ABCB1 Polymorphisms and Drug-Resistant Epilepsy in a Tunisian Population.

BACKGROUND: Epilepsy is one of the most common neurological disorders with about 30% treatment failure rate. An interindividual variations in efficacy of antiepileptic drugs (AEDs) make the treatment of epilepsy challenging, which can be attributed to genetic factors such as ATP-Binding Cassette sub-family B, member1 (ABCB1) gene polymorphisms. OBJECTIVE: The main objective of the present study is to evaluate the association of ABCB1 C1236T, G2677T, and C3435T polymorphisms with treatment response among Tunisian epileptic patients. MATERIALS AND METHODS: One hundred epileptic patients, originated from north of Tunisia, were recruited and categorized into 50 drug-resistant and 50 drug-responsive patients treated with antiepileptic drugs (AEDs) as per the International League Against Epilepsy. DNA of patients was extracted and ABCB1 gene polymorphisms studied using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The C1236T, G2677T, and C3435T polymorphisms were involved into AED resistance. Significant genotypic (C1236T TT (p ≤ 0.001); G2677T TT (p = 0.001); C3435T TT (p ≤ 0.001)) and allelic associations (C1236T T (3.650, p ≤ 0.001); G2677TT (1.801, p = 0.044); C3435T T (4.730, p ≤ 0.001)) with drug resistance epilepsy (DRE) were observed. A significant level of linkage disequilibrium (LD) was also noted between ABCB1 polymorphisms. Patients with the haplotypes CT and TT (C1236T-G2677T); GT, TC, and TT (G2677T-C3435T); CT and TT (C1236T-C3435T); CTT, TTC, TGT, and TTT (C1236T-G2677T-C3435T) were also significantly associated to AED resistance. CONCLUSIONS: The response to antiepileptics seems to be modulated by TT genotypes, T alleles, and the predicted haplotypes for the tested SNPs in our population. Genetic analysis is a valuable tool for predicting treatment response and thus will contribute to personalized medicine for Tunisian epileptic patients.

EGFR mutation status in Tunisian non-small-cell lung cancer patients evaluated by mutation-specific immunohistochemistry.

BACKGROUND: Screening mutations in epidermal growth factor receptor (EGFR) to analyze non-small-cell lung cancer (NSCLC) profile is the criterion to choose the best therapeutic strategy. New Oncology guidelines recommend EGFR mutation analysis before prescribing tyrosine kinase inhibitors (TKIs) treatment. Majority of lung cancer patients are diagnosed at advanced stages and generally only small biopsies materials are available for diagnostic and molecular characterization. The aim of this first work is to screen EGFR mutation status in Tunisian NSCLC by mutation-specific immunohistochemistry (IHC) and molecular biology, to estimate the relevance of proposing TKIs as a new therapeutic line. METHODS: E746-A750 deletion and L858R mutations were screened in 50 unselected NSCLC formalin-fixed paraffin-embedded (FFPE) tissue samples. Mutation expression by IHC was evaluated by intensity and percentage of staining and correlated to patients' data. DNA was extracted and EGFR mutations were analyzed by Sanger sequencing. Positive and negative controls were included for EGFR mutations in order to support the results. RESULTS: Among our patients (48 men and 2 women) all adenocarcinoma (confirmed by histology and IHC with TTF1/Napsin A), 94% were smokers exceeding the tobacco risk threshold (at least 25 pack-years) and the women were none. 44% had EGFR mutation by IHC: 26% had simple mutation and 18% had concurrent mutation. All mutated cases were smokers except a woman who was none. Concurrent mutations patients exceeded 40 pack-years. 91.4% of IHC results were validated by molecular analysis (100% of negative and 85% of positive cases) showing either T > G (exon 21) or 2235-2249 del (exon 19). CONCLUSIONS: These preliminary results confirm the usefulness of IHC to detect EGFR mutations but the frequency of concurrent mutations doesn't appear in favor of EGFR TKIs treatment. In fact, literature reports a significantly worse response compared to those with single mutation when treated by TKIs.

First case report of Cohen syndrome in the Tunisian population caused by VPS13B mutations.

BACKGROUND: Cohen syndrome is a rare autosomal recessive developmental disorder that comprises variable clinical features counting developmental delay, pigmentary retinopathy, myopia, acquired microcephaly, truncal obesity, joint hypermobility, friendly disposition and intermittent neutropenia. VPS13B (vacuolar protein sorting 13, yeast, homologue of B) gene is the only gene responsible for Cohen Syndrome, causative mutations include nonsense, missense, indel and splice-site variants. The integrity of the Golgi apparatus requires the presence of the peripheral membrane protein VPS13B that have an essential function in intracellular protein transport and vesicle-mediated sorting. CASE PRESENTATION: In this study, we performed whole exome sequencing (WES) in a Tunisian family with two young cases having developmental delay, hypotonia, autism spectrum disorder, ptosis and thick hair and eyebrows. The proposita presented also pigmentory retinopathy. Compound heterozygous mutation in VPS13B gene was detected by WES. This mutation inherited from healthy heterozygous parents, supports an unpredictable clinical diagnosis of Cohen Syndrome. The proband's phenotype is explained by the presence of compound heterozygous mutations in the VPS13B gene. This finding refined the understanding of genotype-phenotype correlation. CONCLUSIONS: This is the first report of a Tunisian family with Cohen syndrome mutated in the VPS13B gene.

Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis.

BACKGROUND: Antiepileptic drugs (AEDs) are effective medications available for epilepsy. However, many patients do not respond to this treatment and become resistant. Genetic polymorphisms may be involved in the variation of AEDs response. Therefore, we conducted an updated systematic review and a meta-analysis to investigate the contribution of the genetic profile on epilepsy drug resistance. METHODS: We proceeded to the selection of eligible studies related to the associations of polymorphisms with resistance to AEDs therapy in epilepsy, published from January 1980 until November 2016, using Pubmed and Cochrane Library databases. The association analysis was based on pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: From 640 articles, we retained 13 articles to evaluate the relationship between ATP-binding cassette sub-family C member 1 (ABCB1) C3435T polymorphism and AEDs responsiveness in a total of 454 epileptic AEDs-resistant cases and 282 AEDs-responsive cases. We found a significant association with an OR of 1.877, 95% CI 1.213-2.905. Subanalysis by genotype model showed a more significant association between the recessive model of ABCB1 C3435T polymorphism (TT vs. CC) and the risk of AEDs resistance with an OR of 2.375, 95% CI 1.775-3.178 than in the dominant one (CC vs. TT) with an OR of 1.686, 95% CI 0.877-3.242. CONCLUSION: Our results indicate that ABCB1 C3435T polymorphism, especially TT genotype, plays an important role in refractory epilepsy. As genetic screening of this genotype may be useful to predict AEDs response before starting the treatment, further investigations should validate the association.

Subtelomeric microduplications in three sisters with moderate mental retardation.

Copy number changes of subtelomeric regions are a common cause of mental retardation, occurring in approximately 5% of mentally retarded patients. New molecular techniques allow the identification of subtelomeric microduplications. We report a Tunisian family of three sisters with moderate mental retardation, facial dysmorphism, cardiopathy, and bilateral clinodactyly of the third and fourth toes, explored by MLPA, showing the same associated microduplications, 15q and Xq, without a concurrent deletion.

MLPA subtelomere analysis in Tunisian mentally retarded patients.

Subtelomeric rearrangements significantly contribute to idiopathic mental retardation and result in several mental retardation syndromes; however, most subtelomeric defects lack a characteristic phenotype. Thirty patients with unexplained mental retardation, a normal R banded karyotype at the 550 band, and no clinically recognizable syndrome were screened by Multiplex ligation-dependent probe amplification (MLPA). Four anomalies were identified: deletion 17q, duplications (4q), and associated duplications 15q and Xq. This duplication was found in two sisters of the proband. Anomalies were unidentified by the conventional technique. The prevalence of subtelomeric imbalances in our cohort of moderate to severe mental retardation is around 13% and is consistent with the literature. The sensitivity of the MLPA technique was characterized on cytogenetically verified positive and negative controls. MLPA is a fast, reliable, and relatively inexpensive technique to detect subtelomeric rearrangement in comparison with the fluorescence in situ hybridization (FISH) technique.

[Interest of studying subtelomeric abnormalities by in situ fluorescent hybridization to explore idiopathic mental retardation]. / Intérêts de l'étude des remaniements subtélomériques par la technique d'hybridation fluorescente (FISH) dans l'exploration des retards mentaux idiopathiques.

Nowadays, the genetic basis of mental retardation is a huge field of investigations. Genetic abnormalities frequently give rise to a mental retardation phenotype and are observed in 10 to 40% of known etiologies. New syndromes have identified (chromosome 1p, 22q, 3q29 and 9q34) but for 60% of patients there is no etiology because there is no characteristic phenotype. Many studies involve subtelomeric duplications and deletions in idiopathic mental retardation. The autours describe and discuss the interest and the limits of telomeric FISH [Chromoprobe Multiprobe T System] in exploring mental retardation.