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Cancers Oct 2020Ataxia-Telangiectasia (A-T) is a rare autosomal recessive disorder, first reported in 1926, caused by a deficiency of ATM (Ataxia-Telangiectasia Mutated) protein. The... (Review)
Review
Ataxia-Telangiectasia (A-T) is a rare autosomal recessive disorder, first reported in 1926, caused by a deficiency of ATM (Ataxia-Telangiectasia Mutated) protein. The disease is characterized by progressive cerebellar neurodegeneration, immunodeficiency, leukemia, and lymphoma cancer predisposition. Immunoglobulin replacement, antioxidants, neuroprotective factors, growth, and anti-inflammatory hormones are commonly used for A-T treatment, but, to date, there is no known cure. Bone marrow transplantation (BMT) is a successful therapy for several forms of diseases and it is a valid approach for tumors, hemoglobinopathies, autoimmune diseases, inherited disorders of metabolism, and other pathologies. Some case reports of A-T patients have shown that BMT is becoming a good option, as a correct engraftment of healthy cells can restore some aspects of immunologic capacity. However, due to a high risk of mortality as a result of a clinical and cellular hypersensitivity to ionizing radiation and radiomimetic drugs, a specific non-myeloablative conditioning is required before BMT. Although BMT might be considered as one promising therapy for the treatment of immunological defects and cancer prevention in selected A-T patients, the therapy is currently not recommended or recognized and the eligibility of A-T patients for BMT is a point to deepen and deliberate.
PubMed: 33142696
DOI: 10.3390/cancers12113207 -
Frontiers in Pediatrics 2021Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies are rare autosomal recessive fatty acid β-oxidation...
Newborn Screening for Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase and Mitochondrial Trifunctional Protein Deficiencies Using Acylcarnitines Measurement in Dried Blood Spots-A Systematic Review of Test Accuracy.
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies are rare autosomal recessive fatty acid β-oxidation disorders. Their clinical presentations are variable, and premature death is common. They are included in newborn blood spot screening programs in many countries around the world. The current process of screening, through the measurement of acylcarnitines (a metabolic by-product) in dried blood spots with tandem mass spectrometry, is subject to uncertainty regarding test accuracy. We conducted a systematic review of literature published up to 19th June 2018. We included studies that investigated newborn screening for LCHAD or MTP deficiencies by tandem mass spectrometry of acylcarnitines in dried blood spots. The reference standards were urine organic acids, blood acylcarnitine profiles, enzyme analysis in cultured fibroblasts or lymphocytes, mutation analysis, or at least 10-year follow-up. The outcomes of interest were sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Assessment of titles, abstracts, and full-text papers and quality appraisal were carried out independently by two reviewers. One reviewer extracted study data. This was checked by a second reviewer. Ten studies provided data on test accuracy. LCHAD or MTP deficiencies were identified in 23 babies. No cases of LCHAD/MTP deficiencies were identified in four studies. PPV ranged from 0% (zero true positives and 28 false positives from 276,565 babies screened) to 100% (13 true positives and zero false positives from 2,037,824 babies screened). Sensitivity, specificity, and NPV could not be calculated as there was no systematic follow-up of babies who screened negative. Test accuracy estimates of screening for LCHAD and MTP deficiencies with tandem mass spectrometry measurement of acylcarnitines in dried blood were variable in terms of PPVs. Screening methods (including markers and thresholds) varied between studies, and sensitivity, specificity, and NPVs are unknown.
PubMed: 33816395
DOI: 10.3389/fped.2021.606194 -
Orphanet Journal of Rare Diseases Apr 2017Hereditary proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease of childhood caused by homozygous loss of function of the survival motor neuron (SMN)... (Review)
Review
BACKGROUND
Hereditary proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease of childhood caused by homozygous loss of function of the survival motor neuron (SMN) 1 gene. The presence of a second, nearly identical SMN gene (SMN2) in the human genome ensures production of residual levels of the ubiquitously expressed SMN protein. Alpha-motor neurons in the ventral horns of the spinal cord are most vulnerable to reduced SMN concentrations but the development or function of other tissues may also be affected, and cardiovascular abnormalities have frequently been reported both in patients and SMA mouse models.
METHODS
We systematically reviewed reported cardiac pathology in relation to SMN deficiency. To investigate the relevance of the possible association in more detail, we used clinical classification systems to characterize structural cardiac defects and arrhythmias.
CONCLUSIONS
Seventy-two studies with a total of 264 SMA patients with reported cardiac pathology were identified, along with 14 publications on SMA mouse models with abnormalities of the heart. Structural cardiac pathology, mainly septal defects and abnormalities of the cardiac outflow tract, was reported predominantly in the most severely affected patients (i.e. SMA type 1). Cardiac rhythm disorders were most frequently reported in patients with milder SMA types (e.g. SMA type 3). All included studies lacked control groups and a standardized approach for cardiac evaluation. The convergence to specific abnormalities of cardiac structure and function may indicate vulnerability of specific cell types or developmental processes relevant for cardiogenesis. Future studies would benefit from a controlled and standardized approach for cardiac evaluation in patients with SMA.
Topics: Heart; Humans; Motor Neurons; Muscular Atrophy, Spinal; Spinal Muscular Atrophies of Childhood; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein
PubMed: 28399889
DOI: 10.1186/s13023-017-0613-5 -
International Journal of Molecular... Jan 2017Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important... (Meta-Analysis)
Meta-Analysis Review
Gamma-carboxylation, performed by gamma-glutamyl carboxylase (GGCX), is an enzymatic process essential for activating vitamin K-dependent proteins (VKDP) with important functions in various biological processes. Mutations in the encoding gene are associated with multiple phenotypes, amongst which vitamin K-dependent coagulation factor deficiency (VKCFD1) is best known. Other patients have skin, eye, heart or bone manifestations. As genotype-phenotype correlations were never described, literature was systematically reviewed in search of patients with at least one mutation with a phenotypic description, resulting in a case series of 47 patients. Though this number was too low for statistically valid correlations-a frequent problem in orphan diseases-we demonstrate the crucial role of the horizontally transferred transmembrane domain in developing cardiac and bone manifestations. Moreover, natural history suggests ageing as the principal determinant to develop skin and eye symptoms. VKCFD1 symptoms seemed more severe in patients with both mutations in the same protein domain, though this could not be linked to a more perturbed coagulation factor function. Finally, distinct GGCX functional domains might be dedicated to carboxylation of very specific VKDP. In conclusion, this systematic review suggests that there indeed may be genotype-phenotype correlations for GGCX-related phenotypes, which can guide patient counseling and management.
Topics: Blood Coagulation Disorders, Inherited; Carbon-Carbon Ligases; Congenital Abnormalities; Eye; Gene Knockout Techniques; Genetic Association Studies; Genetic Counseling; Genetic Predisposition to Disease; Genotype; Humans; Mutation; Phenotype; Polymorphism, Single Nucleotide; Protein Interaction Domains and Motifs; Skin; Vitamin K
PubMed: 28125048
DOI: 10.3390/ijms18020240 -
Journal of Sport and Health Science May 2023The aim of this study was to review, systematically, evidence concerning the link between the ACTN3 R577X polymorphism and the rates and severity of non-contact injuries... (Review)
Review
PURPOSE
The aim of this study was to review, systematically, evidence concerning the link between the ACTN3 R577X polymorphism and the rates and severity of non-contact injuries and exercise-induced muscle damage in athletes and individuals enrolled in exercise training programs.
METHODS
A computerized literature search was performed in the electronic databases PubMed, Web of Science, and SPORTDiscus, from inception until November 2020. All included studies compared the epidemiological characteristics of non-contact injury between the different genotypes of the ACTN3 R577X polymorphism.
RESULTS
Our search identified 492 records. After the screening of titles, abstracts, and full texts, 13 studies examining the association between the ACTN3 genotypes and the rate and severity of non-contact injury were included in the analysis. These studies were performed in 6 different countries (Spain, Japan, Brazil, China, the Republic of Korea, and Italy) and involved a total participant pool of 1093 participants. Of the studies, 2 studies involved only women, 5 studies involved only men, and 6 studies involved both men and women. All the studies included were classified as high-quality studies (≥6 points in the Physiotherapy Evidence Database (PEDro) scale score). Overall, evidence suggests there is an association between the ACTN3 R577X genotype and non-contact injury in 12 investigations. Six studies observed a significant association between ACTN3 R577X polymorphism and exercise induced muscle damage: 2 with non-contact ankle injury, 3 with non-contact muscle injury, and 1 with overall non-contact injury.
CONCLUSION
The present findings support the premise that possessing the ACTN3 XX genotype may predispose athletes to a higher probability of some non-contact injuries, such as muscle injury, ankle sprains, and higher levels of exercise-induced muscle damage.
Topics: Male; Humans; Female; Genotype; Polymorphism, Genetic; Exercise; Spain; Athletes; Actinin
PubMed: 34284153
DOI: 10.1016/j.jshs.2021.07.003 -
Obesity Surgery Jun 2023This is a systematic review and meta-analysis that assessed the impact of performing OAGB with a 150-cm BPL versus a 200-cm BPL concerning weight loss, comorbidities... (Meta-Analysis)
Meta-Analysis Review
This is a systematic review and meta-analysis that assessed the impact of performing OAGB with a 150-cm BPL versus a 200-cm BPL concerning weight loss, comorbidities remission, and adverse nutritional effects. The analysis included studies that compared patients who underwent OAGB with a 150-cm BPL and 200-cm BPL. Eight studies were eligible for this review after searching in the EMBASE, PubMed central database, and Google scholar. The pooled analysis revealed favoring the 200-cm BPL limb length for weight loss, with a highly significant difference in the TWL% (p=0.009). Both groups showed comparable comorbidities remission. Significantly higher ferritin and folate deficiency rates were found in the 200-cm BPL group. Considering a 200-cm BPL when performing OAGB delivers a better weight loss outcome than a 150-cm BPL, which is at the expense of a more severe nutritional deficiency. No significant differences were found regarding the comorbidities' remission.
Topics: Humans; Gastric Bypass; Obesity, Morbid; Comorbidity; Protein-Energy Malnutrition; Weight Loss; Retrospective Studies
PubMed: 37022609
DOI: 10.1007/s11695-023-06556-9 -
International Journal of Chronic... 2017Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.
METHODS
Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology.
RESULTS
In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (=0.002), and associated with a small increase in exacerbations 0.29/year (=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema.
CONCLUSION
Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.
Topics: Chi-Square Distribution; Disease Progression; Enzyme Replacement Therapy; Humans; Lung; Lung Transplantation; Observational Studies as Topic; Pneumonectomy; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Randomized Controlled Trials as Topic; Recovery of Function; Treatment Outcome; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency
PubMed: 28496314
DOI: 10.2147/COPD.S130440 -
Frontiers in Endocrinology 2024Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency (IAD) is a rare but potentially fatal disease. (Review)
Review
BACKGROUND
Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency (IAD) is a rare but potentially fatal disease.
METHODS
We comprehensively searched the PubMed database and made a systematic review of immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency. If the status of other anterior pituitary hormones was not mentioned, the case was excluded.
RESULTS
We identified 123 cases diagnosed as immune checkpoint inhibitor-induced IAD, consisting of 44 female and 79 male patients. The average age of these patients was 64.3 ± 12.6 years old, and 67.5% were 60 years old or above. The majority (78.9%) of these patients received anti-programmed cell death protein-1 (anti-PD-1) antibodies or anti-programmed cell death ligand 1 (anti-PD-L1) antibodies or both, and 19.5% received combined therapy, sequential therapy, or both. A total of 26 patients received anti-cytotoxic T lymphocyte antigen 4 antibodies (anti-CTLA-4). The median ICI treatment cycle before the diagnosis of adrenal insufficiency was 8 (6, 12), and the median ICI treatment duration before the diagnosis of adrenal insufficiency was 6 (4, 8) months. Eleven cases developed IAD 1 to 11 months after discontinuation of ICIs. Fatigue and appetite loss were the most common symptoms, and surprisingly, there were two asymptomatic cases of IAD. Most patients (88 cases) had normal pituitary magnetic resonance imaging, only 14 cases reported mild atrophy or swelling pituitary gland, and 21 cases reported no imaging results. Most diagnoses were made by basal hormone levels, and pituitary stimulation tests were performed in only a part of the cases. No cases had been reported of discontinuation of ICI use due to IAD nor had there been any deaths due to IAD.
CONCLUSION
IAD was predominant in elderly male patients mainly receiving anti-PD-1 or anti-PD-L1 antibodies. It was sometimes difficult to recognize IAD at first glance since non-specific symptoms were common and asymptomatic cases of IAD were also reported. Although IAD can be deadly, it usually does not affect the continued use of ICIs.
Topics: Humans; Adrenal Insufficiency; Adrenocorticotropic Hormone; Endocrine System Diseases; Genetic Diseases, Inborn; Hypoglycemia; Immune Checkpoint Inhibitors
PubMed: 38318292
DOI: 10.3389/fendo.2024.1326684 -
PloS One 2016Obesity induced low-grade chronic inflammation disrupts proper immune and metabolic function. Vitamin D deficiency increases inflammation, which is associated with... (Review)
Review
BACKGROUND
Obesity induced low-grade chronic inflammation disrupts proper immune and metabolic function. Vitamin D deficiency increases inflammation, which is associated with cardiometabolic risk. This systematic review examines the association between oral vitamin D (VD) supplementation and circulating inflammatory biomarkers and glycemic outcomes from randomized controlled trials (RCTs) of overweight and/or obese adults.
METHODS
MEDLINE OVID, EMBASE and the Cochrane Central Register of Controlled Trials were searched according to a predefined protocol. Eligible RCTs included adults randomized to receive either oral VD or placebo. Two reviewers independently assessed RCTs for inclusion. Bias was assessed using the Cochrane Collaboration risk of bias tool. Mean differences were calculated comparing end-of-study sample means between the independent VD and placebo groups.
RESULTS
Eleven unique RCTs met inclusion criteria from a total of 3,383 identified citations, including 79 screened articles and 14 full text data extractions. Inflammatory and glycemic measures were reported in 7 and 10 RCTs, respectively. Most trial findings were non-significant with considerable heterogeneity in design, participants and outcomes. All but one trial was rated as either high or unclear risk of bias. Two RCTs reported significant changes in inflammatory biomarkers; however, the mean difference between groups was not statistically significant: C-reactive protein 0.19 mg/L (p = 0.88); Tumor Necrosis Factor -0.54 pg/ml (p = 0.20). Two other trials found significant mean differences in fasting plasma glucose -0.32 mmol/L (p = 0.03), Hemoglobin A1c -0.13% (p = 0.04), and Homeostatic Model Assessment -0.86 (p = 0.02) following VD supplementation.
CONCLUSIONS
Overall, there is no clear established benefit of VD supplementation on inflammatory biomarkers among overweight/obese adults. Baseline serum VD possibly influences the effect of VD repletion on inflammatory markers. Risk of bias was present in most studies, thus supporting the need for higher quality studies in this area to more conclusively understand the role VD supplementation has on inflammatory pathways.
Topics: Adult; Blood Glucose; C-Reactive Protein; Cholecalciferol; Humans; Inflammation; Obesity; Overweight; Randomized Controlled Trials as Topic; Tumor Necrosis Factor-alpha; Vitamin D Deficiency; Vitamins
PubMed: 27116227
DOI: 10.1371/journal.pone.0154215 -
Orphanet Journal of Rare Diseases Feb 2024Alpha 1 Antitrypsin Deficiency (AATD) is a largely underrecognized genetic condition characterized by low Alpha 1 Antitrypsin (AAT) serum levels, resulting from... (Review)
Review
BACKGROUND
Alpha 1 Antitrypsin Deficiency (AATD) is a largely underrecognized genetic condition characterized by low Alpha 1 Antitrypsin (AAT) serum levels, resulting from variations in SERPINA1. Many individuals affected by AATD are thought to be undiagnosed, leading to poor patient outcomes. The Z (c.1096G > A; p.Glu366Lys) and S (c.863A > T; p.Glu288Val) deficiency variants are the most frequently found variants in AATD, with the Z variant present in most individuals diagnosed with AATD. However, there are many other less frequent variants known to contribute to lung and/or liver disease in AATD. To identify the most common rare variants associated with AATD, we conducted a systematic literature review with the aim of assessing AATD variation patterns across the world.
METHODS
A systematic literature search was performed to identify published studies reporting AATD/SERPINA1 variants. Study eligibility was assessed for the potential to contain relevant information, with quality assessment and data extraction performed on studies meeting all eligibility criteria. AATD variants were grouped by variant type and linked to the geographical region identified from the reporting article.
RESULTS
Of the 4945 articles identified by the search string, 864 contained useful information for this study. Most articles came from the United States, followed by the United Kingdom, Germany, Spain, and Italy. Collectively, the articles identified a total of 7631 rare variants and 216 types of rare variant across 80 counties. The F (c.739C > T; p.Arg247Cys) variant was identified 1,281 times and was the most reported known rare variant worldwide, followed by the I (c.187C > T; p.Arg63Cys) variant. Worldwide, there were 1492 Null/rare variants that were unidentified at the time of source article publication and 75 rare novel variants reported only once.
CONCLUSION
AATD goes far beyond the Z and S variants, suggesting there may be widespread underdiagnosis of patients with the condition. Each geographical region has its own distinctive variety of AATD variants and, therefore, comprehensive testing is needed to fully understand the true number and type of variants that exist. Comprehensive testing is also needed to ensure accurate diagnosis, optimize treatment strategies, and improve outcomes for patients with AATD.
Topics: Humans; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Germany; Italy; Lung; Spain
PubMed: 38388492
DOI: 10.1186/s13023-024-03069-1