ABSTRACT
BACKGROUND: Joubert syndrome and related disorders (JSRD) and Jeune syndrome are multisystem ciliopathy disorders with overlapping phenotypes. There are a growing number of genetic causes for these rare syndromes, including the recently described genes ARL3 and CEP120. METHODS: We sought to explore the developmental expression patterns of ARL3 and CEP120 in humans to gain additional understanding of these genetic conditions. We used an RNA in situ detection technique called RNAscope to characterise ARL3 and CEP120 expression patterns in human embryos and foetuses in collaboration with the MRC-Wellcome Trust Human Developmental Biology Resource. RESULTS: Both ARL3 and CEP120 are expressed in early human brain development, including the cerebellum and in the developing retina and kidney, consistent with the clinical phenotypes seen with pathogenic variants in these genes. CONCLUSIONS: This study provides insights into the potential pathogenesis of JSRD by uncovering the spatial expression of two JSRD-causative genes during normal human development.
Subject(s)
ADP-Ribosylation Factors/genetics , Cell Cycle Proteins/genetics , Ciliopathies/genetics , Gene Expression Regulation, Developmental , ADP-Ribosylation Factors/metabolism , Brain/growth & development , Brain/metabolism , Cell Cycle Proteins/metabolism , Ciliopathies/pathology , Ciliopathies/physiopathology , Ganglia, Spinal/growth & development , Ganglia, Spinal/metabolism , Humans , Kidney/growth & development , Kidney/metabolism , Mutation , Phenotype , Retina/growth & development , Retina/metabolismABSTRACT
Nephronophthisis-related ciliopathies (NPHP-RC) are a group of inherited genetic disorders that share a defect in the formation, maintenance or functioning of the primary cilium complex, causing progressive cystic kidney disease and other clinical manifestations. Mutations in centrosomal protein 164 kDa (CEP164), also known as NPHP15, have been identified as a cause of NPHP-RC. Here we have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR) to perform immunohistochemistry studies on human embryonic and foetal tissues to determine the expression patterns of CEP164 during development. Notably expression is widespread, yet defined, in multiple organs including the kidney, retina and cerebellum. Murine studies demonstrated an almost identical Cep164 expression pattern. Taken together, these data support a conserved role for CEP164 throughout the development of numerous organs, which, we suggest, accounts for the multi-system disease phenotype of CEP164-mediated NPHP-RC.
Subject(s)
Cilia/genetics , Ciliopathies/genetics , Kidney Diseases, Cystic/genetics , Microtubule Proteins/genetics , Animals , Cilia/pathology , Ciliopathies/pathology , Disease Models, Animal , Fetus/metabolism , Gene Expression Regulation, Developmental/genetics , Humans , Kidney/metabolism , Kidney/pathology , Kidney Diseases, Cystic/pathology , Mice , Retina/metabolism , Retina/pathologyABSTRACT
This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.
Subject(s)
Immunologic Deficiency Syndromes , Internet , Registries , Female , Humans , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/therapy , Male , United Kingdom/epidemiologyABSTRACT
Baclofen is a gamma-aminobutyric acid agonist used primarily as a muscle relaxant to treat spasticity in children and adults. Withdrawal of oral baclofen is known to cause a withdrawal syndrome in adults. Only one previous case describes a withdrawal syndrome in a term infant, manifested by seizures, associated with the use of oral baclofen in the mother. This case describes a withdrawal syndrome and the unique use of baclofen for withdrawal in a preterm infant.
Subject(s)
Baclofen , Cervical Vertebrae/injuries , Neonatal Abstinence Syndrome , Paraplegia , Pregnancy Complications/drug therapy , Spinal Fractures/complications , Adult , Baclofen/administration & dosage , Baclofen/adverse effects , Cesarean Section/methods , Dose-Response Relationship, Drug , Female , Humans , Infant, Newborn , Infant, Premature , Muscle Relaxants, Central/administration & dosage , Muscle Relaxants, Central/adverse effects , Neonatal Abstinence Syndrome/drug therapy , Neonatal Abstinence Syndrome/etiology , Neonatal Abstinence Syndrome/physiopathology , Paraplegia/drug therapy , Paraplegia/etiology , Pregnancy , Prenatal Exposure Delayed Effects , Treatment OutcomeABSTRACT
BACKGROUND: Primary immune deficiencies of natural killer (NK) cells have been described in patients with a susceptibility to herpes infections. AIMS: To assess the diagnostic utility of measurement of NK cytotoxicity in patients with recurrent oral herpes infections. METHODS: A retrospective audit was carried out on results obtained over an 18-month period, from 28 NK cell cytotoxicity assays (24 patients; all with a history of recurrent oral herpes infections), and 24 control samples (three healthy donors). Percentage specific cytotoxicity (PSC) was determined by measurement of the percentage of K562 target cells lysed by NK cells after incubation, using the NK TEST. Comparison of PSC was made with reference ranges provided. RESULTS: No patient with absent NK/NKT cells or NK cell cytotoxicity was identified (95% CI 0 to 14.8%). Two patients had persistently low PSC. Two patients with reduced PSC showed PSC within the normal reference range on repeat testing. Patient and control samples were seen both above and below the reference ranges. A relationship was expected between NK cell percentage and PSC; however this correlation was not significant (r(s)=0.29, p=0.18, 95% CI -0.14 to 0.63). CONCLUSIONS: A deficiency of NK cell cytotoxicity has not been identified in this cohort. An apparent reduction in cytotoxicity may be due to normal interpersonal and intersample variability in NK cytotoxicity. Without reference ranges established from a large population of control samples to account for this, a reduction in PSC is difficult to define. Further studies are required to identify if a correlation exists between the percentage of NK cells and PSC.
