Pyridoxine-Responsive Seizures in Infantile Hypophosphatasia and a Novel Homozygous Mutation in ALPL Gene.

Hypophosphatasia is a rare inherited disorder of bone and mineral metabolism caused by a number of loss-of-function mutations in the ALPL gene. It is characterized by defective bone and tooth mineralisation associated with low serum and bone alkaline phosphatase activity. The clinical presentation of this disease is extremely variable. For this reason, the diagnosis can be difficult and is often missed out or delayed. Hypophosphatasia is classified into subtypes based on the age of onset and clinical features. The clinical severity is associated with the age at diagnosis and the lack of tissue-nonspecific alkaline phosphatase activity; the severe forms of hypophosphatasia are primarily perinatal and infantile forms. Severe forms may present with many neurological problems such as seizures, hypotonia, irritability. Herein, we report the case of an infantile hypophosphatasia patient who presented with pyridoxine-responsive seizures and a novel homozygous mutation in the ALPL gene was detected. There is a limited number of hypophosphatasia patients with pyridoxine-responsive seizures in the literature, so early diagnosis of infantile hypophosphatasia in the clinically compatible patients allows more effective postnatal care/management and genetic counseling for further pregnancies.

The value of donor lymphocyte infusions in thalassemia patients at imminent risk of graft rejection following stem cell transplantation.

BACKGROUND: The aim was to evaluate the feasibility of donor lymphocyte infusion (DLI) in transplanted patients with thalassemia who were at imminent risk of graft rejection (GR). PROCEDURE: We retrospectively evaluated outcomes in a cohort of 19 patients with thalassemia who received DLI following 21 transplantations. Patients were divided into three groups depending on indication and time of DLI: group I, mixed chimerism-level-3 (MC-level-3) within 2 months and subsequently receiving DLI; group II, MC-level-3 within 2 months and receiving deferred DLI beyond post-transplant 2.5 months; group III, receiving DLI because of a gradual decrease in both donor cells and hemoglobin levels without MC-level-3 within 2 months. RESULTS: Three patients evolved to compete chimerism (16%), 9 patients had MC with transfusion independency (47%) and 7 had GR (37%). Three of 7 patients in group I, 1 of 4 patients in group II and 8 of 10 patients in group III preserved the graft. Although significant increases in the percentage of donor cells were not detected in group III, hemoglobin levels improved (median, 6.8-8.8 g/dl, P = 0.002). CONCLUSION: The risk of GR is high in patients with thalassemia who have MC-level-3 within 2 months after transplantation. DLI is a feasible method for converting unstable MC towards stable MC or full donor chimerism, but its efficacy is partially related to the percentage of residual host cells at the time of infusion. Serial chimerism studies can identify unstable MC earlier and may guide the proper timing of intervention.

Genomic large rearrangement screening of BRCA1 and BRCA2 genes in high-risk Turkish breast/ovarian cancer patients by using multiplex ligation-dependent probe amplification assay.

In this study, MLPA assay was performed for detection of large rearrangements of BRCA1 and BRCA2 genes in 16 familial, 29 early onset, 3 male breast cancer, and 2 bilateral breast/ovarian cancer high risk Turkish index cases. MLPA assay for all exons of both genes and for 1100delC variant of CHEK2 gene were performed. Analyses, revealed no large genomic rearrangements in both genes, and, no 1100del variant in CHEK2 gene. Our data which represents the first results for Turkish patients, suggest that, the frequency of BRCA1 and BRCA2 genes' large rearrangements is very low.

Germline mutations of BRCA1 and BRCA2 genes in Turkish breast, ovarian, and prostate cancer patients.

Distribution and prevalence of germline mutations in BRCA1 and BRCA2 differ among different populations. For the Turkish population, several studies have addressed high-risk breast cancer and ovarian cancer (BC-OC) patients. In most studies, both genes were analyzed in part, and a quite heterogeneous mutation spectrum was observed. For high-risk Turkish prostate cancer (PCa) patients, however, there are no data available about mutations of germline BRCA genes. To accurately determine the contribution of germline mutations in BRCA1 and BRCA2 in Turkish BC, OC, and PCa high-risk patients, 106 high-risk BC-OC patients, 50 high-risk PCa patients, and 50 control subjects were recruited. The study represents the only full screening, to date, of a large series of Turkish high-risk BC-OC patients and the only study in Turkish high-risk PCa patients. Mutation screenings were performed on coding exons of both genes with either denaturing gradient gel electrophoresis or denaturing high performance liquid chromatography, or with both techniques. Three deleterious mutations in BRCA1 and three deleterious mutations in BRCA2 were detected in different BC-OC patients, and one truncating mutation was detected in a high-risk PCa patient. In addition, 28 different unclassified and mostly novel variants were detected in both genes, as well as several silent polymorphisms. These findings reflect the genetic heterogeneity of the Turkish population and are relevant to genetic counseling and clinical management.

Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.11.

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.

Combination of Hb Knossos [Cod 27 (G-T)] and IVSII-745 (C-G) in a Turkish patient with beta-thalassemia major.

Beta-thalassemia is the most common disease among hemoglobinopathies in Antalya, Turkey, as well as world-wide. Mutations found in Turkish beta-thalassemia patients constitute a heterogeneous group, consisting mostly of point mutations. Only in very rare cases did deletions or insertions cause affected or carrier phenotypes. Hb Knossos [beta 27 (B9) Ala-Ser] is a rare variant with a normal HbA2 level. In this study, we aimed to investigate the effect of compound heterozygosity for Hb Knossos [Cod 27 (G-T)] and IVSII-745 (C-G). To our knowledge, this is the first report of such a combination related with beta-thalassemia major phenotype in a Turkish family, where reverse dot blot hybridization (RDBH) and DNA sequencing analysis were used. Heterozygous inheritance of the mutation results in mild beta-thalassemia phenotype, whereas homozygous inheritance leads to intermediate beta-thalassemia. As a result, the compound heterozygosity of Hb Knossos with IVSII-745 appears as the cause of the beta-thalassemia major phenotype in our case. The combination of these mutations [Hb Knossos, Cod 27 (G-T), and IVSII-745, C-G] causes the beta-thalassemia major phenotype, and this is important for genetic counseling.

combination of IVS2.849 A-G witH IVS1.1 G-A: a mutation of beta-globin gene in a Turkish beta-thalessemia major patient.

Beta-thalassemia, which is an autosomal recessive disease, is among the most common hemoglobinopathies in Antalya, Turkey. Mutations found in Turkish beta-thalassemia patients constitute a heterogeneous group, which is mostly composed of point mutations and, only in very rare cases, a deletion or an insertion causes affected or carrier phenotypes. Reverse dot blot hybridization (RDBH) method is used for screening common mutations, and sequence analysis and silver staining were performed consecutively to detect any uncommon mutation. The authors report a first Turkish family with a rare variant--intervening sequence 2 (IVS2) 849 (A-G). The proband's mother and father were determined as carriers of IVS2.849 (A-G) and IVS1.1 (G-A) mutations, respectively. Proband is the first child of the family and she has an IVS2.849 (A-G)/IVS1.1 (G-A) genotype with ss-thalassemia major phenotype. Prenatal diagnosis was performed for the second child, and genotype of the fetus was determined as IVS2.849 (A-G)/Normal. This first report of IVS2.849 (A-G) mutation in Turkish population shows that there are many more mutations contributing the heterogeneity of the mutation spectrum of beta-globin gene in the Turkish population, which indicates migrations of different ethnic origins.

Lack of association between RNASEL Arg462Gln variant and the risk of breast cancer.

BACKGROUND: The RNASEL G1385A variant was recently found to be implicated in the development of prostate cancer. Considering the function of RNase L and the pleiotropic effects of mutations associated with cancer, we sought to investigate whether the RNASEL G1385A variant is a risk factor for breast cancer. PATIENTS AND METHODS: A total of 453 breast cancer patients and 382 age- and sex-matched controls from Greece and Turkey were analyzed. Genotyping for the RNASEL G1385A variant was performed using an Amplification Refractory Mutation System (ARMS). RESULTS: Statistical evaluation of the RNASEL G1385A genotype distribution among breast cancer patients and controls revealed no significant association between the presence of the risk genotype and the occurrence of breast cancer. CONCLUSION: Although an increasing number of studies report an association between the RNASEL G1385A variant and prostate cancer risk; this variant does not appear to be implicated in the development of breast cancer.

AZF microdeletions on the Y chromosome of infertile men from Turkey.

Intervals V and VI of Yq11.23 regions contain responsible genes for spermatogenesis, and are named as "azoospermia factor locus" (AZF). Deletions in these genes are thought to be pathogenetically involved in some cases of male infertility associated with azoospermia or oligozoospermia. The aim of this study was to establish the prevalence of microdeletions on the Y chromosome in infertile Turkish males with azoospermia or oligozoospermia. We applied multiplex polymerase chain reaction (PCR) using several sequence-tagged site (STS) primer sets, in order to determine Y chromosome microdeletions. In this study, 61 infertile males were enrolled for the molecular AZF screening program. In this cohort, one infertile male had 46,XX karyotype and the remaining had 46,XY karyotypes. Forty-eight patients had a diagnosis of azoospermia and 13 had oligozoospermia. Microdeletions in AZFa, AZFb and AZFc (DAZ gene) regions were detected in two of the 60 (3.3%) idiopathic infertile males with normal karyotypes and a SRY translocation was determined on 46,XX male. Our findings suggest that genetic screening should be advised to infertile men before starting assisted reproductive treatments.