply from the maternal circulation. Maternal hyposulphataemia leads to foetal sulphate deficiency and late gestational foetal death in mice. In humans, reduced sulphonation capacity has been linked to skeletal dysplasias, ranging from the mildest form, multiple epiphyseal dysplasia, to achondrogenesis Type IB, which results in severe skeletal underdevelopment and death in utero or shortly after birth. Despite being essential for numerous cellular and metabolic functions, the nutrient sulphate is largely unappreciated in clinical settings. This article will review the physiological roles and regulation of sulphate during pregnancy, with a particular focus on animal models of disturbed sulphate homeostasis and links to human pathophysiology.
Topics: Amino Acids, Sulfur; Animals; Deficiency Diseases; Diet; Female; Fetal Development; Humans; Pregnancy; Pregnancy Complications; Prenatal Nutritional Physiological Phenomena; Sulfates
PubMed: 25746011
DOI: 10.3390/nu7031594 -
Diagnostics (Basel, Switzerland) Sep 2023This paper presents a rare case of fetal hydrops detected at just 23 weeks of gestation in a 22-year-old woman's first pregnancy. The fetal ultrasound revealed severe...
This paper presents a rare case of fetal hydrops detected at just 23 weeks of gestation in a 22-year-old woman's first pregnancy. The fetal ultrasound revealed severe skeletal anomalies, craniofacial deformities, and thoracic abnormalities, suggesting a complex and severe skeletal dysplasia, potentially type IA Achondrogenesis-a lethal autosomal recessive condition marked by ossification delay. This case highlights the significance of advanced genetic testing, such as next-generation sequencing (NGS) and whole-genome sequencing (WGS), in diagnosing and understanding skeletal dysplasias. Skeletal dysplasias represent a group of genetic disorders that affect osteogenesis. The prevalence of this condition is 1 in 4000 births. Sadly, 25% of affected infants are stillborn, and around 30% do not survive the neonatal period. There is a wide range of rare skeletal dysplasias, each with its own specific recurrence risk, dysmorphic expression, and implications for neonatal survival and quality of life. When skeletal dysplasia is incidentally discovered during routine ultrasound screening in a pregnancy not known to be at risk of a specific syndrome, a systematic examination of the limbs, head, thorax, and spine is necessary to reach the correct diagnosis. Prenatal diagnosis of skeletal dysplasia is crucial for providing accurate counselling to future parents and facilitating the proper management of affected pregnancies. An accurate diagnosis can be a real challenge due to the wide spectrum of clinical presentations of skeletal dysplasia but advances in imaging technologies and molecular genetics have improved accuracy. Additionally, some of these skeletal dysplasias may present clinical overlap, making it especially difficult to distinguish. After the 11th revision of genetic skeletal disorder nosology, there are 771 entities associated with 552 gene mutations. The most common types of skeletal dysplasia are thanatophoric dysplasia, osteogenesis imperfect, achondroplasia, achondrogenesis, and asphyxiating thoracic dystrophy.
PubMed: 37761271
DOI: 10.3390/diagnostics13182905 -
Molecular Genetics and Metabolism Feb 2015Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation,... (Review)
Review
Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs.
Topics: Animals; Anti-Inflammatory Agents; Bone Diseases; Bone and Bones; Chondrocytes; Disease Progression; Enzyme Replacement Therapy; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Mucopolysaccharidoses
PubMed: 25537451
DOI: 10.1016/j.ymgme.2014.12.001 -
Developmental Dynamics : An Official... Apr 2022Primary cilia are dynamic compartments that regulate multiple aspects of cellular signaling. The production, maintenance, and function of cilia involve more than 1000... (Review)
Review
Primary cilia are dynamic compartments that regulate multiple aspects of cellular signaling. The production, maintenance, and function of cilia involve more than 1000 genes in mammals, and their mutations disrupt the ciliary signaling which manifests in a plethora of pathological conditions-the ciliopathies. Skeletal ciliopathies are genetic disorders affecting the development and homeostasis of the skeleton, and encompass a broad spectrum of pathologies ranging from isolated polydactyly to lethal syndromic dysplasias. The recent advances in forward genetics allowed for the identification of novel regulators of skeletogenesis, and revealed a growing list of ciliary proteins that are critical for signaling pathways implicated in bone physiology. Among these, a group of protein kinases involved in cilia assembly, maintenance, signaling, and disassembly has emerged. In this review, we summarize the functions of cilia kinases in skeletal development and disease, and discuss the available and upcoming treatment options.
Topics: Animals; Cilia; Ciliopathies; Homeostasis; Mammals; Polydactyly; Proteins
PubMed: 34582081
DOI: 10.1002/dvdy.426 -
American Journal of Medical Genetics.... Dec 2020Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive... (Review)
Review
Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive character. In this article, we review the state of clinical and research SD resources available in Latin America, including three specific countries (Brazil, Argentina, and Chile), that have established multidisciplinary clinics for the care of these patients. From the epidemiological point of view, the SD prevalence of 3.2 per 10,000 births from nine South American countries included in the ECLAMC network represents the most accurate estimate not just in Latin America, but worldwide. In Brazil, there are currently five groups focused on SD. The data from one of these groups including the website www.ocd.med.br, created to assist in the diagnosis of SD, are highlighted showing that telemedicine for this purpose represents a good strategy for the region. The experience of more than 30 years of the SD multidisciplinary clinic in an Argentinian Hospital is presented, evidencing a solid experience mainly in the follow-up of the most frequent SD, especially those belonging the FGFR3 group and OI. In Chile, a group with 20 years of experience presents its work with geneticists and pediatricians, focusing on diagnostic purposes and clinical management. Altogether, although SD health-care and research activities in Latin America are in their early stages, the experience in these three countries seems promising and stimulating for the region as a whole.
Topics: Argentina; Bone and Bones; Humans; Latin America; Osteochondrodysplasias; Prevalence
PubMed: 33219737
DOI: 10.1002/ajmg.c.31861 -
Clinics in Perinatology Jun 2015The skeletal dysplasias are a group of more than 450 heritable disorders of bone. They frequently present in the newborn period with disproportion, radiographic... (Review)
Review
The skeletal dysplasias are a group of more than 450 heritable disorders of bone. They frequently present in the newborn period with disproportion, radiographic abnormalities, and occasionally other organ system abnormalities. For improved clinical care, it is important to determine a precise diagnosis to aid in management, familial recurrence, and identify those disorders highly associated with mortality. Long-term management of these disorders is predicated on an understanding of the associated skeletal system abnormalities, and these children are best served by a team approach to health care surveillance.
Topics: Bone Diseases, Developmental; Genetic Testing; Global Health; Humans; Infant, Newborn; Morbidity
PubMed: 26042906
DOI: 10.1016/j.clp.2015.03.003 -
Annual Review of Genomics and Human... 2015Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately... (Review)
Review
Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately 1/5,000 births, and some are lethal. Since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders, genetic causes of 56 skeletal disorders have been uncovered. This remarkable rate of discovery is largely due to the expanded use of high-throughput genomic technologies. In this review, we discuss these recent discoveries and our understanding of the molecular mechanisms behind these skeletal dysplasia phenotypes. We also cover potential therapies, unusual genetic mechanisms, and novel skeletal syndromes both with and without known genetic causes. The acceleration of skeletal dysplasia genetics is truly spectacular, and these advances hold great promise for diagnostics, risk prediction, and therapeutic design.
Topics: Animals; Body Height; Bone Diseases, Developmental; Disease Models, Animal; Dwarfism; Epigenesis, Genetic; High-Throughput Nucleotide Sequencing; Histone Acetyltransferases; Humans; Mice; MicroRNAs; Mutation; Osteochondrodysplasias; Proteus Syndrome
PubMed: 25939055
DOI: 10.1146/annurev-genom-090314-045904 -
AACE Clinical Case Reports 2020To present a case of pyknodysostosis (PKND), a rare genetic cause of skeletal dysplasia that often goes undiagnosed even in patients with classic features.
OBJECTIVE
To present a case of pyknodysostosis (PKND), a rare genetic cause of skeletal dysplasia that often goes undiagnosed even in patients with classic features.
METHODS
We report a case of PKND that went undiagnosed over many years despite classic features. We performed physical examination, imaging studies, and genetic testing on the patient.
RESULTS
A 21-year-old female presented to endocrinology to establish care. On evaluation, she was noted to have disproportionate short stature and a past medical history notable for bilateral blindness due to optic atrophy secondary to bone enlargement and thickening of the optic nerve canal before age 7 years. She also had a history of foot fractures occurring with ambulation. Her family history was significant for consanguineous parents and relatives with similar clinical features. Physical examination revealed a short, 128-cm tall female with open anterior and mastoid fontanels, mild frontal bossing and micrognathia, evidence of double rows of teeth, and digits of varied length in both hands and feet. Plain radiographs demonstrated diffuse sclerosis and marked cortical thickening of the pelvis, femurs, metacarpals, proximal phalanges, and metatarsals as well as decreased phalangeal length and acro-osteolysis of the hands and feet. Dual energy X-ray absorptiometry demonstrated increased bone mineral density ( scores +2.5 lumbar spine, +3.7 femoral neck, +4.5 total hip). Genetic testing revealed a exon 5-homozygous mutation in the cathepsin K () gene consistent with PKND.
CONCLUSION
Patients with PKND come to medical attention for a variety of reasons but often go undiagnosed even when presenting with classic features due to the rarity of the condition and the overlap with other skeletal dysplasias.
PubMed: 32984533
DOI: 10.4158/ACCR-2020-0169