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European Journal of Medical Genetics Apr 2024Lenz-Majewski hyperostotic dwarfism (LMHD) is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, dysmorphic facial features,...
Lenz-Majewski hyperostotic dwarfism (LMHD) is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, dysmorphic facial features, brachydactyly, symphalangism and cutis laxa. Nineteen cases have been reported in the literature so far, eleven of them with PTDSS1 mutations. Although studies have had clinically similar findings, in some cases the authors have reported even rarer features such as hydrocephalus, facial paralysis, and cleft palate. We, hereby, report the case of the first patient with Lenz-Majewski syndrome (LMS) with molecular confirmation from Turkey. Although our patient had characteristic features described in the literature, she also had immunodeficiency, which has not been reported before. Although there is no established phenotype-genotype correlation, molecular mechanisms can be explained with the reporting of more patients.
Topics: Female; Humans; Intellectual Disability; Short Rib-Polydactyly Syndrome; Bone Diseases, Developmental; Otitis Media; Abnormalities, Multiple
PubMed: 38262577
DOI: 10.1016/j.ejmg.2024.104910 -
Journal of Lipid Research Nov 2023Phosphatidylserine (PS) is an acidic phospholipid that is involved in various cellular events. Heterologous dominant mutations have been identified in the gene encoding...
Phosphatidylserine (PS) is an acidic phospholipid that is involved in various cellular events. Heterologous dominant mutations have been identified in the gene encoding PS synthase 1 (PSS1) in patients with a congenital disease called Lenz-Majewski syndrome (LMS). Patients with LMS show various symptoms, including craniofacial/distal-limb bone dysplasia and progressive hyperostosis. The LMS-causing gain-of-function mutants of PSS1 (PSS1) have been shown to synthesize PS without control, but why the uncontrolled synthesis would lead to LMS is unknown. Here we investigated the effect of PSS1 on osteoclasts (OCs) to elucidate the causative mechanism of LMS. PSS1 did not affect the expression of OC-related genes but inhibited the formation, multinucleation, and activity of OCs. Especially, OCs expressing PSS1 showed abnormal patterns and dynamics of actin podosome clusters, which have roles in OC migration and fusion. PSS1 did not affect the level of PS but changed the acyl chain compositions of PS and phosphatidylethanolamine, and decreased the level of phosphatidylinositol. The introduction of a catalytically inactive mutation into PSS canceled the changes in phospholipids and the phenotypes observed in OCs expressing PSS1. A gain-of-function mutant of PSS2 (PSS2 R97K) also impaired OC formation and caused changes in phospholipid composition similar to the changes caused by PSS1. Our results suggest that uncontrolled PS synthesis by PSS1 causes changes in the quantity or fatty acid composition of certain phospholipid classes, impairing OC formation and function, which might be a cause of osteosclerosis in patients with LMS.
Topics: Humans; Abnormalities, Multiple; Intellectual Disability; Osteoclasts; Phospholipids
PubMed: 37714410
DOI: 10.1016/j.jlr.2023.100443 -
BMC Medical Genomics Dec 2023Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal...
BACKGROUND
Short-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias.
METHODS
Systemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues.
RESULTS
The major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively.
CONCLUSION
Our findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.
Topics: Pregnancy; Female; Humans; DNA Copy Number Variations; Ellis-Van Creveld Syndrome; Prenatal Diagnosis; Osteochondrodysplasias; Polydactyly; Ciliopathies; Cytoskeletal Proteins; Adaptor Proteins, Signal Transducing
PubMed: 38062428
DOI: 10.1186/s12920-023-01753-y -
Journal of Clinical Medicine Oct 2023Electrolyte disturbances related to sodium and potassium affect patients with mental disorders undergoing electroconvulsive therapy (ECT). The objective of this study... (Review)
Review
INTRODUCTION
Electrolyte disturbances related to sodium and potassium affect patients with mental disorders undergoing electroconvulsive therapy (ECT). The objective of this study was to systematically summarize the data regarding ECT and electrolyte disturbances related to sodium and potassium.
MATERIALS AND METHODS
A systematic literature review in accordance with PRISMA guidelines was conducted. Clinical studies of patients receiving ECT with electrolyte disturbances reported before or after treatment were included.
RESULTS
We identified nine case reports and two retrospective studies describing electrolyte abnormalities occurring before or after ECT. ECT was effective and safe in patients with hyponatremia and hypernatremia, including the elderly patient population. This treatment was also effective in treating psychiatric symptoms that may persist after ionic equalization. Electrolyte disturbances after ECT were rare. Reports have suggested that succinylcholine used as a muscle relaxant was the main cause of hyperkalemia after ECT.
CONCLUSIONS
Electrolyte control is a crucial aspect of guiding ECT therapy. In the context of sodium-related disorders, it is critical to control patient hydration as part of therapy. In addition, succinylcholine should not be used in patients with immobilization, such as catatonia or neuroleptic malignant syndrome. It is necessary to conduct further studies to clarify whether electrolyte concentration affects ECT parameters and clinical efficacy. In addition, it is necessary to assess the influence of various anesthetics on these conditions during ECT. The result of this review should be interpreted bearing in mind the small number of studies conducted to date and the low quality of the evidence they provide.
PubMed: 37892815
DOI: 10.3390/jcm12206677 -
The Journal of Maternal-fetal &... Dec 2023Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias...
Early prenatal diagnosis of a recurrent case of short-rib thoracic dysplasia 3 due to compound heterozygosity for variations in the DYNC2H1 gene: an "ultrasound first" approach.
Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias associated with homozygous or compound heterozygous mutations of DYNC2H1. We describe the case of a couple with two consecutive therapeutic abortions due to a diagnosis of short-rib thoracic dysplasia mutations. In the first pregnancy, the diagnosis has been made at 21 weeks. In the second one, an accurate and early ultrasound examination allowed a diagnosis at 12 weeks. DYNC2H1 mutations were confirmed in both cases. In this report, we underline the importance of an ultrasound evaluation at the end of the first trimester of pregnancy in the detection of early signs of skeletal dysplasias. An early prenatal diagnosis of a short-rib skeletal dysplasia, such as for other severe skeletal dysplasias, is critical to offer a couple the chance of a weighted, informed, and less traumatic decision about the continuation of the pregnancy.
Topics: Pregnancy; Female; Humans; Short Rib-Polydactyly Syndrome; Prenatal Diagnosis; Ultrasonography; Osteochondrodysplasias; Ribs; Ultrasonography, Prenatal; Cytoplasmic Dyneins
PubMed: 37100787
DOI: 10.1080/14767058.2023.2205985 -
Nucleic Acids Research Dec 2023Molnupiravir (EIDD-2801) is an antiviral that received approval for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Treatment of...
Molnupiravir (EIDD-2801) is an antiviral that received approval for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. Treatment of bacteria or cell lines with the active form of molnupiravir, β-d-N4-hydroxycytidine (NHC, or EIDD-1931), induces mutations in DNA. Yet these results contrast in vivo genotoxicity studies conducted during registration of the drug. Using a CRISPR screen, we found that inactivating the pyrimidine salvage pathway component uridine-cytidine kinase 2 (Uck2) renders cells more tolerant of NHC. Short-term exposure to NHC increased the mutation rate in a mouse myeloid cell line, with most mutations being T:A to C:G transitions. Inactivating Uck2 impaired the mutagenic activity of NHC, whereas over-expression of Uck2 enhanced mutagenesis. UCK2 is upregulated in many cancers and cell lines. Our results suggest differences in ribonucleoside metabolism contribute to the variable mutagenicity of NHC observed in cancer cell lines and primary tissues.
Topics: Animals; Mice; Antiviral Agents; Cytidine; Mutagenesis; Mutagens; RNA, Viral; Uridine Kinase
PubMed: 37953355
DOI: 10.1093/nar/gkad1002