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Frontiers in Immunology 2020Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous...
Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare combined immunodeficiency (CID) caused by recessive homozygous/compound heterozygous loss-of-function mutations in the gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Therefore, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. We searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. ZAP-70 deficient patients have been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%), and increased risk of malignancies (8.1%). The predominant immunologic phenotype was low CD8+ T cell counts (97.9%). Immunologic profiling showed defective antibody production (57%) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95%). Mutations of the gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51%) of the patients, 18 patients survived transplantation, while two patients died and three required a second transplant in order to achieve full remission. Newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT can lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients.
Topics: Autoimmunity; CD8-Positive T-Lymphocytes; Delayed Diagnosis; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Loss of Function Mutation; Lymphopenia; Male; Phenotype; Severe Combined Immunodeficiency; Treatment Outcome; ZAP-70 Protein-Tyrosine Kinase
PubMed: 32431715
DOI: 10.3389/fimmu.2020.00831 -
Journal of Gastroenterology and... Mar 2013The prevalence of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiencies in portal vein system thrombosis (PVST) and Budd-Chiari syndrome (BCS) are... (Meta-Analysis)
Meta-Analysis Review
Prevalence of inherited antithrombin, protein C, and protein S deficiencies in portal vein system thrombosis and Budd-Chiari syndrome: a systematic review and meta-analysis of observational studies.
BACKGROUND AND AIM
The prevalence of inherited antithrombin (AT), protein C (PC), and protein S (PS) deficiencies in portal vein system thrombosis (PVST) and Budd-Chiari syndrome (BCS) are substantially varied in different studies. No quantitative syntheses of these studies have been performed. A systematic review and meta-analysis were conducted to examine the prevalence of inherited AT, PC, and PS deficiencies in these patients and to compare the prevalence with healthy subjects.
METHODS
PubMed, EMBASE, and Cochrane Library databases were employed to identify all studies in which inherited AT, PC, and PS deficiencies in PVST and/or BCS were evaluated by family study or gene analysis. Prevalence and odds ratios of these inherited deficiencies were pooled; heterogeneity among studies was evaluated.
RESULTS
Nine studies were included in our meta-analysis. The pooled prevalence of inherited AT, PC, and PS deficiencies were 3.9%, 5.6%, and 2.6% in PVST, and 2.3%, 3.8%, and 3.0% in BCS, respectively. Heterogeneity among studies was not significant except for the analysis of inherited PC deficiency in BCS. Three studies compared the prevalence of these inherited deficiencies between PVST patients and healthy subjects. The pooled odds ratios of inherited AT, PC, and PS deficiencies for PVST patients were 8.89 (95% confidence interval [CI] 2.34-33.72, P = 0.0011), 17.63 (95% CI 1.97-158.21, P = 0.0032), and 8.00 (95% CI 1.61-39.86, P = 0.011), respectively. Only one study demonstrated that no inherited deficiency was found in both BCS patients and healthy subjects.
CONCLUSIONS
Inherited AT, PC, and PS deficiencies are rare in PVST and BCS. These inherited deficiencies increase the risk of PVST.
Topics: Antithrombin Proteins; Asia; Budd-Chiari Syndrome; Europe; Humans; Odds Ratio; Portal System; Prevalence; Protein C Deficiency; Protein S Deficiency; Thrombophilia; Venous Thrombosis
PubMed: 23216127
DOI: 10.1111/jgh.12085 -
European Journal of Pediatrics Apr 2015Serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are conventionally considered available for the diagnosis of growth... (Meta-Analysis)
Meta-Analysis Review
UNLABELLED
Serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) are conventionally considered available for the diagnosis of growth hormone deficiency (GHD), but the results about their diagnostic values are inconsistent among some recent epidemiological studies. The aim of this study is to assess the diagnostic values of serum IGF-1 and IGFBP-3 for GHD by conducting a systematic review and meta-analysis. Studies on serum IGF-1 and IGFBP-3 used in GHD diagnosis were systematically searched from databases PubMed, EMBASE, and CNKI (up to December 2013). Characteristics of the studies and data were independently collected according to the inclusion criteria by two authors. The quality of included studies was assessed using quality assessment of diagnostic accuracy studies (QUADAS). Both sensitivity (SEN) and specificity (SPE) of IGF-1 and IGFBP-3 in GHD diagnosis were estimated on statistical software Meta-DiSc and Stata. A total of 12 studies were included for the final analysis. IGF-1 had SEN of 0.66, SPE of 0.69, positive likelihood ratio (PLR) of 2.48, negative likelihood ratio (NLR) of 0.51, area under the summary receiver operating characteristic curve (SROC) of 0.78, and Q* value of 0.72. Serum IGFBP-3 had SEN of 0.50, SPE of 0.79, PLR of 2.69, NLR of 0.64, area under SROC of 0.80, and Q* value of 0.73.
CONCLUSION
Serum IGF-1 and IGFBP-3 are useful for the diagnosis of GHD and can be utilized as auxiliary diagnosis indexes for provocative test.
Topics: Growth Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; ROC Curve; Reproducibility of Results; Sensitivity and Specificity
PubMed: 25213432
DOI: 10.1007/s00431-014-2406-3 -
Experimental Gerontology Aug 2020Nutrition is critical to the health of the elderly, since most of them have a deficiency in key nutrient. The use of whey protein may be a food strategy to increase... (Review)
Review
UNLABELLED
Nutrition is critical to the health of the elderly, since most of them have a deficiency in key nutrient. The use of whey protein may be a food strategy to increase protein intake. The objective of this work was to evaluate the ingestion of whey protein for the elderly and the association with physical performance and clinical outcomes. A systematic review was conducted in order to find papers that shed some light in the correlation between whey protein and the elderly.
INCLUSION CRITERIA
population: elderly; intervention: use of whey protein when compared to control group; outcome: related to health, nutrition, or quality of life.
DATABASE
PubMed, with papers published in the last 5 years.
SEARCH STRATEGY
(elder OR senior OR elderly OR aging OR aged OR old OR older) AND (whey OR "whey protein"). 35 papers were selected of which 22 had a physical performance outcome and 13 had clinical outcomes. Studies indicate that whey protein supplements promote protein synthesis in the elderly, improving muscle performance and aerobic capacity, protecting against sarcopenia and reducing the risk for falls. In the papers studied, the age group considered to be elderly was ≥65 years in 27 papers and ≥60 years in the other 8 papers. Whey protein also appears to contribute to improved health, recovery from disease, prevention of cardiovascular and metabolic risks, and hepatic steatosis complications. Data suggest that whey protein supplements may be promising for the health improvement of the elderly.
Topics: Aged; Diet; Dietary Supplements; Eating; Humans; Physical Functional Performance; Quality of Life; Whey Proteins
PubMed: 32289487
DOI: 10.1016/j.exger.2020.110936 -
The Cochrane Database of Systematic... Feb 2015Phenylketonuria is an inherited metabolic disorder characterised by an absence or deficiency of the enzyme phenylalanine hydroxylase. The aim of treatment is to lower... (Review)
Review
BACKGROUND
Phenylketonuria is an inherited metabolic disorder characterised by an absence or deficiency of the enzyme phenylalanine hydroxylase. The aim of treatment is to lower blood phenylalanine concentrations to the recommended therapeutic range to prevent developmental delay and support normal growth. Current treatment consists of a low-phenylalanine diet in combination with a protein substitute which is free from or low in phenylalanine. Guidance regarding the use, dosage, and distribution of dosage of the protein substitute over a 24-hour period is unclear, and there is variation in recommendations among treatment centres. This is an update of a Cochrane review first published in 2005, and previously updated in 2008.
OBJECTIVES
To assess the benefits and adverse effects of protein substitute, its dosage, and distribution of dose in children and adults with phenylketonuria who are adhering to a low-phenylalanine diet.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which consists of references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. We also contacted manufacturers of the phenylalanine-free and low-phenylalanine protein substitutes for any data from published and unpublished randomised controlled trials.Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 03 April 2014.
SELECTION CRITERIA
All randomised or quasi-randomised controlled trials comparing: any dose of protein substitute with no protein substitute; an alternative dosage; or the same dose, but given as frequent small doses throughout the day compared with the same total daily dose given as larger boluses less frequently.
DATA COLLECTION AND ANALYSIS
Both authors independently extracted data and assessed trial quality.
MAIN RESULTS
Three trials (69 participants) are included in this review. One trial investigated the use of protein substitute in 16 participants, while a further two trials investigated the dosage of protein substitute in a total of 53 participants. Due to issues with data presentation in each trial, described in full in the review, formal statistical analyses of the data were impossible. Investigators will be contacted for further information.
AUTHORS' CONCLUSIONS
No conclusions could be drawn about the short- or long-term use of protein substitute in phenylketonuria due to the lack of adequate or analysable trial data. Additional data and randomised controlled trials are needed to investigate the use of protein substitute in phenylketonuria. Until further evidence is available, current practice in the use of protein substitute should continue to be monitored with care.
Topics: Adult; Child; Dietary Proteins; Food, Formulated; Humans; Phenylalanine; Phenylalanine Hydroxylase; Phenylketonurias; Randomized Controlled Trials as Topic
PubMed: 25723866
DOI: 10.1002/14651858.CD004731.pub4 -
JIMD Reports Jul 2022Arginase 1 deficiency (ARG1-D) is a rare, progressive and debilitating urea cycle disorder characterized by clinical manifestations including spasticity, seizures,...
BACKGROUND
Arginase 1 deficiency (ARG1-D) is a rare, progressive and debilitating urea cycle disorder characterized by clinical manifestations including spasticity, seizures, developmental delay, and intellectual disability. The aim of this systematic review was to identify and summarize the natural history of ARG1-D and the unmet needs of patients.
METHODS
A comprehensive search of published case reports was undertaken to identify patients with ARG1-D regardless of interventions, comparisons, or outcomes. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and other evidence-based medicine literature databases were searched on 20 April 2020. Quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. (PROSPERO registration: CRD42020212142.).
RESULTS
One hundred and fifty seven ARG1-D patients were included from 111 publications (good overall quality based on JBI's Checklist); 84 (53.5%) were males. Motor deficits (including spasticity), intellectual disability, and seizures were reported in >50% of the cases. Mean age (SD) at diagnosis was 6.4 years and the laboratory findings most commonly reported to support diagnosis included elevated plasma arginine (81.5%), mutation in gene through genetic testing (60%), and absence/reduction of red blood cell arginase activity (51%). Reported management approaches mainly included dietary protein restriction (68%), nitrogen scavengers (45%), and essential amino acid supplements (21%). Author-reported clinical improvement was documented for 26% of patients, 15% deteriorated, and 19% had limited or no change; notably, no indication of clinical outcome was reported for 40% cases.
CONCLUSION
This review illustrates a significant burden of disease and highlights a considerable unmet need for clinically effective treatment options for patients with ARG1-D.
PubMed: 35822089
DOI: 10.1002/jmd2.12283 -
Molecular Genetics and Metabolism Aug 2014Creatine transporter deficiency (CTD) is an X-linked inborn error of creatine metabolism characterized by reduced intra-cerebral creatine, developmental... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Creatine transporter deficiency (CTD) is an X-linked inborn error of creatine metabolism characterized by reduced intra-cerebral creatine, developmental delay/intellectual disability, (ID), behavioral disturbance, seizures, and hypotonia in individuals harboring mutations in the SLC6A8 gene. Treatment for CTD includes supplementation with creatine, either alone or in combination with creatine precursors (arginine or glycine). Unlike other disorders of creatine metabolism, the efficacy of its treatment remains controversial.
METHODS
We present our systematic literature review (2001-2013) comprising 7 publications (case series/reports), collectively describing 25 patients who met the inclusion criteria, and 3 additional cases treated at our institution. Definitions were established and extracted data analyzed for cognitive ability, psychiatric and behavioral disturbances, epilepsy, and cerebral proton magnetic resonance spectroscopy measurements at pre- and post-treatment.
RESULTS
Treatment regimens varied among the 28 cases: 2 patients received creatine-monohydrate supplementation; 7 patients received L-arginine; 2 patients received creatine-monohydrate and L-arginine; and 17 patients received a combination of creatine-monohydrate, L-arginine and glycine. Median treatment duration was 34.6 months (range 3 months-5 years). Level of evidence was IV. A total of 10 patients (36%) demonstrated response to treatment, manifested by either an increase in cerebral creatine, or improved clinical parameters. Seven of the 28 patients had quantified pre- and post-treatment creatine, and it was significantly increased post-treatment. All of the patients with increased cerebral creatine also experienced clinical improvement. In addition, the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. 90% of the patients who improved were initiated on treatment before nine years of age.
CONCLUSIONS
Acknowledging the limitations of this systematic review, we conclude that a proportion of CTD patients show amenability to treatment-particularly milder cases with residual brain creatine, and therefore probable residual protein function. We propose systematic screening for CTD in patients with ID, to allow early initiation of treatment, which currently comprises oral creatine, arginine and/or glycine supplementation. Standardized monitoring for safety and evaluation of treatment effects are required in all patients. This study provides effectiveness on currently available treatment, which can be used to discern effectiveness of future interventions (e.g. cyclocreatine).
Topics: Adolescent; Brain Diseases, Metabolic, Inborn; Child; Child, Preschool; Creatine; Female; Humans; Infant; Magnetic Resonance Imaging; Male; Membrane Transport Proteins; Mental Retardation, X-Linked; Plasma Membrane Neurotransmitter Transport Proteins; Treatment Outcome
PubMed: 24953403
DOI: 10.1016/j.ymgme.2014.05.011 -
Chinese Clinical Oncology Jun 2023Mutations in the BRCA1/2 (BRCA) genes are associated with response to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). In addition, there are different homologous... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Mutations in the BRCA1/2 (BRCA) genes are associated with response to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). In addition, there are different homologous recombination deficiency (HRD) biomarkers available in clinical practice [e.g., genome-wide loss-of-heterozygosity (gLOH) and myChoice® score] that identify patients who can benefit from PARPi. Inconsistencies in biomarkers used in PARPi clinical trials make it challenging to identify clinically relevant predictive biomarkers. This study aims to compare clinically available HRD biomarkers in terms of benefits from PARPi.
METHODS
We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a Random Effects model. Patients were classified according to their HRD status: (I) BRCAm (patients with BRCA mutation of germline or somatic origin); (II) non-BRCA HRD [patients BRCA wild-type (wt) with another HRD biomarker-gLOH or myChoice®]; and (III) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice®+ with gLOH-high.
RESULTS
Five studies (3,225 patients) analyzing PARPi in first line setting were included. Patients with BRCAmut had progression-free survival (PFS) with hazard ratio (HR) 0.33 [95% confidence interval (CI): 0.30-0.43]; patients with non-BRCA HRD had a PFS HR 0.49 (95% CI: 0.37-0.65), and patients with HRP had a PFS HR 0.78 (95% CI: 0.58-1.03). Eight studies (5,529 patients) with PARPi including first line and recurrence settings were included. BRCAmut had PFS HR 0.37 (95% CI: 0.30-0.48), BRCAwt & HRD 0.45 (95% CI: 0.37-0.55) and HRP 0.70 (95% CI: 0.57-0.85). Patients with BRCAwt & myChoice® ≥42 had PFS HR 0.43 (95% CI: 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95% CI: 0.28-0.62).
CONCLUSIONS
Patients with HRD derived significantly more benefit from PARPi when compared to patients with HRP. The benefit of PARPi in patients with HRP tumors was limited. Careful cost-effectiveness analysis, and alternative therapies or clinical trial enrollment should strongly be considered for patients with HRP tumors. Among patients with BRCAwt, a similar benefit was found in patients with gLOH-high and those myChoice®+. The clinical development of further HRD biomarkers (e.g., Sig3) may help identify more patients who benefit from PARPi.
Topics: Humans; Female; BRCA1 Protein; BRCA2 Protein; Poly(ADP-ribose) Polymerase Inhibitors; Ovarian Neoplasms; Homologous Recombination; Biomarkers
PubMed: 37211773
DOI: 10.21037/cco-22-114 -
Clinical Endocrinology Dec 2015Combined pituitary hormonal deficiency (CPHD) can result from mutations within genes that encode transcription factors. This study evaluated the frequency of mutations... (Review)
Review
OBJECTIVE
Combined pituitary hormonal deficiency (CPHD) can result from mutations within genes that encode transcription factors. This study evaluated the frequency of mutations in these genes in a cohort of 144 unrelated Italian patients with CPHD and estimated the overall prevalence of mutations across different populations using a systematic literature review.
MATERIAL AND METHODS
A multicentre study of adult and paediatric patients with CPHD was performed. The PROP1, POU1F1, HESX1, LHX3 and LHX4 genes were analysed for the presence of mutations using direct sequencing. We systematically searched PubMed with no date restrictions for studies that reported genetic screening of CPHD cohorts. We only considered genetic screenings with at least 10 individuals. Data extraction was conducted in accordance with the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
RESULTS
Global mutation frequency in Italian patients with CPHD was 2·9% (4/136) in sporadic cases and 12·5% (1/8) in familial cases. The worldwide mutation frequency for the five genes calculated from 21 studies was 12·4%, which ranged from 11·2% in sporadic to 63% in familial cases. PROP1 was the most frequently mutated gene in sporadic (6·7%) and familial cases (48·5%).
CONCLUSION
The frequency of defects in genes encoding pituitary transcription factors is quite low in Italian patients with CPHD and other western European countries, especially in sporadic patients. The decision of which genes should be tested and in which order should be guided by hormonal and imaging phenotype, the presence of extrapituitary abnormalities and the frequency of mutation for each gene in the patient-referring population.
Topics: Female; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; Hypopituitarism; Italy; LIM-Homeodomain Proteins; Male; Transcription Factor Pit-1; Transcription Factors
PubMed: 26147833
DOI: 10.1111/cen.12849 -
Clinical Genetics Jan 2020Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes...
Neurexins are presynaptic cell adhesion molecules critically involved in synaptogenesis and vesicular neurotransmitter release. They are encoded by three genes (NRXN1-3), each yielding a longer alpha (α) and a shorter beta (β) transcript. Deletions spanning the promoter and the initial exons of the NRXN1 gene, located in chromosome 2p16.3, are associated with a variety of neurodevelopmental, psychiatric, neurological and neuropsychological phenotypes. We have performed a systematic review to define (a) the clinical phenotypes most associated with mono-allelic exonic NRXN1 deletions, and (b) the phenotypic features of NRXN1 bi-allelic deficiency due to compound heterozygous deletions/mutations. Clinically, three major conclusions can be drawn: (a) incomplete penetrance and pleiotropy do not allow reliable predictions of clinical outcome following prenatal detection of mono-allelic exonic NRXN1 deletions. Newborn carriers should undergo periodic neuro-behavioral observations for the timely detection of warning signs and the prescription of early behavioral intervention; (b) the presence of additional independent genetic risk factors should always be sought, as they may influence prognosis; (c) children with exonic NRXN1 deletions displaying early-onset, severe psychomotor delay in the context of a Pitt-Hopkins-like syndrome 2 phenotype, should undergo DNA sequencing of the spared NRXN1 allele in search for mutations or very small insertions/deletions.
Topics: Calcium-Binding Proteins; Cell Adhesion Molecules, Neuronal; Genetic Predisposition to Disease; Humans; Intellectual Disability; Mental Disorders; Mutation; Nervous System Diseases; Neural Cell Adhesion Molecules; Neurodevelopmental Disorders; Phenotype
PubMed: 30873608
DOI: 10.1111/cge.13537