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Medicine Sep 2023Acute intermittent porphyria (AIP) is caused by a partial deficiency of hydroxymethylbilane synthase and affects heme biosynthesis. Mutations in the HMBS gene result in...
BACKGROUND
Acute intermittent porphyria (AIP) is caused by a partial deficiency of hydroxymethylbilane synthase and affects heme biosynthesis. Mutations in the HMBS gene result in HMBS deficiency. AIP is a rare disease, and there been insufficient studies on it. This report describes the molecular epidemiology of HMBS gene defects and hydroxymethylbilane synthase activity levels in classical AIP.
METHODS
Databases of PubMed, CNKI, and Wang Fang Database were searched for eligible studies to investigate HMBS gene mutations in peripheral blood samples and HMBS activity in erythrocytes of patients with classical AIP. Relevant studies published up to July 15, 2023, from several databases were independently searched and selected by 2 reviewers. Accuracy data and relevant information were extracted from each eligible study by 2 independent researchers and analyzed using statistical software.
RESULTS
After pooling the accuracy data from 232 patients of the 15 eligible studies, 90.5% (210/232) of AIP patients had decreased erythrocyte hydroxymethylbilane synthase activity (<70%), and 96 different mutations were identified in 232 patients, including 33 missense (34.4%), 27 splice (28.1%), 19 deletion (19.8%), 8 nonsense (8.3%), 9 insertion (9.4%) mutations. Residual enzyme activities (%) for different groups of type were expressed using mean and 95% confidence interval (95% CI): missense (51.2, 48.5-53.9), splice (57.5, 52.0-59.1), deletion (54.9, 50.7-59.1), nonsense (52.2, 44.4-60.0), insertion (53.2, 47.4-59.0), group analysis P = .17. Subgroups of missense mutations, domain 1 (50.2, 46.0-54.4), domain 2 (52.8, 49.1-56.4), and domain 3 (49.2, 38.3-60.0), Subgroup analysis, P = .62.
CONCLUSION
Different mutation types and mutation positions are not associated with the level of hydroxymethylbilane synthase activity. Erythrocyte hydroxymethylbilane synthase activity is often reduced to half of normal in patients with AIP, and the enzyme activity assay has a high diagnostic value in AIP. AIP is highly molecularly heterogeneous, with missense mutations being the most common, followed by splice mutations. R173W and G111R are high-frequency mutations and have been found in multiple families from different countries.
Topics: Humans; Porphyria, Acute Intermittent; Hydroxymethylbilane Synthase; Mutation; Mutation, Missense
PubMed: 37773850
DOI: 10.1097/MD.0000000000035144 -
European Journal of Medical Research Aug 2023Previous studies showed that the combination of bevacizumab and erlotinib (combination therapy) significantly prolonged progression-free survival (PFS) but no overall... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Previous studies showed that the combination of bevacizumab and erlotinib (combination therapy) significantly prolonged progression-free survival (PFS) but no overall survival (OS) compared to erlotinib alone (monotherapy) for advanced EGFR-mutant non-small cell lung cancer (NSCLC). Two phase III randomized controlled trials (RCTs) had reported the OS results in 2021. This meta-analysis aimed to include the results of the two RCTs to make a decision.
MATERIALS AND METHODS
We systematically searched relevant databases for RCTs on the use of bevacizumab plus erlotinib in advanced EGFR-mutant NSCLC. The main outcomes of interest were PFS, OS, and the reported hazard ratio (HR). Fixed-effect model was used to estimate pooled HR.
RESULTS
Total 5 RCTs with 935 patients were eligible for this meta-analysis. All studies reached their primary study endpoints including PFS and OS. Compared to monotherapy, combination therapy remarkably prolonged PFS (HR = 0.60, 95% confidence interval CI 0.51-0.70; p < 0.00001); however, OS was similar between the two groups (HR = 0.90, 95% CI 0.76-1.08; p = 0.26). Subgroup analysis demonstrated that in deletion within exon 19 (19del) mutation subgroup, the combination therapy could only prolong PFS (HR = 0.60, 95% CI 0.47-0.76; p < 0.0001) but not OS (HR = 1.00, 95% CI 0.73-1.37; p = 1.00), and also in leucine-to-arginine substitution in exon 21 (L858R) mutation subgroup (HR = 0.59, p < 0.0001 and HR = 0.80, p = 0.18, respectively). For patients with brain metastasis at baseline, the combination therapy achieved a significant better PFS than the monotherapy (HR = 0.60, 95% CI 0.39-0.90; p = 0.01), and a better OS with the difference marginally significant (HR = 0.69, 95% CI 0.46-1.02; p = 0.06).
CONCLUSIONS
Combination of bevacizumab and erlotinib can prolong progression-free survival but not overall survival compared to erlotinib alone in advanced EGFR-mutant non-small cell lung cancer patients. The combination therapy not only can prolong progression-free survival but also has a tendency to prolong overall survival for patients with brain metastasis at baseline.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Bevacizumab; Erlotinib Hydrochloride; Randomized Controlled Trials as Topic; Brain Neoplasms; Lung Neoplasms; ErbB Receptors
PubMed: 37635242
DOI: 10.1186/s40001-023-01272-7 -
Journal of Reproductive Immunology Sep 2023Preeclampsia remains enigmatic and responsible for vast maternal and fetal morbidity and mortality worldwide. Our objective was to assess the strength of the effect of... (Meta-Analysis)
Meta-Analysis Review
Preeclampsia remains enigmatic and responsible for vast maternal and fetal morbidity and mortality worldwide. Our objective was to assess the strength of the effect of the 14 bp deletion/insertion polymorphism in exon 8 of the 3'UTR region of the human leukocyte antigen-G (HLA-G) gene on preeclampsia risk across different populations. A systematic review by a meta-analysis was performed to summarize the scattered epidemiologic evidence, which remains inconclusive and controversial. A systematic literature search according to the PRISMA guidelines was conducted to screen relevant publications. Odds ratio and corresponding 95% confidence interval were estimated to measure the magnitude of the association between this polymorphism and preeclampsia onset. Thirty studies comprising 9402 subjects were eligible. Pooled estimates suggested that both fetal and paternal insertion variants were significantly associated with increased odds of this disease. Nevertheless, the presence of the 14 bp insertion sequence in mothers does not seem to increase the risk of preeclampsia. Moreover, the results of subgroup analysis suggested that the fetal, maternal, and paternal polymorphism has a significant deleterious impact on the preeclampsia risk in the Asian population. In addition, the significant association between the paternal polymorphism and preeclampsia in primigravida was observed in the pooled estimation with a small sample size. By summarizing the amount of significant evidence, our study nominated this polymorphism as a potential biomarker for early risk stratification for Asians. Further large-scale validation is needed to establish fully solid and conclusive evidence for the impact of the insertion polymorphism on preeclampsia risk.
Topics: Female; Humans; Pregnancy; 3' Untranslated Regions; Asian; Fetus; Pre-Eclampsia; HLA-G Antigens
PubMed: 37633154
DOI: 10.1016/j.jri.2023.104135 -
Cureus Jul 2023Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which... (Review)
Review
Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which in turn results in a multi-systemic disorder. There are numerous known CF alleles associated with different mutations of the CFTR gene, with the most common CF allele being a three-base-pair deletion known as ΔF508. One common manifestation of CF is glycemic dysregulation associated with decreased insulin secretion, often progressing into a distinct form of diabetes known as cystic fibrosis-related diabetes (CFRD). In the past decade, a class of drugs known as CFTR modulators has entered clinical practice. These drugs interact with the CFTR protein to restore its function, with different modulators (or combinations of modulators) suitable for patients with different CFTR mutations. Previous research has established that the modulator ivacaftor is effective in decreasing blood glucose and sometimes resolving CFRD in patients with certain CFTR mutations (class III mutations). However, early modulator therapies for individuals with the common ΔF508 mutation (e.g., a combination of the modulators lumacaftor and ivacaftor) have largely proven ineffective in improving glucose regulation. More recently, a combination therapy of three modulators, namely elexacaftor, tezacaftor, and ivacaftor (ETI), has entered clinical practice for patients with the ΔF508 mutation. However, it is not clear whether this therapy is effective in treating dysglycemia. We searched for studies of any design that examined the effects of ETI on measures of blood glucose. All available studies were observational studies comparing patients before and after initiating ETI therapy. Measures of daily-life blood glucose (those obtained with continuous glucose monitoring systems or by measuring glycated hemoglobin (HbA1c)) and post-prandial glucose spikes from oral glucose tolerance tests showed significant improvements in at least some studies. The majority of studies showed significant improvements from pre- to post-ETI in one or more blood glucose measures. While the interpretation of this evidence is complicated by the lack of randomized controlled trials, it appears that ETI therapy is associated with improved glucose regulation for at least some patients with the ΔF508 mutation.
PubMed: 37575762
DOI: 10.7759/cureus.41697 -
Orphanet Journal of Rare Diseases Jun 2023CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain... (Review)
Review
CSF1R mutations cause autosomal-dominant CSF1R-related leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) and autosomal-recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS). The former is increasingly recognized, and disease-modifying therapy was introduced; however, literature is scarce on the latter. This review analyzes BANDDOS and discusses similarities and differences with CSF1R-ALSP.We systematically retrieved and analyzed the clinical, genetic, radiological, and pathological data on the previously reported and our cases with BANDDOS. We identified 19 patients with BANDDOS (literature search according to the PRISMA 2020 guidelines: n = 16, our material: n = 3). We found 11 CSF1R mutations, including splicing (n = 3), missense (n = 3), nonsense (n = 2), and intronic (n = 2) variants and one inframe deletion. All mutations disrupted the tyrosine kinase domain or resulted in nonsense-mediated mRNA decay. The material is heterogenous, and the presented information refers to the number of patients with sufficient data on specific symptoms, results, or performed procedures. The first symptoms occurred in the perinatal period (n = 5), infancy (n = 2), childhood (n = 5), and adulthood (n = 1). Dysmorphic features were present in 7/17 cases. Neurological symptoms included speech disturbances (n = 13/15), cognitive decline (n = 12/14), spasticity/rigidity (n = 12/15), hyperactive tendon reflex (n = 11/14), pathological reflexes (n = 8/11), seizures (n = 9/16), dysphagia (n = 9/12), developmental delay (n = 7/14), infantile hypotonia (n = 3/11), and optic nerve atrophy (n = 2/7). Skeletal deformities were observed in 13/17 cases and fell within the dysosteosclerosis - Pyle disease spectrum. Brain abnormalities included white matter changes (n = 19/19), calcifications (n = 15/18), agenesis of corpus callosum (n = 12/16), ventriculomegaly (n = 13/19), Dandy-Walker complex (n = 7/19), and cortical abnormalities (n = 4/10). Three patients died in infancy, two in childhood, and one case at unspecified age. A single brain autopsy evidenced multiple brain anomalies, absence of corpus callosum, absence of microglia, severe white matter atrophy with axonal spheroids, gliosis, and numerous dystrophic calcifications.In conclusion, BANDDOS presents in the perinatal period or infancy and has a devastating course with congenital brain abnormalities, developmental delay, neurological deficits, osteopetrosis, and dysmorphic features. There is a significant overlap in the clinical, radiological, and neuropathological aspects between BANDDOS and CSF1R-ALSP. As both disorders are on the same continuum, there is a window of opportunity to apply available therapy in CSF1R-ALSP to BANDDOS.
Topics: Humans; Neuroglia; Leukoencephalopathies; Brain; Mutation; Nervous System Malformations; Atrophy
PubMed: 37349768
DOI: 10.1186/s13023-023-02772-9 -
Frontiers in Immunology 2023Primary complement system (C) deficiencies are rare but notably associated with an increased risk of infections, autoimmunity, or immune disorders. Patients with...
Primary complement system (C) deficiencies are rare but notably associated with an increased risk of infections, autoimmunity, or immune disorders. Patients with terminal pathway C-deficiency have a 1,000- to 10,000-fold-higher risk of infections and should be therefore promptly identified to minimize the likelihood of further infections and to favor vaccination. In this paper, we performed a systematic review about clinical and genetic patterns of C7 deficiency starting from the case of a ten-year old boy infected by and with clinical presentation suggestive of reduced C activity. Functional assay Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum. Sanger sequencing of genomic DNA extracted from peripheral blood of the patient allowed the identification of two pathogenetic variants in the C7 gene: the already well-characterized missense mutation G379R and a novel heterozygous deletion of three nucleotides located at the 3'UTR (c.*99_*101delTCT). This mutation resulted in an instability of the mRNA; thus, only the allele containing the missense mutation was expressed, making the proband a functional hemizygote for the expression of the mutated C7 allele.
Topics: Male; Humans; Child; 3' Untranslated Regions; Alleles; Autoimmunity; Biological Assay
PubMed: 37304269
DOI: 10.3389/fimmu.2023.1192690 -
Seizure Jul 2023Interstitial 6q deletions are associated with rare genetic syndromes characterized by different signs, including developmental delay, dysmorphisms, and Prader-Willi...
PURPOSE
Interstitial 6q deletions are associated with rare genetic syndromes characterized by different signs, including developmental delay, dysmorphisms, and Prader-Willi (PWS)-like features. Drug-resistant epilepsy, a relatively rare finding in this condition, is often a challenge in terms of therapeutic approach. Our aim is to present a new case of interstitial 6q deletion and to conduct a systematic review of the literature with an emphasis on the neurophysiological and clinical traits of afflicted individuals.
METHODS
We report a patient with an interstitial 6q deletion. Standard electroencephalograms (EEG), video-EEG with polygraphy and MRI features are discussed. We also conducted a literature review of previously described cases.
RESULTS
We describe a relatively small interstitial 6q deletion (2 Mb circa), detected by CGH-Array, not encompassing the previously described 6q22 critical region for epilepsy occurrence. The patient, a 12-year-old girl, presented with multiple absence-like episodes and startle-induced epileptic spasms since the age of 11, with partial polytherapy control. Treatment with lamotrigine induced the resolution of startle-induced phenomena. From the literature review, we identified 28 patients with overlapping deletions, often larger than our patient's mutation. Seventeen patients presented with PWS-like features. Epilepsy was reported in 4 patients, and 8 patients presented abnormal EEG findings. In our patient, the deletion included genes MCHR2, SIM1, ASCC3, and GRIK2, but, interestingly, it did not encompass the 6q22 critical region for epilepsy occurrence. The involvement of GRIK2 in the deletion may play a role.
CONCLUSION
Literature data are limited, and specific EEG or epileptological phenotypes cannot yet be identified. Epilepsy, although uncommon in the syndrome, deserves a specific diagnostic workup. We speculate on the existence of an additional locus in the 6q16.1-q21 region, different from the already hypothesized q22, promoting the development of epilepsy in affected patients.
Topics: Humans; Prader-Willi Syndrome; Chromosome Deletion; Phenotype; Mutation; Drug Resistant Epilepsy; Epilepsy; DNA Helicases
PubMed: 37210930
DOI: 10.1016/j.seizure.2023.05.011 -
Annals of Hematology Aug 2023IKZF1 (IKAROS family Zinc Finger 1) alteration is an essential regulator of both T- and B-cell lineage specification with leukemogenic potential. IKZF1 deletion have... (Meta-Analysis)
Meta-Analysis
IKZF1 (IKAROS family Zinc Finger 1) alteration is an essential regulator of both T- and B-cell lineage specification with leukemogenic potential. IKZF1 deletion have been described in childhood acute lymphoblastic leukemia (ALL) with varying prevalence often influenced by underlying cytogenetics and also shown to have diverse prognostic significance. We aimed to evaluate the prevalence and prognostic significance of IKZF1 deletion among childhood ALL. Electronic databases of MEDLINE, EMBASE and SCOPUS were searched and 32 studies found eligible. Estimated prevalence of IKZF1 deletion among BCR::ABL1 negative and BCR::ABL1 positive ALL patients was 14% (95%CI:13-16%, I = 79%; 26 studies) and 63% (95%CI:59-68% I = 42%; 10 studies) respectively. Most common site of IKZF1 deletion was whole chromosome (exon1-8) deletion in 32.3% (95%CI: 23.8-40.7%) followed by exon 4-7 deletion in 28.6% (95%CI: 19.7-37.5%). A positive minimal residual disease at the end of induction was more common among patients with IKZF1 deletion, odds ratio: 3.09 (95%CI:2.3-4.16, I = 54%; 15 studies). Event-free survival and overall survival were significantly worse for IKZF1 deletion, hazard ratio (HR): 2.10 (95%CI:1.90-2.32, I = 28%; 31 studies) and HR: 2.38 (95%CI:1.93-2.93, I = 40; 15 studies) respectively. In summary, the current meta-analysis highlights the frequency of IKZF1 deletion and its negative impact on survival in childhood ALL. Further studies exploring the influence of IKZF1 deletion in the presence of classical cytogenetic and other copy number alterations would further help in characterising its prognostic role.
Topics: Child; Humans; Prognosis; Prevalence; Ikaros Transcription Factor; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Progression-Free Survival; Gene Deletion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37154889
DOI: 10.1007/s00277-023-05250-1 -
Journal of Magnetic Resonance Imaging :... Nov 2023As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in... (Review)
Review
As an important genomic marker for oligodendrogliomas, early determination of 1p/19q co-deletion status is critical for guiding therapy and predicting prognosis in patients with glioma. The purpose of this study is to systematically review the literature concerning the magnetic resonance imaging (MRI) with artificial intelligence (AI) methods for predicting 1p/19q co-deletion status in glioma. PubMed, Scopus, Embase, and IEEE Xplore were searched in accordance with the Preferred Reporting Items for systematic reviews and meta-analyses guidelines. Methodological quality of studies was assessed according to the Quality Assessment of Diagnostic Accuracy Studies-2. Finally, 28 studies were included in the quantitative analysis. Diagnostic test accuracy reached an area under the ROC curve of 0.71-0.98 were reported in 24 studies. The remaining four studies with no available AUC provided an accuracy of 0.75-0. 89. The included studies varied widely in terms of imaging sequences, input features, and modeling methods. The current review highlighted that integrating MRI with AI technology is a potential tool for determination 1p/19q status pre-operatively and noninvasively, which can possibly help clinical decision-making. However, the reliability and feasibility of this approach still need to be further validated and improved in a real clinical setting. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: 2.
Topics: Humans; Artificial Intelligence; Brain Neoplasms; Reproducibility of Results; Chromosome Deletion; Glioma; Isocitrate Dehydrogenase; Oligodendroglioma; Mutation
PubMed: 37083159
DOI: 10.1002/jmri.28737 -
Neuropediatrics Oct 2023Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE)....
BACKGROUND
Autosomal dominant mutations of the gene can cause two epileptic disorders: benign familial neonatal seizures (BFNS) and developmental epileptic encephalopathy (DEE). This systematic review aims to identify the best reported therapy for these patients, relating to phenotype, neurodevelopmental outcome, and an eventual correlation between phenotype and genotype.
METHODS
We searched on PubMed using the search terms "" AND "therapy" and "" AND "treatment"; we found 304 articles. Of these, 29 met our criteria. We collected the data from 194 patients. All 29 articles were retrospective studies.
RESULTS
In all, 104 patients were classified as DEE and 90 as BFNS. After treatment began, 95% of BFNS patients became seizure free, whereas the seizures stopped only in 73% of those with DEE. Phenobarbital and sodium channel blockers were the most used treatment in BFNS. Most of the DEE patients (95%) needed polytherapy for seizure control and even that did not prevent subsequent developmental impairment (77%).Missense mutations were discovered in 96% of DEE patients; these were less common in BFNS (50%), followed by large deletion (16%), truncation (16%), splice donor site (10%), and frameshift (7%).
CONCLUSION
Phenobarbital or carbamazepine appears to be the most effective antiseizure medication for children with a "benign" variant. On the contrary, polytherapy is often needed for DEE patients, even if it does not seem to improve neurological outcomes. In DEE patients, most mutations were located in S4 and S6 helix, which could serve as a potential target for the development of more specific treatment in the future.
Topics: Child; Infant, Newborn; Humans; Retrospective Studies; KCNQ2 Potassium Channel; Epilepsy, Benign Neonatal; Mutation; Seizures; Phenotype; Genotype; Phenobarbital
PubMed: 36948217
DOI: 10.1055/a-2060-4576