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Journal of Sleep Research Aug 2022Sleepwalking is a common non-rapid eye movement (NREM) parasomnia and a significant cause of sleep-related injuries. While evidence suggest that the occurrence of this...
Sleepwalking is a common non-rapid eye movement (NREM) parasomnia and a significant cause of sleep-related injuries. While evidence suggest that the occurrence of this condition is partly determined by genetic factors, its pattern of inheritance remains unclear, and few molecular studies have been conducted. One promising candidate is the adenosine deaminase (ADA) gene. Adenosine and the ADA enzyme play an important role in the homeostatic regulation of NREM sleep. In a single sleepwalking family, genome-wide analysis identified a locus on chromosome 20, where ADA lies. In this study, we examined if variants in the ADA gene were associated with sleepwalking. In total, 251 sleepwalking patients were clinically assessed, and DNA samples were compared to those from 94 unaffected controls. Next-generation sequencing of the whole ADA gene was performed. Bio-informatic analysis enabled the identification of variants and assessed variants enrichment in our cohort compared to controls. We detected 25 different coding and non-coding variants, of which 22 were found among sleepwalkers. None were enriched in the sleepwalking population. However, many missense variants were predicted as likely pathogenic by at least two in silico prediction algorithms. This study involves the largest sleepwalking cohort in which the role of a susceptibility gene was investigated. Our results did not reveal an association between ADA gene and sleepwalking, thus ruling out the possibility of ADA as a major genetic factor for this condition. Future work is needed to identify susceptibility genes.
Topics: Adenosine Deaminase; Humans; Parasomnias; Sleep; Sleep, Slow-Wave; Somnambulism
PubMed: 34913218
DOI: 10.1111/jsr.13537 -
Seminars in Hematology Oct 1998Adenosine deaminase (ADA) deficiency is the first known cause of severe combined immunodeficiency disease (SCID). Over the past 25 years, the metabolic basis for immune... (Review)
Review
Adenosine deaminase (ADA) deficiency is the first known cause of severe combined immunodeficiency disease (SCID). Over the past 25 years, the metabolic basis for immune deficiency has largely been established. The clinical spectrum associated with ADA deficiency is now quite broad, including older children and adults. The ADA gene has been sequenced, the structure of the enzyme has been determined, and over 50 ADA gene mutations have been identified. There appears to be a quantitative relationship between residual ADA activity, determined by genotype, and both metabolic and clinical phenotype. ADA deficiency has become a focus for novel approaches to enzyme replacement and gene therapy. Enzyme replacement with polyethylene glycol (PEG)-modified ADA, used to treat patients who lack a human leukocyte antigen (HLA)-matched bone marrow donor, is safe and effective, but expensive. Several approaches to gene therapy have been investigated in patients receiving PEG-ADA. Persistent expression of transduced ADA cDNA in T lymphocytes and myeloid cells has occurred in a few patients, but significant improvement in immune function because of the transduced cells has not been shown. The major barrier to effective gene therapy remains the low efficiency of stem cell transduction with retroviral vectors.
Topics: Adenosine Deaminase; Genetic Therapy; Humans; Severe Combined Immunodeficiency
PubMed: 9801258
DOI: No ID Found -
Expert Opinion on Investigational Drugs Mar 2000In the past decade, the advent of gene therapy has been acclaimed as a revolutionary medical intervention, embraced with great enthusiasm. However, recent disappointing... (Review)
Review
In the past decade, the advent of gene therapy has been acclaimed as a revolutionary medical intervention, embraced with great enthusiasm. However, recent disappointing results of the considerable clinical trials have also clearly demonstrated that such an initial expectation was an overestimation of gene therapy. There are only a few successful cases despite the 3000 patients who have been treated with various forms of gene therapy. Gene therapy for severe combined immunodeficiency (SCID) caused by adenosine deaminase (ADA) deficiency is one of the few such cases where results have been promising. In particular, peripheral T-lymphocytes-directed gene therapy provides further immunological improvements for patients with ADA-SCID receiving the PEG-ADA treatment whereas gene therapy targeting haematopoietic stem cell has so far proved insufficient for clinical benefits. This report will review crucial problems elucidated in the past five clinical trials for ADA-SCID and gives an outline of the next generation of stem cell gene therapy in Japan.
Topics: Adenosine Deaminase; Animals; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Transfusion; Severe Combined Immunodeficiency; T-Lymphocytes
PubMed: 11060694
DOI: 10.1517/13543784.9.3.543 -
International Journal of Cardiology Jun 2016Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which... (Review)
Review
Purines perform many important functions in the cell, being the formation of the monomeric precursors of nucleic acids DNA and RNA the most relevant one. Purines which also contribute to modulate energy metabolism and signal transduction, are structural components of some coenzymes and have been shown to play important roles in the physiology of platelets, muscles and neurotransmission. All cells require a balanced quantity of purines for growth, proliferation and survival. Under physiological conditions the enzymes involved in the purine metabolism maintain in the cell a balanced ratio between their synthesis and degradation. In humans the final compound of purines catabolism is uric acid. All other mammals possess the enzyme uricase that converts uric acid to allantoin that is easily eliminated through urine. Overproduction of uric acid, generated from the metabolism of purines, has been proven to play emerging roles in human disease. In fact the increase of serum uric acid is inversely associated with disease severity and especially with cardiovascular disease states. This review describes the enzymatic pathways involved in the degradation of purines, getting into their structure and biochemistry until the uric acid formation.
Topics: 5'-Nucleotidase; Adenosine Deaminase; Cardiovascular Diseases; Humans; Metabolic Networks and Pathways; Purines; Uric Acid; Xanthine Dehydrogenase
PubMed: 26316329
DOI: 10.1016/j.ijcard.2015.08.109 -
Advances in Experimental Medicine and... 2003
Review
Topics: Adenosine Deaminase; Animals; Antineoplastic Agents; Asparaginase; Clinical Trials as Topic; Excipients; Humans; Neoplasms; Polyethylene Glycols
PubMed: 12675207
DOI: 10.1007/0-306-47932-X_3 -
Annals of the Rheumatic Diseases Feb 2022
Topics: Adenosine Deaminase; Biomarkers; Humans
PubMed: 32001434
DOI: 10.1136/annrheumdis-2020-217007 -
Current Opinion in Rheumatology Jan 2020To recap the expanding clinical spectrum, genotype-phenotype associations and treatment options in the light of recently published articles regarding the deficiency of... (Review)
Review
PURPOSE OF REVIEW
To recap the expanding clinical spectrum, genotype-phenotype associations and treatment options in the light of recently published articles regarding the deficiency of adenosine deaminase 2 (DADA2).
RECENT FINDINGS
Whole-exome sequencing enabled novel clinical phenotypes associated with ADA2 mutations. Since its discovery, the phenotypic spectrum of DADA2 has substantially expanded to cover Diamond-Blackfan anaemia, cytopenia and immunodeficiency syndromes. In addition to elevated TNF alpha levels, increased levels of interferon-stimulated genes were also detected in patients with DADA2. Given the absence of clinical trials until now, no standard treatment strategy exists for DADA2. Currently, anti-TNF alpha agents are the mainstay of treatment, based on the data both from the initial two reports and from subsequent studies. However, it is still unclear how to manage asymptomatic patients with ADA2 mutation and/or with absent ADA2 activity and what is the optimal duration of anti-TNF therapy.
SUMMARY
Among a total of 206 DADA2 patients described so far, the overall mortality was found as 8.3%. Biallelic homozygous G47R mutations were mostly associated with a vascular phenotype, whereas patients with homozygous R169Q mutations seem to display a mixed clinical phenotype including vascular, haematological and immunological manifestations. HSCT should be reserved as a curative treatment option for DADA2 patients unresponsive to the anti-TNF therapy, as it carries a significant morbidity.
Topics: Adenosine Deaminase; Genetic Association Studies; Humans; Immunologic Deficiency Syndromes; Mutation; Phenotype; Tumor Necrosis Factor-alpha; Vasculitis; Exome Sequencing
PubMed: 31599797
DOI: 10.1097/BOR.0000000000000669 -
The Journal of Allergy and Clinical... Mar 2019Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine... (Review)
Review
Inherited defects in adenosine deaminase (ADA) cause a subtype of severe combined immunodeficiency (SCID) known as severe combined immune deficiency caused by adenosine deaminase defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. We review the evidence currently available and propose a consensus management strategy. In addition to treatment of the immune deficiency seen in patients with ADA-SCID, patients should be followed for specific noninfectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal first-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) should be pursued. The excellent safety and efficacy observed in more than 100 patients with ADA-SCID who received gammaretrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT can be continued or reinstituted, and HSCT with alternative donors should be considered. The outcomes of novel HSCT, ERT, and HSC-GT strategies should be evaluated prospectively in "real-life" conditions to further inform these management guidelines.
Topics: Adenosine Deaminase; Agammaglobulinemia; Animals; Consensus; Enzyme Replacement Therapy; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Severe Combined Immunodeficiency
PubMed: 30194989
DOI: 10.1016/j.jaci.2018.08.024 -
Immunodeficiency 1994Adenosine deaminase (ADA) deficiency is an autosomal recessive disorder resulting in immunodeficiency. Since the cDNA for ADA was cloned approximately 10 years ago,... (Review)
Review
Adenosine deaminase (ADA) deficiency is an autosomal recessive disorder resulting in immunodeficiency. Since the cDNA for ADA was cloned approximately 10 years ago, investigators have determined the molecular basis for disease in many patients with ADA deficiency. Mutations that have been identified include point mutations causing amino acid substitutions, premature stop codons, RNA splicing errors, and deletion mutations. Approximately one third of patients are homozygous for their mutation; in some of these cases the parents are known to be related. One mutation, Ala329-Val, is the most common, being present in 8 of the 21 ADA-deficient SCID patients whose mutations have been reported.
Topics: Adenosine Deaminase; Amino Acid Sequence; Base Sequence; Cell Line; DNA Mutational Analysis; Humans; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; RNA, Messenger; Severe Combined Immunodeficiency
PubMed: 8032366
DOI: No ID Found -
Science (New York, N.Y.) Aug 2020Bacteria and archaea are frequently attacked by viruses and other mobile genetic elements and rely on dedicated antiviral defense systems, such as restriction...
Bacteria and archaea are frequently attacked by viruses and other mobile genetic elements and rely on dedicated antiviral defense systems, such as restriction endonucleases and CRISPR, to survive. The enormous diversity of viruses suggests that more types of defense systems exist than are currently known. By systematic defense gene prediction and heterologous reconstitution, here we discover 29 widespread antiviral gene cassettes, collectively present in 32% of all sequenced bacterial and archaeal genomes, that mediate protection against specific bacteriophages. These systems incorporate enzymatic activities not previously implicated in antiviral defense, including RNA editing and retron satellite DNA synthesis. In addition, we computationally predict a diverse set of other putative defense genes that remain to be characterized. These results highlight an immense array of molecular functions that microbes use against viruses.
Topics: Adenosine Deaminase; Archaea; Archaeal Proteins; Archaeal Viruses; Bacteria; Bacterial Proteins; Bacteriophages; CRISPR-Cas Systems; Genes, Archaeal; Genes, Bacterial; Protein Domains; RNA Editing
PubMed: 32855333
DOI: 10.1126/science.aba0372