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Biomedical subjects

A Iolascon

Publications and source records attributed to A Iolascon.

At least 55 records · Page 3Linked to original sources
PubMed1999

The congenital dyserythropoietic anaemias.

Congenital dyserythropoietic anaemias (CDA) are a category of rare genetic diseases that affect erythropoiesis. Dyserythropoiesis is associated with abnormal erythroblasts and leads to altered red cells, the amount of which is insufficient. There are three main, well-defined CDAs, CDA I, II and III. Their characterization is based on a careful examination of the bone marrow under light and electron microscopes. In addition, a number of rare or unique forms of dyserythropoiesis have been reported. At least with respect to CDA I to III, the clinical evaluation is reaching an ever increasing refinement: age of discovery, determinants of iron overload and/or biliary complications. Over the past few years, a more promising breakthrough has been the localization of the genes responsible for CDA I, II and III, that is, 15q15.1-q15.3, 20q11.2 and 15q21-q25, respectively. Epidemiological studies have now become possible. The identification of the genes is pending.

Anemia, Dyserythropoietic, Congenital↗
PubMed1999

An autosomal dominant thrombocytopenia gene maps to chromosomal region 10p.

The increasing number of diagnosed cases of inherited thrombocytopenias, owing to the routine practice of including platelet counts in blood tests, suggests that this condition is not so rare as expected. In the majority of cases, the molecular basis of the disease is unknown, although the defect is likely to affect thrombocytopoiesis and regulation of the normal platelet count. Here we report a genomewide search in a large Italian family affected by autosomal dominant thrombocytopenia. Patients showed a moderate thrombocytopenia with minimal symptoms characterized by normocellular bone marrow, normal medium platelet volume, and positive aggregation tests. Microsatellite analysis demonstrated that the disease locus (THC2) is linked to chromosome 10p11.1-12, within a candidate region of 6 cM between markers D10S586 and D19S1639. A maximum LOD score of 8.12 at recombination fraction.00 was obtained with the microsatellite D10S588. These data localized the first locus of an autosomal dominant thrombocytopenia, and the subsequent identification of the gene will provide new insight into the basic mechanism of megakaryocytopoiesis disorders.

Chromosome Mapping↗
PubMed1999

Hereditary dehydrated and overhydrated stomatocytosis: recent advances.

The hereditary stomatocytoses and allied disorders are genetic defects of the erythrocyte membrane that result in abnormal permeability to the univalent cations Na+ and K+. Although rare, these conditions reflect abnormalities in physiologic mechanisms that are of paramount interest. All cases (as defined here) show increased plasma membrane permeability to Na+ and K+ and, to a greater or lesser degree, stomatocytic morphology. Dehydrated hereditary stomatocytosis, the most common form of hereditary stomatocytosis, is more heterogeneous than previously thought and includes kindreds showing pseudohyperkalemia or perinatal edema, or both. The gene responsible for both dehydrated hereditary stomatocytosis and familial pseudohyperkalemia, a nonhemolytic variant that presents with high plasma K+ levels, has been mapped to 16q23-qter. The cause of overhydrated hereditary stomatocytosis remains elusive despite the manifest lack of the enigmatic protein stomatin in the erythrocyte membrane. In all cases where splenectomy has been performed, this procedure has conferred a marked risk for thrombosis in adult life. This finding stresses the importance of diagnostic distinction between these conditions and hereditary spherocytosis.

Adult↗
PubMed1999

Bilirubin levels in the acute hemolytic crisis of G6PD deficiency are related to Gilbert's syndrome.

In this study we analyzed the effect of the (TA)7 polymorphism of the UGT1A gene associated with Gilbert's syndrome in G6PD-deficient subjects during an acute hemolytic crisis (fabic crisis). DNA from 44 subjects originating from the same geographic area in Sardinia was analyzed for the UGT1A promoter polymorphism. The increase of unconjugated bilirubin level during fabic crisis and its relationship with UGT1A polymorphism was evaluated. The UGT1A (TA)7 TATA box variant was found in 9/44 (21%) of the G6PD deficient subjects examined. The median value for unit of increase of bilirubin (mg/dl)/unit of decrease of hemoglobin (g/dl) was higher in variant homozygous than in heterozygous and normal subjects. These findings imply a contribution of the UGT1A polymorphism associated to Gilbert's syndrome to development of the hyperbilirubinemia in G6PD deficient subjects during acute hemolytic anemia.

Anemia, Hemolytic↗
PubMed1999

Homozygous prothrombin gene mutation and ischemic cerebrovascular disease: a case report.

We report the case of a 31-year-old woman who, at the age of 26 suffered from an episode of superficial thrombophlebitis in the left leg, experienced two episodes of transient ischemic attacks at the age of 30 and had an ischemic stroke with left-sided hemiparesis at the age of 31 years. A cerebral CT scan showed an ischemic lesion in the right sylvian area involving the opercular and nucleocapsular regions. Her father had had an ischemic stroke at the age of 54 years and died at the age of 58; her mother had had a myocardial infarction at the age of 48 years and died at 51 years from breast cancer. Laboratory investigation of the patient demonstrated high levels of fibrinogen, F II, F VII, F 1 + 2, FPA and ACA-IgG with low levels of HDL cholesterol associated with homozygosity for the 20210 A genotype. There were no other genetic or acquired prothrombotic defects. In conclusion, this case strongly suggests a clinically significant role ot the prothrombin gene mutation in both arterial and venous thrombosis.

Adult↗
PubMed1999

Familial dominant thrombocytopenia: clinical, biologic, and molecular studies.

Inherited thrombocytopenias are a heterogenous group of disorders. Different criteria have been suggested to classify the forms, such as the inheritance mechanism and the platelet volume as well as the number and morphology of megakaryocytes. However, the classification is often descriptive, and the precise mechanism of thrombocytopenia still remains unknown. We describe the clinical, biologic, and molecular findings of an autosomal dominant thrombocytopenia in a large family. The 17 patients had normocellular bone marrow and normal platelet volume. Platelets also showed a normal aggregation test and normal response to ADP and thrombopoietin (TPO). In the affected subjects, the mean +/- SD levels of platelet count and plasma TPO were 62+/-25 and 258+/-151, respectively. Comparative analysis showed that the patients with platelet count <70000 had higher plasma TPO concentration. The data are consistent with a mild clinical form of the disease associated with only a few episodes of bleeding. To exclude the possible role of TPO and its receptor c-mpl in the etiology of this condition, linkage analysis was performed using microsatellite markers close to the TPO and c-mpl genes on chromosomes 3q26.3-q27 and 1p34, respectively. The absence of cosegregation within the affected family indicated that these genes, as well as two other candidate loci on chromosomes 11 and 21, are not responsible for this hereditary dominant form of thrombocytopenia. A genome-wide search and subsequent identification of the gene will provide new insight into the pathogenesis of this disorder.

Blood Platelets↗
PubMed1999

Gilbert's syndrome and jaundice in glucose-6-phosphate dehydrogenase deficient neonates.

BACKGROUND AND OBJECTIVE: The pathogenesis of the hyperbilirubinemia present in approximately 30% of neonates affected by glucose-6-phosphate dehydrogenase deficiency is an unsolved problem. We evaluated the effect of Gilbert's syndrome, the most common defect of bilirubin conjugation, on the hyperbilirubinemia of these neonates. DESIGN AND METHODS: One hundred and two neonates affected by glucose-6-phosphate dehydrogenase deficiency were enrolled in this study: 56 had hyperbilirubinemia and 46 had normal bilirubin levels. The analysis of the A(TA)nTAA motif in the promoter region of the UGT1A gene was performed by means of PCR, followed by separation on 6% denaturing polycrylamide gel. RESULTS: The frequency of the three different genotypes of the A(TA)nTAA motif was similar in the study and control groups. Our results demonstrated no difference in the percentage of homozygotes for the UGT1A (TA)7 variant associated with Gilbert's syndrome. INTERPRETATION AND CONCLUSIONS: These findings indicate that Gilbert's syndrome does not account for the hyperbilirubinemia occurring in some neonates with glucose-6-phosphate dehydrogenase deficiency. Furthermore our results suggest that hemolysis is not the major event in the pathogenesis of hyperbilirubinemia in these patients.

Gilbert Disease↗
PubMed1999

(TA)8 allele in the UGT1A1 gene promoter of a Caucasian with Gilbert's syndrome.

BACKGROUND AND OBJECTIVE: Gilbert's syndrome, a chronic non-hemolytic unconjugated hyperbilirubinemia, is caused by a reduction in the activity of hepatic bilirubin UDP-glucuronosyltransferase (UGT1A1). This reduction has been shown to be due to a polymorphism in the promoter region of the UGT1A1 gene. The presence of seven thymine adenine (TA) repeats reduces the efficiency of transcription of the UGT1A1 gene. To elucidate the genetic background of a patient affected by Gilbert's syndrome, we collected blood samples from family members for the analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene. DESIGN AND METHODS: Analysis of the A(TA)nTAA motif in the promoter region of the UGT1A1 gene was performed by PCR. Estimation of UGT1A1 promoter containing the variable (TA) repeats was performed by using a luciferase reporter system. RESULTS: Three different genotypes were identified due to the presence of (TA)6, (TA)7 and (TA)8 repeats. The production of luciferase decreases in inverse relation to the number of repeats. INTERPRETATION AND CONCLUSIONS: The (TA)7 polymorphism, associated with Gilbert syndrome, is the only allele found up to now in white populations, while two other variants (TA)5 and (TA)8 have been identified in black populations. We describe here the first case of a subject affected by Gilbert's syndrome who is heterozygous for the (TA)8 allele in the promoter region of the UGT1A1 gene. This polymorphism, as well as the (TA)7 one, is associated with an increased level of bilirubin and a significant reduction of transcription activity of the UGT1A1 gene.

Alleles↗
PubMed1999

Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes.

BACKGROUND AND OBJECTIVE: Crigler-Najjar syndromes type I and II and Gilbert's syndrome are familial unconjugated hyperbilirubinemias caused by genetic lesions involving a single complex locus encoding for bilirubin-UDP-glucuronosyltransferase which is involved in the detoxification of bilirubin by conjugation with glucuronic acid. Over the last few years a number of different mutations affecting this gene have been characterized. The aim of this work is to review the molecular pathology of Crigler-Najjar and Gilbert's syndromes, to discuss its impact on the clinical and genetic classification of these conditions, and on the diagnostic evaluation of clinical pictures associated with unconjugated hyperbilirubinemia. EVIDENCE AND INFORMATION SOURCES: The authors of the present review are involved in the clinical management of patients with familial unconjugated hyperbilirubinemia as well as in the characterization of its molecular bases. Evidence from journal articles covered by the Science Citation Index and Medline has been reviewed and collated with personal data and experience. STATE OF THE ART AND PERSPECTIVES: It has been known for many years that mild to severe deficiency of bilirubin UDP-glucuronosyltransferase in the liver is the cause of two types of familial unconjugated hyperbilirubinemia, Crigler-Najjar syndromes I and II, and Gilbert's syndrome. Since the characterization of the gene encoding for bilirubin UDP-glucuronosyltransferase, a number of mutations affecting the expression of this gene have been identified. These mutations can be classified into three groups: mutations which result in a reduced production of a normal enzyme; mutations which give rise to the synthesis of a structurally abnormal and dysfunctional enzyme; mutations which completely abolish the expression of the affected allele. The combination of mutations affecting the coding region of the gene and of promoter mutations which reduce the expression of the gene accounts for the wide clinical spectrum of familial unconjugated hyperbilirubinemias, ranging from the clinically negligible Gilbert's syndrome to the severe and often fatal Crigler-Najjar type I syndrome. A better understanding of the genetics of these conditions and the availability of molecular diagnosis will improve the diagnostic efficiency and afford better informed genetic counseling, not only for Crigler-Najjar and Gilbert's syndromes, but also for several acquired conditions characterized by unconjugated hyperbilirubinemia.

Crigler-Najjar Syndrome↗
PubMed1998

Interstitial and large chromosome 1p deletion occurs in localized and disseminated neuroblastomas and predicts an unfavourable outcome.

We studied chromosome 1p loss of heterozygosity (1p-LOH) in 53 neuroblastomas (NBs) using 15 (CA)n repeat loci, which covered a region of 90 cM. We also assessed chromosome 1p36 deletion by fluorescence in situ hybridization (FISH) on interphase nuclei. 1p-LOH was found in 19 (36%, 95% confidence interval (CI) 23-50%) NBs. We detected interstitial and large deletion in both localized and disseminated tumours and in one tumour of a patient at stage 4S. Allelic loss was frequently observed in 1p36 and 1p32 regions. In patients older than 1 year of age (53 versus 13%, P < 0.002) we detected significant chromosome 1p deletion and it was associated with MYCN amplification (P = 0.001). Overall survival (OS) analysis showed that 1p-LOH is predictive of a poor outcome (odds ratio 16.5, 95% CI 5.4-50.9%); therefore, 1p-LOH should be regarded as an additional tumour progression marker in neuroblastoma.

Adolescent↗
PubMed1998

Cytogenetic analysis of hepatoblastoma: hypothesis of cytogenetic evolution in such tumors and results of a multicentric study.

Hepatoblastoma is a rare pediatric malignant tumor of the liver. Previous cytogenetic reports are sporadic. We karyotyped nine consecutive hepatoblastomas from the Italian centers participating in a multicentric study on hepatic tumors (SIOPEL 1). Six cases showed abnormal karyotypes. The most common abnormalities were trisomies of chromosomes 2 and 20. Four cases showed abnormalities of chromosome 1. On the basis of findings, we speculate the possibility of a cytogenetic evolutive pattern of hepatoblastomas.

Child, Preschool↗
PubMed1998

Analysis of CDKN2A, CDKN2B, CDKN2C, and cyclin Ds gene status in hepatoblastoma.

The status and the expression of cyclin-dependent kinase inhibitor A (CDKN2A) family genes, named CDKN2A, CDKN2B, and CDKN2C and of cyclin Ds (D1, D2, and D3) genes were investigated in 14 cases of human hepatoblastomas. These genes were selected because: 1) CDKN2A and CDKN2B are very frequently inactivated in human cancers; 2) cyclin Ds are overexpressed in several tumors and 3) CDKN2A is posttranscriptionally silenced in hepatocellular carcinomas. Structural analysis of the CDKN2A, CDKN2B, and CDKN2C genes in hepatoblastoma cases showed the absence of deletions and/or point mutations. Moreover, a detailed investigation of loss of heterozygosity at 9p21 and 1p32 (the chromosomal regions where CDKN2A genes are located) rules out the possible loss of one allele. Messenger RNA (mRNA) analysis showed that CDKN2C is expressed in all hepatoblastoma samples studied, while both CDKN2A and CDKN2B genes are not transcribed in the cancer specimens as well as in the matched normal liver tissues. Interestingly, an alternative mRNA expressed by the CDKN2A gene (beta-transcript) is detectable in 100% of the samples investigated. The analysis of cyclin D genes expression revealed that cyclin D1 is highly transcribed in normal hepatic tissue while cyclin D2 or D3 genes were extensively expressed in the matched transformed samples. Investigation at protein level confirmed the data obtained on RNA analysis. Indeed, p16INK4A and p15INK4B (products of expression of CDKN2A and CDKN2B respectively) were not observable while pl8INK4C (which is codified by CDKN2C) was clearly detectable in the samples analyzed. Moreover, a noticeable decrease of cyclin D1 content and increase of cyclin D3 level were observable in tumor tissues versus normal counterparts. Our findings demonstrated the following: 1) CDKN2A, CDKN2B, and CDKN2C genes are structurally unmodified in human hepatoblastoma, and 2) CDKN2A (alpha-transcript) and CDKN2B are transcriptionally silenced in normal liver whereas CDKN2A (beta-transcript) and CDKN2C were clearly expressed. Finally, a clear shift in cyclin D type expression was observable during malignant transformation. These results show that CDKN2A gene family alterations are not involved in hepatoblastoma development, whereas changes in cyclin D types might play a role in this type of tumor. Furthermore, a highly regulated expression of CDKN2A seems to occur in normal hepatic tissue.

Carrier Proteins↗
PubMed1998

Frequent de novo monoallelic expression of beta-spectrin gene (SPTB) in children with hereditary spherocytosis and isolated spectrin deficiency.

This report represents an attempt to define the rate of beta-spectrin de novo mutations affecting mRNA accumulation in patients with hereditary spherocytosis (HS). 19 HS children with haematologically normal parents and varying degrees of spectrin deficiency were studied. 13 of the 19 cases who were heterozygous at the genomic level for polymorphisms in the beta-spectrin coding region were further studied. However, in an analysis of reverse-transcripted amplified cDNA from the regions of the polymorphisms, seven patients appeared to be homozygous, suggesting the occurrence of de novo mutational events affecting expression of one beta-spectrin allele. We conclude that in HS patients with isolated spectrin reduction and normal parents the apparently recessive pattern of inheritance may frequently be associated with de novo monoallelic expression of beta-spectrin.

Child↗