Comorbidity in the Tunisian population.

Genetic diseases in the Tunisian population represent a real problem of public health as their spectrum encompasses more than 400 disorders. Their frequency and distribution in the country have been influenced by demographic, economic and social features especially consanguinity. In this article, we report on genetic disease association referred to as comorbidity and discuss factors influencing their expressivity. Seventy-five disease associations have been reported among Tunisian families. This comorbidity could be individual or familial. In 39 comorbid associations, consanguinity was noted. Twenty-one founder and 11 private mutations are the cause of 34 primary diseases and 13 of associated diseases. As the information dealing with this phenomenon is fragmented, we proposed to centralize it in this report in order to draw both clinicians' and researcher's attention on the occurrence of such disease associations in inbred populations as it makes genetic counseling and prenatal diagnosis challenging even when mutations are known.

Piracetam for reducing the incidence of painful sickle cell disease crises.

BACKGROUND: Sickle cell disease is one of the most common genetic disorders. Sickle cell crises in which irregular and dehydrated cells contribute to blocking of blood vessels are characterised by episodes of pain. Treatment is mainly supportive and symptomatic. In vitro studies with piracetam indicate that it has the potential for inhibition and a reversal of the process of sickling of erythrocytes. OBJECTIVES: To assess the effectiveness of piracetam for reducing the incidence of painful sickle cell disease crises. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of the last search of the Group's Haemoglobinopathies Trials Register: February 2007. SELECTION CRITERIA: Randomised controlled trials comparing orally administered piracetam to placebo or standard care in people, of all ages and both sexes, with sickle cell disease. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Trial authors were contacted for additional information. Adverse effects data were collected from the trials. MAIN RESULTS: Three trials involving 169 participants were included in the review. A limited amount of data addressing some of the primary and some of the secondary outcomes were provided, but data were incomplete and based on unvalidated assumptions used in the evaluation of outcomes. One trial reported a reduction in the number of pain crises and their severity with active intervention than placebo but presented no data to confirm these results. A second trial presented a monthly global pain score based on the number of sickle cell crises and severity of pain but included no separate data for these primary outcomes. Although there was no significant difference between the piracetam and placebo periods for the number of days of hospitalisation (P = 0.87) in one trial, inconsistencies in the criteria necessary for hospitalisation during sickle crises did not permit accurate conclusions to be drawn. Two of the trials reported participant satisfaction with piracetam but provided no details as to how this satisfaction had been assessed. There were no reports of toxicity or adverse effects with piracetam other than one participant who experienced dizziness. AUTHORS' CONCLUSIONS: The small number of included trials and their poor methodological quality provided insufficient reliable evidence to support the routine use of this medication for preventing the incidence of painful sickle cell disease crises.

History and origin of beta-thalassemia in Turkey: sequence haplotype diversity of beta-globin genes.

In the present study we report the sequence haplotypes associated with 22 beta-globin gene mutations present in Turkey. Nine nucleotide polymorphisms and an (AT)xTy motif located at the 5' end of the beta-globin gene form the sequence haplotypes that were investigated in 204 unrelated beta-thalassemia and wild-type chromosomes from Turkey. Twelve sequence haplotypes were observed in the chromosomes analyzed and haplotypic heterogeneity was found in the wild-type beta-globin genes. Samples from the Black Sea region demonstrated a remarkable level of haplotypic heterogeneity in contrast to the homogeneity present in Central Anatolian samples. Of the 22 beta-globin mutations analyzed, 18 were related with single sequence haplotypes. This simple association led to the attempt to determine the origin of these mutations by comparing their frequencies in Turkey with those in other countries and/or the world distribution of the haplotypes carrying them. However, the presence of several exceptions for the "one haplotype/one mutation" rule showed that the beta-globin gene cluster is far from static. Each of the IVS-I-110 (G-->A), Cd 39 (C-->T), IVS-I-6 (T-->C), and -30 (T-->A) beta-globin mutations was associated with a minimum of two sequence haplotypes. This fact is best explained by the likelihood of strong recombination mechanisms taking place, rather than by assuming multiple origins for each of these alleles. According to our results, malarial selection for the oldest beta-thalassemia allele in Anatolia (i.e., IVS-I-110 G-->A) may have occurred between 6500 and 2000 B.C. From that date on, most of the common beta-thalassemia mutations in Turkey were established, and by the 13th century A.D. most of them were brought to frequencies close to those observed at present.

A rare mutation [IVS-I-130 (G-A)] in a Turkish beta-thalassemia major patient.

Here we describe the identification of the rare beta-thalassemia mutation IVS-I-130 (G-A) for the first time in Turkey. The hematological evaluation of the patient showed classical signs of beta-thalassemia major requiring regular blood transfusions every 30-35 days. DNA analysis was carried out using reverse dot-blot hybridization and restriction endonuclease digestion, as well as genomic sequencing. The patient was found to be heterozygous for the IVS-I-6 (T-C) and IVS-I-130 (G-A) mutations. In order to deduce a possible origin for the IVS-I-130 (G-A) mutation, the sequence polymorphisms in the DNA of the patient and her family were characterized. The method included the analysis of nine polymorphic nucleotides and the hypervariable microsatellite of composite sequence (AT)(x)T(y) 5' to the beta-globin gene by DNA sequencing. The sequence haplotype (HT4) carrying the IVS-I-130 (G-A) mutation is also observed in Algeria. This favors a Northeastern African origin for this allele. The observed results agree well with a recent introduction of this mutation to Turkey from Egypt toward the end of the 19th century.

Identification of the Chinese IVS-II-654 (C-->T) beta-thalassemia mutation in an immigrant Turkish family: recurrence or migration?

In this study we describe the Chinese IVS-II-654 (C-->T) beta-thalassemia mutation for the first time in an immigrant Turkish family living in Istanbul and originating from Xanthe, Greece. Four members of the family, representing 3 generations, are heterozygous for this mutation. A detailed family history demonstrated a Greek origin for members of 5 generations with no records of migration or consanguineous marriages. Analysis of polymorphic nucleotides located at the 5' end of the beta-globin chromosomes bearing the IVS-II-654 mutation in the family described carried the (AT)9(T)5 type of microsatellite sequence and the ACATCCCCA haplotype. These 2 haplotype components favor a non-Eastern Asian origin for this chromosome, hence suggesting an independent origin for the IVS-II-654 mutation described in this family.

Genetic disorders in Arabs as for OMIM.

Full text is available as a scanned copy of the original print version.

HbS/beta(del)-thalassemia associated with high levels of hemoglobins A2 and F in a Turkish family.

Beta-thalassemia and sickle cell disease (SCD) are common disorders in Turkey. Compound heterozygosity for these two disorders (betaS/beta-thalassemia) is encountered frequently. In this report we present hematological and molecular data of two Turkish siblings with betaS/beta(del)-thalassemia caused by a 290 base pair (bp) deletion and associated with increased levels of hemoglobin A2 (HbA2) and hemoglobin F (HbF). Clinical analysis of the two patients showed a mild course of the disease. Haplotypic factors involved in increasing the levels of HbF were analyzed. The two patients showed no changes from the normal sequences at the XmnI site of Ggamma-globin promoter and the (AT)xTy microsatellite 5' to the beta-globin mRNA cap site. The removal of the region between positions -125 to +78 relative to the beta-globin gene mRNA cap site by the 290 bp deletion is thought to allow the beta-locus control region to interact with the promoters of the delta- and gamma-globin genes, leading to increased HbA2 and HbF levels.

Molecular and population genetic analyses of beta-thalassemia in Turkey.

In this report we describe the molecular analysis of 795 chromosomes derived from unrelated Turkish beta-thalassemia and sickle cell anemia carriers identified in hematology clinics in Istanbul, Ankara, Izmir, Adana, and Antalya. The determination of the molecular pathology of 754 beta-thalassemia and 42 abnormal hemoglobin genes and analysis of the frequency distribution in six distinct regions of Turkey was accomplished. The experimental strategy, based on PCR amplification of the beta-globin gene, included dot-blot hybridization with 18 probes specific for the Mediterranean populations, denaturing gradient gel electrophoresis, and genomic sequencing. When the regional results are compared with the overall frequency of mutations in the country, it is observed that the frequencies in the western and southern parts of Turkey are in good accordance with the overall distribution, whereas the northern and eastern parts have a more region/population-specific profile with some rare mutations having a significantly high occurrence in these regions. Further evaluation of the data with respect to region- or population-dependent differences will contribute to a better understanding of the mechanisms leading to the marked genetic heterogeneity in Turkey, but could also be extremely valuable in facilitating rapid identification of mutations in families at risk for different hemoglobinopathies.

Rare beta-thalassemia mutation in a Turkish patient: FSC-36/37 (-T).

We describe the rare beta-thalassemia mutation at codons 36/37 (-T) for the first time in Turkey. The propositus is a Turkish patient with beta-thalassemia major who originated in Adana but now resides in Istanbul. Molecular analysis revealed a compound heterozygosity for the common eastern Mediterranean mutation IVS-I-110 (G-A) along with mutation FSC-36/37 (-T). The FSC-36/37 (-T) mutation could have arisen somewhere in the region, including northern Iran and the inaccessible mountainous region of eastern Anatolia. The mutation could have followed two migration routes during the time of Ottoman rule, the first being to Azerbaijan and the second, probably a more recent one, passing through southeastern Anatolia and reaching southern Bulgaria.

Prenatal diagnosis of beta-thalassaemia and sickle cell anaemia in Turkey.

This paper reports our experience of molecular analysis and diagnosis of beta-thalassaemia and sickle cell anaemia (HbS) in 70 prospective parents of Turkish descent and their fetuses. Molecular screening was carried out by allele-specific oligonucleotide (ASO) hybridization of amplified DNA to the 12 most common mutations in the Turkish population. By using this approach, we were able to define the mutation in 95 per cent of chromosomes investigated. Genomic sequencing led to the additional detection of three rare mutations: Cd 44 (-C), IVS-I-5 (G-C), and IVS-I-116 (T-G). All diagnoses were successfully accomplished and no misdiagnosis occurred. Consanguineous marriage appears to contribute significantly to the frequency of affected births in Turkey. Out of the 14 homozygous fetuses, six were the result of close consanguinity. This study indicates that fetal diagnosis of beta-thalassaemia and HbS may be obtained in practically all cases, even in a heterogeneous population like the Turkish population, when early methods of fetal sampling are combined with polymerase chain reaction (PCR)-based techniques. Until gene therapy becomes a reality, the only approaches to the control of haemoglobinopathies are prevention and avoidance. The most relevant and common aspects of the programmes, which have been very effective in reducing the birth rate of beta-thalassaemia major in several at-risk areas of the Mediterranean basin, are the continuous educational campaigns directed at the population at large, the voluntary basis, and non-directive counselling. The most important challenge for the eradication of the haemoglobinopathies in Turkey is the organization of a nation-wide and comprehensive genetic preventive programme based on DNA technology.