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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 -
Orphanet Journal of Rare Diseases Jan 2023Woodhouse-Sakati syndrome (WSS) is a rare, autosomal recessive genetic disorder with variable clinical manifestations mainly affecting the endocrine and nervous systems.... (Review)
Review
BACKGROUND
Woodhouse-Sakati syndrome (WSS) is a rare, autosomal recessive genetic disorder with variable clinical manifestations mainly affecting the endocrine and nervous systems. The aim of this study was to systematically review the genetic basis of WSS and report the genetic variants and clinical phenotypes associated with the disease.
METHODS
PubMed, Science Direct, Scopus, and Web of Science databases were searched from the time of inception until June 2022. Broad search terms were used to capture the literature describing all genetic variants associated with WSS. The search keywords used are "Woodhouse Sakati" along with the term "mutation" OR "gene" OR "variant" OR "polymorphism".
RESULTS
Twenty-five eligible studies were included in this study. One hundred and eighty-five patients in 97 families from 12 different countries were diagnosed with WSS. In patients from the Greater Middle East (GME) region, consanguineous marriages were common (67%). Thirteen different DCAF17 variants were associated with WSS development (including 8 identified in the GME region). The most frequent variant was a frameshift deletion variant (c.436delC, p.Ala147Hisfs*9) unique to Arabs that was reported in 11 cases from Tunisia, Kuwait, Qatar, Bahrain, and Saudi Arabia. There were no clear genotype-phenotype correlations for the different variants.
CONCLUSIONS
This systematic review highlights the molecular basis and clinical manifestations of WSS globally, including the GME region, where the disease is prevalent due to consanguinity. Additional studies are now needed to understand the genotype-phenotype correlation for different DCAF17 variants and their impact on the phenotypic heterogeneity observed in WSS patients.
Topics: Humans; Molecular Epidemiology; Middle East; Diabetes Mellitus; Alopecia; Nuclear Proteins; Ubiquitin-Protein Ligase Complexes
PubMed: 36721231
DOI: 10.1186/s13023-023-02614-8 -
Frontiers in Immunology 2022Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies... (Meta-Analysis)
Meta-Analysis
Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in patients with relapsed or refractory lymphoid neoplasms: A systematic review and meta-analysis of prospective clinical trials.
BACKGROUND
Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies support the efficacy of duvelisib, the safety of duvelisib remains with great attention. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid neoplasm types.
METHODS
We searched prospective clinical trials from PUBMED, EMBASE, Cochrane Library, and ClinicalTrials.gov. For efficacy analysis, Overall response rate (ORR), complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), rate of progressive disease (PDR), median progression-free survival (mPFS), 12-/24-month PFS, and 12-month overall survival (OS) were assessed. For safety analysis, the incidences of any grade and grade ≥3 adverse events (AEs), serious AEs, and treatment-related discontinuation and death were evaluated. Subgroup analysis based on the disease type was performed.
RESULTS
We included 11 studies and 683 patients, including 305 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 187 B-cell indolent non-Hodgkin lymphoma (iNHL), 39 B-cell aggressive non-Hodgkin lymphoma (aNHL), and 152 T-cell non-Hodgkin lymphoma (T-NHL) patients. The pooled ORR in CLL/SLL, iNHL, aNHL and T-NHL was 70%, 70%, 28% and 47%, respectively. Additionally, the pooled ORR in CLL/SLL patients with or without TP53 mutation/17p-deletion (62% vs. 74%, p=0.45) and in follicular lymphoma (FL) or other iNHL (69% vs. 57%, p=0.38) had no significant differences. Mantle cell lymphoma (MCL) patients had higher pooled ORR than other aNHL (68% vs. 17%, p=0.04). Angioimmunoblastic TCL (AITL) patients had higher pooled ORR than other PTCL patients (67% vs. 42%, p=0.01). The pooled incidence of any grade, grade ≥3, serious AEs, treatment-related discontinuation and death was 99%, 79%, 63%, 33% and 3%, respectively. The most frequent any-grade AEs were diarrhea (47%), ALT/AST increase (39%), and neutropenia (38%). The most frequent grade ≥3 AEs were neutropenia (25%), ALT/AST increased (16%), diarrhea (12%), and anemia (12%).
CONCLUSION
Generally, duvelisib could offer favorable efficacy in patients with RR CLL/SLL, iNHL, MCL, and AITL. Risk and severity in duvelisib treatment may be mitigated through proper identification and management.
Topics: Humans; Adult; Phosphatidylinositol 3-Kinases; Leukemia, Lymphocytic, Chronic, B-Cell; Prospective Studies; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Lymphoma, B-Cell; Neutropenia; Diarrhea
PubMed: 36685572
DOI: 10.3389/fimmu.2022.1070660 -
BMC Medical Genomics Dec 2022The incidence of hereditary spherocytosis (HS) is approximately 1:2000 in the western population, while it is much lower in the Chinese population. It is difficult to...
BACKGROUND
The incidence of hereditary spherocytosis (HS) is approximately 1:2000 in the western population, while it is much lower in the Chinese population. It is difficult to make a definite diagnosis due to the variable genotypic features and the lack of well-documented evidence for HS patients. Gene sequence examination is helpful for clear diagnosis.
CASE PRESENTATION
We presented the case of a 29-year-old male HS patient with skin yellowness, anorexia, and cholecystolithiasis as the first manifestations. Laboratory examination of the patient and his parents showed a mild reduction in hemoglobin and mean corpuscular hemoglobin concentration, increased reticulocytes, and promotion of indirect bilirubin in the patient and his father. Furthermore, small globular red blood cells with increased osmotic fragility were observed. In particular, the eosin-5'-maleimide binding test provided the strong evidence that band 3 protein was deleted in the erythrocyte membrane. Next-generation sequencing (NGS) and Sanger sequencing further demonstrated a heterozygous nonsense variant (exon16, c.G1985A: p.W662X) in SLC4A1, inherited from his father. Thus, the patient was diagnosed with HS, and then was effectively treated. After splenectomy, the anemia was relieved without any obvious unpleasant side effects.
CONCLUSION
We report an extremely rare case of HS in China that presented with hereditary hemolytic anemia with band 3 deletion resulting from a novel variant of SLC4A1, and systematically review a large number of related literatures. This study, therefore, significantly contributes to the literature on HS.
Topics: Adult; Humans; Male; Anion Exchange Protein 1, Erythrocyte; Asian People; Erythrocytes; Genotype; Heterozygote; Spherocytosis, Hereditary
PubMed: 36463227
DOI: 10.1186/s12920-022-01399-2 -
BMC Cancer Nov 2022Combination chemoimmunotherapy (CIT) consisting of anti-CD20 has improved the progression-free survival (PFS) and overall survival (OS) of patients with chronic... (Meta-Analysis)
Meta-Analysis
Prognostic markers in patients with chronic lymphocytic leukaemia on targeted therapy, chemoimmunotherapy with anti-CD20 monoclonal antibody: a systematic review and meta-analysis of prognostic factors.
Combination chemoimmunotherapy (CIT) consisting of anti-CD20 has improved the progression-free survival (PFS) and overall survival (OS) of patients with chronic lymphocytic leukaemia (CLL). We performed a comprehensive synthesis of prognostic factors in patients with CLL on combined CIT with anti-CD20 antibodies compared with standard chemotherapy alone or targeted therapy.We searched the MEDLINE and academic search complete electronic databases as well as clinicaltrials.gov (from inception up to 01 August 2022) for randomised controlled trials examining chemoimmunotherapy and targeted therapy in patients with CLL. The risk of bias and the quality of evidence was assessed using the quality in prognostic studies tool (QUIPS).A total of 10 prognostic factors were identified and evaluated in patients with CLL on anti-CD20 antibody-containing CIT. The predictive value of the following prognostic factors was confirmed and associated with poor patient outcomes; deletion 17p (HR = 3.39), Immunoglobulin heavy chain variable region gene mutation status (HR = 0.96) and βmicroglobulin (HR = 1.41).Conventional predictive factors may have retained prognostic value and could be useful in the stratification of patients who may be non-responsive to CIT.Trial registration: International Prospective Register of Systematic Reviews (PROSPERO) registry (CRD42021218997).
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis; Antibodies, Monoclonal; Immunotherapy; Antineoplastic Agents
PubMed: 36434612
DOI: 10.1186/s12885-022-10223-0 -
Neuro-oncology Advances 2022Disseminated pediatric low-grade gliomas and glioneuronal tumors (dpLGG/GNTs) are associated with a poorer prognosis than nondisseminated pLGG/GNTs. To date there is no...
BACKGROUND
Disseminated pediatric low-grade gliomas and glioneuronal tumors (dpLGG/GNTs) are associated with a poorer prognosis than nondisseminated pLGG/GNTs. To date there is no comprehensive report characterizing the genome profile of dpLGG/GNTs and their relative survival. This systematic review aims to identify the pattern of genetic alterations and long-term outcomes described for dpLGG/GNT.
METHODS
A systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively.
RESULTS
Fifty studies published from 1994 to 2020 were included in this review with 366 cases reported. There was sporadic reporting of genetic alterations. The most common molecular alterations observed among subjects were 1p deletion (75%) and fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of subjects demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone (59%) to surgical resection (41%) and CSF diversion (28%). Overall, 73% of cases were alive at last follow-up. Survival did not vary by tumor type or timing of dissemination. All studies reviewed either ranked low or moderate for both quality and risk of bias assessments.
CONCLUSIONS
Chromosome 1p deletion and fusion were the most common alterations identified in dpLGG/GNT cases reviewed. The relative molecular heterogeneity between DLGG and DLGNT, however, deserves further exploration and ultimately correlation with their biologic behavior to better understand the pathogenesis of dpLGG/GNT.
PubMed: 36382112
DOI: 10.1093/noajnl/vdac122 -
Neurogenetics Oct 2022C-terminal binding proteins (CtBP1/2) are transcriptional coregulators that play a significant role during vertebrate neurodevelopment. This systematic review aims to... (Review)
Review
C-terminal binding proteins (CtBP1/2) are transcriptional coregulators that play a significant role during vertebrate neurodevelopment. This systematic review aims to identify case reports with genetic variants in CTBP1 and CTBP2 associated with brain development syndromes.We screened different databases (PubMed, Scopus, Google Scholar, LILACS) by systematically searching journals and checking reference lists and citations of background papers. We found fourteen cases (10 males) from five papers carrying two pathogenic, heterozygous variants in the CTBP1 gene (13 individuals carried the missense mutation c.991C T, p.Arg342Trp, and one subject carrying the 2-base pair deletion c.1315_1316delCA, p.Gln439ValfsTer84). These mutations were de novo in 13 cases and one case of maternal germinal mosaicism. Two variants are in the same domain of the protein: Pro-Leu-Asp-Leu-Ser (PLDLS) C terminal. Patients with these mutations exhibit a phenotype with intellectual disability, HADDTS syndrome (hypotonia, ataxia, developmental delay, and tooth enamel defects), and cerebellar volume loss. We did not identify reported cases associated with homozygous mutations harbored in CTBP1. We did not identify any report of neurodevelopment phenotypes associated with heterozygous or homozygous CTBP2 mutations. Due to CTBP2/RIBEYE being a gene with dual function, identifying and interpreting the potential pathogenic variants is challenging.Further, homozygous mutations in the CTBP2 gene may be lethal. The mechanisms involved in the pathogenesis of neurodevelopment due to variants of these proteins have not yet been elucidated, despite some functional evidence. Further studies should be conducted to understand these transcription factors and their interaction with each other and their partners.
Topics: Humans; Alcohol Oxidoreductases; Ataxia; Co-Repressor Proteins; Muscle Hypotonia; Mutation; Mutation, Missense; Transcription Factors
PubMed: 36331689
DOI: 10.1007/s10048-022-00700-w -
Journal of Oncology 2022To compare the efficacy of EGFR-TKIs combined with antiangiogenic agents between non-small cell lung cancer patients with exon 19 deletion and patients with exon 21...
Comparison of the Efficacy of EGFR-TKIs Combined with Antiangiogenic Agents between Patients with Exon 19 Deletion and Patients with Exon 21 Leu858 Arg Mutation: A Systematic Review and Meta-Analysis.
PURPOSE
To compare the efficacy of EGFR-TKIs combined with antiangiogenic agents between non-small cell lung cancer patients with exon 19 deletion and patients with exon 21 Leu858 Arg mutation.
METHODS
Electronic databases (PubMed, Embase, and the Cochrane Central Register of Controlled Trials) were systematically searched for studies published until March 2022. Randomized control trials comparing the survival of EGFR-TKIs plus antiangiogenic agents with EGFR-TKI were extracted. The primary endpoint was progression-free survival (PFS).
RESULTS
Five randomized control trials involving 1533 patients were as follows: 818 patients had exon 19 deletion, and 715 patients with exon 21 Leu858 Arg mutation. The methodological quality of the 5 randomized control trials was high. EGFR-TKIs plus antiangiogenic agents improved PFS in patients with exon 19 deletion (hazard ratio [HR] = 0.62, 95% confidence interval [CI]: 0.51-0.75) and exon 21 Leu858 Arg mutation (HR = 0.61, 95% CI: 0.50-0.75). PFS did not differ between the exon 19 deletion and exon 21 Leu858 Arg mutation groups ( = 0.07, =0.94).
CONCLUSIONS
PFS was comparable between patients receiving EGFR-TKIs combined with antiangiogenic agents with exon 19 deletion and those with exon 21 Leu858 Arg mutation.
PubMed: 36312218
DOI: 10.1155/2022/9399797 -
Cureus Sep 2022A cystic fibrosis (CF) transmembrane conductor regulator (CFTR) gene modulating triple therapy combining elexacaftor-tezacaftor-ivacaftor (Trikafta) has been recently... (Review)
Review
A cystic fibrosis (CF) transmembrane conductor regulator (CFTR) gene modulating triple therapy combining elexacaftor-tezacaftor-ivacaftor (Trikafta) has been recently discovered. Its approval by the Food and Drug Administration (FDA) in 2019 has expanded the target therapy group to individuals aged twelve and up with at least one Phe508del (phenylalanine 508 deletion) mutation in the CFTR gene. This systematic review aims to assess this combination therapy's safety and efficacy. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, an in-depth search was performed. The search was done by utilizing databases such as PubMed Central (PMC), Google Scholar, and Science Direct for articles related to this topic. Studies published in the last five years in the English language were chosen preliminarily. Further eligibility criteria and quality assessment tools were employed to assess the risk of bias and finalize ten articles to be used in this review. The chosen articles constituted four randomized control trials (RCTs), four systematic reviews, and two narrative reviews. The last date for data collection was April 24, 2022. Based on the findings of this review, we concluded that by combining three CFTR modulators, this therapy had outperformed all the currently available medications in terms of improving pulmonary function, reducing exacerbations, and enhancing the quality of life of CF patients. In clinical trials, headache and rash were the most common side effects, and laboratory testing to assess liver function is suggested. Long-term safety and effectiveness must be confirmed by the continued review of real-life patient data. Studies done on triple therapy thus far have been promising. Unfortunately, a small proportion of the CF population remains ineligible for any form of CFTR modulator therapy owing to their type of genetic mutation, and this provides ground for further research in this field.
PubMed: 36284811
DOI: 10.7759/cureus.29359 -
Oncology Letters Nov 2022The prognostic value of tumor protein P53 (TP53) mutation for tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant non-small-cell lung cancer (NSCLC) remains...
The prognostic value of tumor protein P53 (TP53) mutation for tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant non-small-cell lung cancer (NSCLC) remains controversial. Therefore, the present meta-analysis was performed to investigate the potential association between the prognosis of TKI treatment for patients with advanced EGFR mutation-positive NSCLC and the presence or absence of concurrent TP53 mutations. In the present study, 24 eligible studies from the PubMed, Embase and Cochrane databases were identified by screening prior to inclusion. Data were extracted by two independent investigators and analyzed using STATA 14.0 software. Pooled odds ratios (ORs) with 95% confidence interval (CIs) were used to determine the association between objective response rates (ORRs) and TP53 mutations. In addition, differences in the incidence of TP53 mutations between patients with exon 21 L858R mutations and exon 19 deletions of EGFR were evaluated using this method. Pooled hazard ratios (HRs) with 95% CIs were used to calculate the prognostic value of TP53 mutations for progression-free survival (PFS) and overall survival (OS). No significant difference in the incidence of TP53 mutations was detected between the patients with exon 21 L858R mutation and those with exon 19 deletion (OR=0.91; 95% CI=0.65-1.27; P=0.568). However, the pooled results revealed that TP53 mutations were significantly associated with shorter PFS (HR=1.51; 95% CI=1.33-1.71; P<0.001) and OS (HR=1.64; 95% CI=1.33-2.02; P<0.001). By contrast, TP mutations were not associated with the ORR of EGFR-TKI treatment (OR=0.91; 95% CI=0.69-1.21; P=0.529). In conclusion, a worse prognosis for TKI treatment was observed in patients with EGFR-mutant NSCLCs and concurrent TP53 mutations, suggesting that TP53 mutations is associated with primary resistance to EGFR-TKIs.
PubMed: 36238360
DOI: 10.3892/ol.2022.13504