Mitochondrial DNA Aberrations and Pathophysiological Implications in Hematopoietic Diseases, Chronic Inflammatory Diseases, and Cancers

Mitochondria are important intracellular organelles that produce energy for cellular development, differentiation, and growth. Mitochondrial DNA (mtDNA) presents a 10- to 20-fold higher susceptibility to genetic mutations owing to the lack of introns and histone proteins. The mtDNA repair system is relatively inefficient, rendering it vulnerable to reactive oxygen species (ROS) produced during ATP synthesis within the mitochondria, which can then target the mtDNA. Under conditions of chronic inflammation and excess stress, increased ROS production can overwhelm the antioxidant system, resulting in mtDNA damage. This paper reviews recent literature describing the pathophysiological implications of oxidative stress, mitochondrial dysfunction, and mitochondrial genome aberrations in aging hematopoietic stem cells, bone marrow failure syndromes, hematological malignancies, solid organ cancers, chronic inflammatory diseases, and other diseases caused by exposure to environmental hazards.

Isochromosome X mosaicism in a child with Kabuki syndrome phenotype: A rare cytogenetic association.

Isochromosome is a structurally unbalanced chromosome consisting of two short arms or two long arms, which are derived by abnormal centromere division or sister-chromatid exchange. Most autosomal isochromosomes are unusual, while those involving sex chromosomes are common. Kabuki syndrome (KS, OMIM 147920) is a multiple malformation/mental retardation syndrome of unknown etiology. A conventional cytogenetic study on lymphocytes from a 4-year-old girl with physical features suggestive of KS was found to have mosaicism for isochromosome for the long arm of the X. Although most manifestations present in this patient have been described before, this report is a rare association of clinical and cytogenetic findings in this syndrome. A genome-wide analysis and a larger number of patient groups studied could improve our understanding of the genetic basis of KS.

Hemocromatose hereditária: associação entre as mutações no gene HFE e o estado de ferro em doadores de sangue e pesquisa de mutações nos genes HFE, HJV, HAMP, TFR2 e SLC40A1 em pacientes com sobrecarga de ferro primária / Hereditary hemochromatosis: relationship between HFE gene mutations and iron status in blood donors and HFE, HJV, HAMP, TFR2 and SLC40A1 gene sequencing in primary iron overload patients

A hemocromatose hereditária é caracterizada pelo aumento da absorção intestinal de ferro, acarretando progressivo acúmulo no organismo. Os objetivos foram: 1- determinar as frequências das mutações p.C282Y, p.H63D e p.S65C no gene HFE e avaliar os efeitos nas concentrações dos parâmetros do ferro em doadores de sangue; 2- pesquisar mutações nos genes: 2.1- HFE, 2.2- HJV e HAMP, 2.3- TFR2 e SLC40A1, em pacientes portadores de sobrecarga de ferro primária. Participaram 542 doadores de sangue provenientes do Hemocentro da Santa Casa de São Paulo. Foram incluídos 51 pacientes que apresentavam saturação de transferrina ≥ 50% (para mulheres) e ≥ 60% (para homens) e ausência de causas secundárias. Os genótipos para as mutações nos genes HFE foram avaliados pela PCR-RFLP. Foi realizado sequenciamento direto bidirecional para cada éxon dos genes, utilizando o sequenciador Genetic Analizer 3500XL®. Nos doadores de sangue, as frequências dos alelos HFE 282Y, HFE 63D e HFE 65C foram 2,1, 13,6 e 0,6%, respectivamente. Os homens que doaram pela primeira vez, portadores do genótipo HFE 282CY, apresentaram maiores valores de saturação de transferrina; e também os portadores dos genótipos HFE 63DD e 63HD apresentaram maiores concentrações de ferritina sérica, em relação aos de genótipo selvagem. Para os pacientes, 72,5% (37/51) apresentaram ao menos 1 alteração no gene HFE e 11 foram identificados como homozigotos para a mutação p.C282Y. Uma mutação não descrita na literatura (p.V256I) foi identificada no gene HFE e a modelagem molecular (análises de ligação e estrutural) detectou que a mutação não reduziu a afinidade entre as proteínas HFE e β2-microglobulina. No sequenciamento dos éxons dos genes HJV e HAMP foram identificadas as alterações já descritas: HJV p.E302K, HJV p.A310G, HJV p.G320V e HAMP p.R59G. Para o gene TFR2, foram identificados 3 polimorfismos já descritos (p.A75V, p.A617A e p.R752H). No gene SLC40A1 foram observados 6 polimorfismos (rs13008848, rs11568351...

Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption, which leads to a progressive accumulation of iron in the body. The aims were: 1- to assess the frequency of HFE gene mutations (p.C282Y, p.H63D and p.S65C) and to identify their relationship to iron status in blood donors; 2- to search in primary iron overload patients: 2.1- HFE, 2.2- HJV and HAMP, 2.3- TFR2 and SLC40A1 gene mutations. Blood donors (n=542) were recruited from Hemocentro of Santa Casa Hospital, Sao Paulo, Brazil. The study included 51 patients with transferrin saturation ≥ 50% (women) and ≥ 60% (men) and absence of secondary causes. The genotypes for HFE mutations were evaluated by PCR-RFLP. Subsequent bidirectional sequencing for each gene was performed using the Genetic Analizer sequencer 3500XL®. The frequencies of HFE 282Y, HFE 63D and HFE 65C alleles were 2.1, 13.6 and 0.6% in blood donors, respectively. The first time male donors carrying heterozygous genotype for the p.C282Y mutation had higher transferrin saturation values; and men carrying HFE 63DD and 63HD genotypes had higher serum ferritin concentrations when compared to the wild genotype. Thirtyseven (72.5%) out of the 51 patients presented at least one HFE mutation and 11 were identified as homozygous for the mutation p.C282Y. One novel mutation (p.V256I) in the HFE gene was indentified and molecular modeling (free energy and structural analysis in silico) showed that p.V256I mutation did not reduce the affinity binding between HFE and β2-microglobulin. Sequencing in the HJV and HAMP genes revealed HJV p.E302K, HJV p.A310G, HJV p.G320V and HAMP p.R59G alterations. Sequencing in the TFR2 gene observed 3 polymorphisms (p.A75V, p.A617A e p.R752H); and sequencing in the SLC40A1 gene identified 6 polymorphisms (rs13008848, rs11568351, rs11568345, rs11568344, rs2304704 e rs11568346) and 1 p.G204S non-described mutation. The conclusions were: 1- for blood donors, the presence of HFE 282Y and...

Effect of hydroxyurea on thalassemia major and thalassemia intermedia in iranian patients

Hydroxyurea has been used in thatassemia major [T.M.] and thalassemia intermedia patients since 1994 with some success in different centers. The objective was to evaluate the effect and possible side effects of hydroxyurea in these patients. This was a descriptive study done in 2007 after nine years of initiation of Hydroxyurea. Medical records of 1050 patients were reviewed. Patients who had received hydroxyurea for at Least three continuous months were enrolled into the study. Clinical and laboratory data during six months before and six month after starting hydroxyurea were compared. Two hundred ninety seven patients were enrolled of these two hundred forty eight [83.8%] were thalassemia major and forty eight [16.2%] were thatassemia intermedia. Dose of hydroxyurea was 15.5 +/- 6.4mg/kg /day and duration was 5.2 +/- 2 years [ranging 0.5-9 years]. Transfusions were completely stopped in one hundred eleven [44.7%] of thalassemia major patients with a mean Hb of l0g/dl. After 22.5 +/- 18 months, using Desferal was stopped in sixty six [26.6%] patients. The reasons for stopping hydroxiurea were "ineffectiveness" in 20%, "poor compliance" in 12.4% and side effects in 13.4% of patients. The side effects were nausea, palpitation, transient leucopenia and transient raising of creatinin. Hydroxyurea is effective and safe in thalassemia major and thalassemia intermedia patients and saves them from side effects of blood transfusions

Neonatal Screening for genetic blood diseases

Previous neonatal screening in 1986 showed that the incidence of sickle cell disease [SCD] is 2.1% and [SCT] is l1%. Since 1984 the Ministry of Health [MOH] instituted a prevention campaign. The incidence has been falling gradually since then. To update the national data on the incidence of SCD among the newborns and to compare it with the previously available data. All Bahraini newborns delivered at the [MOH] maternity hospitals for a period of three months from February to April 2002 were targeted. Cord blood samples were analyzed by HPLC. Two thousand newborns constituted the study population five were excluded. Eighteen were found to be affected with SCD with an incidence of 0.9%. SCT was found in 325 [16.3%]. G6PD deficiency was found in 18% of males, and 10% of females. Parental age distribution and consanguinity were documented. Bahrain has for the first time recorded less than 1% babies with SCD

Inferferência da malária na fisiologia e na fiosiopatologia do eritrócito: parte 3: relaçäo com deficiência de G6PD, talassemias e outros aspectos hereditários do eritrócito / Malaria interference of physiologic and physiopathology of erythrocyte: part 3: relation of G6PD deficiency, thalassemis and other hereditary aspects of erythrocyte

Os autores enfocam os aspectos fisiológicos e fisiopatológicos do eritrócito que se relacionam com a malária. Esta revisäo visa compreender a açäo seletiva da malária sobre as doenças hereditárias do glóbulo vermelho (anemia falciforme e hemoglobinopatias associadas, talassemias, deficiência de glicose-6-fosfato desidrogenase, ovalocitose hereditária) e do sistema Duffy, focalizando a discussäo nos aspectos associados ao ciclo evolutivo do parasita no inseto e no homem. Descrevem a fisiopatologia da deficiência de G6PD, talassemias, hemoglobinopatias C e E ovalocitose, sistema Duffy e as inter-relações com a malária

Chromosome fragility in hematologic disease presumably induced by environmental pollutants

Chromosome instability consists of chromosome abnoprmalities as multiple breaks in in metaphase chromosomes in syndromes of chromosaome instability such as fanconi's anemia (FA) which is mainly characaterized by bone marrow aplasia; some cases progress to acute leukemia. FA is a hereditary disease with recessive and monogenic transmission. This pair of mutated genes is related to chromosome fragility and therefore is responsible for the inefficiency of DNA repair. In normal individuals, these genes are assumed to be expressed normally, but their products ara insufficient to perform DNA repair when the intensity of the polluting agent lelads to exposure above basal levels. In the present study, the bone marrow of four patients with different hematologic diseases was submitted to cytogenetic analysis. Two had aplastic anemia, and one bad lymphoblastic leukemia. These patients were from towns unb the Amazon Region where the mercuri used for gold prospecting and the substances used and/or released in aluminium mining have been introduced into the environment. The last patient had fanconi's anemia and was used as a model in the discussion of the results. The cytogenetic findings were similar for all patients, the major ones being chromosome fragmentation and pulverization. In view of these findings, we believe that chromosome fragility, observed in the first three patients, presumably was induced by environmental pllutants

The importance of molecular biology in hematologic disorders

The advances in molecular biology and recombinant DNA technology have permitted the understanding of numerous diseases. Some of the earliest advances have occurred in the field of hematology when these approaches revealed genetic alterations in the hemoglobin gene of patients with sickle-cell anemia and thalassemias. In the field of onco-hematology, these powerful tools allowed to identify the chemical and biological changes that happen during the transformation of normal to malignant cells. Futhermore, it has led to the development of new agents for cancer therapy, such as interleukins and interferons. We describe here basic concepts of molecular biology, and the effect this technology had on the diagnostic capabilities for defining, diagnosing, and predicting the natural history of hematologic diseases.

Mothers at risk of alloimmunization to the Rh(D) antigen and availability of gamma-globulin at the Mexican Institute of Social Security

Hemolytic disease of the newborn develops mainly when an Rh negative (D-) mother becomes sensitized and produces anti-Rh possitve (anti-D) antibodies capable of hemolysing D+ fetal erythrocytes. Maternal alloimmunization can be prevented by the administration of anti-D gamma-globulin immediately after the birth of each Rh positive child. In order to identify the frequency of prevention of alloimmunization at the Instituto Mexicano del Seguro Social(IMSS), the amount of mothers at risk of sensitization from 1985 to 1995 was estimated from Rh and ABO blood group frequencies and with the number of deliveries and abortions at the Medical Institutions. Also, information in regard to the dose of gamma-globulin units purchased by the Institute of Social Security from 1985 to 1993 was obtained. The number of mothers at risk stedily increased from 16,616 in 1985 to 21,071 in 1995, amounting to a total of 203,203 in the 10-year period, while only 120,800 gamma-globulin units were purchased in that same period. The findings in this study suggest the need to define reasonable policies for the acquisition of gamma-globulin lots to prevent alloisoimmunization of mothers at risk