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Biomedical subjects

R Galanello

Publications and source records attributed to R Galanello.

At least 91 records · Page 5Linked to original sources
PubMed1987

The same beta-globin gene mutation is present on nine different beta-thalassemia chromosomes in a Sardinian population.

The predominant beta-thalassemia in Sardinia is the beta 0 type in which no beta-globin chains are synthesized in the homozygous state. We determined the beta-thalassemia mutations in this population by the oligonucleotide-probe method and defined the chromosome haplotypes on which the mutation resides. The same beta 39(CAG----TAG) nonsense mutation was found on nine different chromosome haplotypes. Although this mutation may have arisen more than once, the multiple haplotypes could also be generated by crossing over and gene conversion events. These findings underscore the frequency of mutational events in the beta-globin gene region.

Chromosome Mapping↗
PubMed1986

Molecular pathology of haemoglobin H disease in Sardinians.

We investigated the molecular basis for haemoglobin H disease in 50 Sardinian patients by restriction endonuclease analysis. We found that the majority (78% of the cases) are due to gene deletion (- -/- alpha). Among those with a combination of deletion and nondeletion defects (- -/alpha alpha th), the most prevalent nondeletion lesion (70% of the nondeletion defects) was the initiation codon mutation of the alpha 2 gene (alpha Nco alpha), previously discovered in this population. Of the remaining patients with the (- -/alpha alpha th) genotype, two showed the IVS-1 splice junction lesion and one a mutation in the alpha 1 gene, removing the Nco I site within the 5' part of the alpha 1 gene, which may arise from a process of gene conversion from the initiation codon mutant of the alpha 2 gene. A single patient had the homozygous state for the initiation codon mutant of the alpha 2 gene. Study of genotype-phenotype correlations indicates that the (alpha Nco alpha) haplotype is associated with a more severe defect in the alpha-globin chain output than that resulting from the (-alpha) haplotype. We may conclude that restriction endonuclease analysis is a powerful method for the definition of the molecular heterogeneity of haemoglobin H disease.

Adolescent↗
PubMed1986

Alpha-thalassemia in premature newborns.

In this study we have carried out alpha-globin gene mapping, hemoglobin (Hb) Bart's quantitation serum bilirubin, and red blood cell indices determination in a group of Sardinian appropriate for gestational age premature infants (from 32 to 35 wk gestation) in order to define the incidence in this population of the different alpha-thalassemia syndromes, their expression rate, and the correlation between the alpha-globin genotype and phenotype at this developmental stage. The gene frequencies of deletion (-alpha) and nondeletion (alpha alpha th) alpha-thalassemia were 0.29 and 0.04, respectively, and thus not different from those found in full-term newborns from the same population. The majority of premature newborns with a single alpha-globin gene deletion [(-alpha/alpha alpha) genotype] were hematologically silent. Those who manifested increased Hb Bart's (1.2 to 3.4%) had slightly reduced Hb levels (17.4 +/- 2.6 g/dl), mean corpuscular volume (102.6 +/- 6.3 fl), and mean corpuscular Hb (34.8 +/- 2.0 pg) values. Those infants with the deletion of two alpha-globin structural genes (-alpha/-alpha) showed without exception moderate amount of Hb Bart's in the 3.5-8.1% range and an obvious decrease of Hb levels (16.1 +/- 1.6 g/dl) mean corpuscular Hb (30.6 +/- 3.5 pg), and mean corpuscular volume (88.5 +/- 11.5 fl) values. The only infant with the deletion of 3 alpha-globin structural genes had 25% Hb Bart's associated with a moderate microcytic anemia at birth and developed the clinical picture of Hb H disease. Carriers of nondeletion alpha-thalassemia (alpha alpha/alpha alpha th) showed variable amount of Hb Bart's always associated with thalassemia-like red cell indices.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Mapping↗
PubMed1985

Stimulation of F-cell production in patients with sickle-cell anemia treated with cytarabine or hydroxyurea.

To investigate the mechanism of pharmacologic stimulation of fetal hemoglobin in sickle-cell anemia (hemoglobin S disease), we treated two patients with homozygous disease with various doses of cytarabine (also known as Ara-C) or hydroxyurea and evaluated the effects of each treatment on F-reticulocyte production and on hemopoiesis. The treatments stimulated F-cell production in a dose-related fashion. Treatments that increased F-cell production also increased the patient's hematocrit and caused only minor, transient decreases in white cells. The main effect on erythropoiesis consisted of cytoreduction of the mature erythron (as assessed by measurements of reticulocytes) or a decrease in the compartment of erythroid progenitors (colony-forming units--erythroid and burst-forming units--erythroid). The reduction phase was followed by reticulocyte regeneration, during which most of the increase in the absolute numbers of F reticulocytes took place. Lower doses of cytarabine or hydroxyurea resulted in smaller waves of reticulocyte regeneration and lesser effects on F-reticulocyte production. These results suggest that the main cause of stimulation of fetal hemoglobin in patients with sickle-cell anemia treated with cell cycle-specific compounds is the erythroid regeneration triggered by the drug treatment.

Adult↗
PubMed1985

Genetic counseling and genetic heterogeneity in the thalassemias.

In this study, we have compared the hemoglobin A2 levels (Hb A2) of alpha-thalassemia carriers (-alpha/-alpha and -alpha/alpha alpha genotypes) with those of double heterozygotes for delta+ and beta thalassemia genes, who were identified by family studies and polymorphic restriction site analysis within the beta-globin gene cluster. We found that double heterozygotes for the delta+ and beta thalassemia have significantly (p less than 0.001) higher Hb A2 levels as compared with carriers of alpha-thalassemia. This finding has practical implications in the genetic counseling of subjects with a thalassemia-like phenotype associated with normal or borderline Hb A2 levels.

DNA Restriction Enzymes↗
PubMed1985

Hb F production in stressed erythropoiesis: observations and kinetic models.

The mechanism of stimulation of Hb F in stressed erythropoiesis is examined. Conditions known to produce a transient elevation of F-cells (acute anemia; acute expansion; treatment with cytotoxic compounds) have a common element, the acute kinetic perturbations of erythroid differentiation/maturation they trigger. Cell cycling must be shortened and the total time of differentiation (from BFUe to erythroblast) must be shortened. We propose that F-cells are formed either because of the shortening of erythroid differentiation time or because of shortening of cell cycle of erythroid cells. With the model of shortened differentiation time F-cell formation is attributed to "premature commitment" of progenitors. gamma-gene expression occurs either because chromatin changes that normally inactivate the gamma genes are not completed or because critical divisions in which the gamma genes are normally inactivated are skipped. The model of faster cycling explains F-cell formation by assuming that gamma-gene transcription is activated when the cycle (and especially the duration of G0/G1) of progenitors or erythroblasts falls below a critical time. The proposed models can readily explain the F-cells of the normal adult as the products of random deviation from normal erythroid kinetics. The two models can also explain F-cell formation in chronic erythropoietic stress (chronic hemolytic anemias, patients with hemoglobinopathies). Differences in the degree of F-cell elevation in such patients may reflect differences in the intensity of kinetic perturbation of their erythropoiesis.

Anemia↗
PubMed1984

Multiple mutations produce delta beta 0 thalassemia in Sardinia.

In Sardinia the common form of beta thalassemia is a beta 0 thalassemia due to a nonsense mutation at codon 39. delta beta 0 Thalassemia is rare in Sardinia and is associated with increased production of hemoglobin F of the A gamma type. In this study we used a synthetic oligomer assay and detected the beta 39 nonsense mutation on the delta beta 0 thalassemia chromosome. Hence at least two different mutations have occurred on this chromosome; one that increases A gamma globin synthesis and another that silences the beta globin gene.

Chromosomes, Human↗
PubMed1984

Alpha thalassaemia in Sardinian newborns.

In this study we describe the correlation between the haematological parameters (red cell indices and Hb Bart's levels) and the alpha-globin genotype in Sardinian newborns. Increased Hb Bart's levels at birth always indicates alpha-thalassaemia, either of the deletion or non-deletion variety. Infants with two alpha-globin genes deleted (- alpha/- alpha and --/ alpha alpha genotypes) had microcytosis, low MCH and Hb Bart's in the 2.0-7.1% range. A minority (38.9%) of infants with the (- alpha/ alpha alpha) globin genotype had detectable Hb Bart's, in the 0.78-2.5% range, frequently associated with minimal microcytosis while the remainder (61.1%) were completely silent. Infants carriers of a non-deletion type of alpha-thalassaemia showed Hb Bart's levels within the range found in the (- alpha / alpha alpha) genotype. The association of heterozygous beta 0-thalassemia seems to have no effect on the expression of any of these alpha-thalassaemia lesions at birth.

Chromosome Mapping↗
PubMed1984

Control of homozygous beta-thalassemia by carrier screening and antenatal diagnosis in Sardinians.

This paper reports the present results of an ongoing program aimed at preventing homozygous beta-thalassemia by means of heterozygote screening and antenatal diagnosis in the Sardinian population. Screening based on the knowledge of carrier frequency and types of thalassemia prevalent in this population was designed to discover all heterozygotes except the few silent beta-thalassemia carriers. Most of the couples at risk were informed and accepted testing. Information was conveyed by mass media, midwives and marriage registry offices. Antenatal diagnosis was accepted by the majority of the couples counselled. The results of antenatal testing were very accurate. There was only one misdiagnosis out of 949 pregnancies tested. This risk of fetal loss was 7.5%. The program was highly effective, as shown by the decline of the incidence of the homozygous state from 1:205 live births in 1976 to 1:557 in 1981.

DNA↗
PubMed1984

A genetic combination of silent beta-thalassaemia, high Hb A2 beta-thalassaemia, and single alpha globin gene deletion causing mild thalassaemia intermedia.

This paper reports a Sardinian patient, who was a compound heterozygote for silent beta-thalassaemia and high Hb A2 beta o-thalassaemia with the clinical phenotype of mild thalassaemia intermedia; alpha globin gene mapping showed a single alpha globin gene deletion. The reduced alpha globin chain output resulted in more balanced globin chain synthesis, which in turn accounted for the mild clinical phenotype.

Child↗
PubMed1984

Hemoglobin inclusions in heterozygous alpha-thalassemia according to their alpha-globin genotype.

In this study we have correlated the presence/absence of rare red blood cells with HbH inclusions with the alpha-globin genotype in a group of Sardinian alpha-thalassemia carriers, whose genotype have been defined by alpha-globin gene mapping. We found that the majority of the carriers investigated, including those with the deletion of a single or two alpha-globin genes and those with non-deletion lesions, have rare blood cells with inclusions, with no significant difference in the frequency of positive finding related to the alpha-globin genotype.

Adult↗
PubMed1984

Longitudinal study of a newborn with a combination of deletion and nondeletion alpha-thalassemia-2.

In this study we have characterized by DNA analysis the molecular basis of an alpha-thalassemia condition found in an infant, with 16% Hb Bart's at birth, who developed an hematologic picture similar to the alpha-thalassemia carrier state. Restriction endonuclease analysis and hybridization with alpha and zeta specific probes have provided strong evidence that this patient carries a genetic compound of deletion alpha-thalassemia-2 lesion (-alpha) and a non-deletion defect [(alpha alpha)th] with both alpha-structural genes intact on chromosome 16. He inherited the deletion alpha-thalassemia-2 chromosome (-alpha) from the father and the chromosome with non-deletion alpha-thalassemia defect from the mother. Because the deletion of one, two, or three alpha-globin structural genes is associated with 1-2%, 5-6%, or 25%, Hb Bart's respectively, these findings suggest that the non-deletion chromosome [(alpha alpha)th] contains two alpha-globin structural genes that are less active than a single alpha gene (-alpha).

Child, Preschool↗
PubMed1984

Hemoglobin constitution of double heterozygotes for alpha or beta-thalassemia and Hb J Sardegna.

In this study, we carried out alpha-globin gene mapping in 12 heterozygotes for Hb J Sardegna and in 5 double heterozygotes for this variant and beta-thalassemia. Then, we correlated the Hb pattern with the alpha and beta-globin genotype. In heterozygotes for Hb J Sardegna with a deletion of a single alpha-globin gene (alpha alpha/-alpha) the amount of the abnormal Hb was significantly (p much less than 0.001) higher than in heterozygotes for this variant with a full complement of 4 alpha-globin structural genes (27.5% versus 20.4%). Double heterozygotes for the abnormal hemoglobin and beta-thalassemia with a full complement of 4 alpha-globin structural genes tended to have lower amount of the abnormal Hb than heterozygotes for this variant who do not have beta-thalassemia.

Chromosome Mapping↗
PubMed1983

Alpha globin gene analysis in a Sardinian family with interacting alpha and beta thalassaemia genes.

This paper reports the results of alpha globin gene analysis in a Sardinian family with interacting alpha and beta thalassaemia genes. The propositus, who was identified in a newborn survey as he had 26.0% Hb Bart's and 74.0% Hb F, successively developed the clinical and haematological picture of a transfusion-dependent thalassaemia major. According to the haemoglobin pattern, restriction endonuclease analysis of the DNA from this patient showed the deletion of three of the four alpha-globin structural genes. Thus beta 0-thalassaemia homozygotes with the delection of three alpha-structural genes seem to have a severe clinical phenotype similar to that of patients with a full complement of four alpha-globin structural genes.

Chromosome Deletion↗
PubMed1983

Phenotype-genotype correlation in haemoglobin H disease in childhood.

In this study we used restriction endonuclease mapping to characterise the molecular defect responsible for haemoglobin H disease in 14 Sardinian children. The resulting genotypes were then correlated with the respective clinical and haematological phenotypes. We found that patients with the combination of non-deletion alpha(+)-thalassaemia [(alpha alpha)th] and deletion alpha(0)-thalassaemia (-Med) have a more severe phenotype than that resulting from the interaction of deletion alpha(0)-thalassaemia (-Med) and alpha(+)-thalassaemia (-alpha) determinants. Clinically, presentation was earlier and with moderate anaemia or haemolytic crisis, enlargement of the liver and spleen, and thalassaemic bone changes. Haematologically, the anaemia was more severe and there were higher bilirubin levels, reticulocyte counts, Hb H levels, and percentage of red blood cells with inclusion bodies. These results suggest that in those Hb H disease patients with the non-deletion [(alpha alpha)th] determinant, two alpha globin genes produce fewer alpha globin chains than a single alpha globin locus.

Adolescent↗
PubMed1983

Serum ferritin levels in hemoglobin H disease.

This study shows that hemoglobin H disease patients aged between 0.5 and 44 years, usually (27 out of 30) have normal serum ferritin levels according to age. This reconfirms that in this disease there are usually normal iron stores. However, in a few patients (3 out of 30) increased levels were found. This may be due to inappropriate iron medication, transfusions or associated idiopathic hereditary hemocromatosis gene.

Adolescent↗