Assuntos
Eritrócitos/metabolismo , Hemoglobinas/metabolismo , Policitemia/sangue , Adulto , Idoso , Feminino , Hematócrito , Humanos , Masculino , Pessoa de Meia-Idade , Valores de ReferênciaRESUMO
Hereditary xerocytosis is a rare hemolytic anemia occurring secondary to a defect in cell membrane potassium flux. We report a case of severe fetal anemia and non-immune hydrops secondary to hereditary xerocytosis that was managed successfully with in utero erythrocyte and albumin transfusion.
Assuntos
Anemia Hemolítica/terapia , Transfusão de Sangue Intrauterina , Transfusão de Eritrócitos , Doenças Fetais/terapia , Hidropisia Fetal/etiologia , Adulto , Amniocentese , Anemia Hemolítica/complicações , Anemia Hemolítica/genética , Cordocentese , Feminino , Idade Gestacional , Humanos , Hidropisia Fetal/terapia , Gravidez , Albumina Sérica/uso terapêuticoRESUMO
Hereditary disorders of erythrocytes are common in many areas of the world, including the Middle East. In some regions of the Middle East more than 10% of the population are carriers of a gene for one of these conditions. When patients from the Middle East seek medical care in the West, an unrecognized but clinically important erythrocyte disorder can result in serious complications during routine medical care, such as a drug-induced hemolytic crisis. This article reviews the most important and most common inherited red blood cell disorders in Middle Eastern patients, including glucose-6-phosphate dehydrogenase deficiency, the thalassemias, and sickle cell disorders. We discuss when to suspect such conditions, how to determine their presence, and how to avoid potential complications related to them. Although a detailed discussion of treatment of erythrocyte disorders is beyond the scope of this article, some general management principles are described.
Assuntos
Anemia Hemolítica Congênita/epidemiologia , Anemia Hemolítica Congênita/genética , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Eritrócitos Anormais , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , Humanos , Oriente Médio/epidemiologia , Oriente Médio/etnologia , Talassemia/epidemiologia , Talassemia/genéticaRESUMO
We report a novel mutation at alpha66(E15)Leu-->Pro (alpha2) (CTG-->CCG), that we have named Hb Dartmouth for the medical center at which the patients were cared for, in monozygotic twins who also inherited the Southeast Asian alpha-thalassemia-1 deletion. The mother, of Khmer ancestry, is heterozygous for alpha-thalassemia-1. The father, who is of Scottish-Irish ancestry, is a silent carrier of the codon 66 mutation. The twins had severe neonatal anemia requiring transfusion.
Assuntos
Anemia Neonatal/genética , Hemoglobinas Anormais/genética , Talassemia alfa/genética , Adulto , Substituição de Aminoácidos , Anemia Neonatal/etiologia , Camboja/etnologia , Análise Mutacional de DNA , Saúde da Família , Feminino , Hemoglobinas Anormais/efeitos adversos , Humanos , Recém-Nascido , Masculino , Mutação Puntual , Gêmeos , Reino Unido/etnologiaRESUMO
Hereditary atransferrinemia is a rare but instructive disorder that has previously been reported in only 8 patients in 6 families. It is characterized by microcytic anemia and by iron loading, and can be treated effectively by plasma infusions. We now report the first case known in the United States. We determined the sequences flanking the exons of the human transferrin gene and sequenced all of the exons and some of the flanking regions of the patient's DNA and that of her parents. The patient's DNA revealed a 10-base pair (bp) deletion, followed by a 9-bp insertion of a duplicated sequence. There was also a G-->C transversion at complementary DNA (cDNA) nt 1429, predicting that a proline was substituted for the alanine in amino acid position 477 (Ala 477 Pro). The latter mutation occurs at an evolutionarily highly conserved site; 704 control alleles were screened and this point mutation was not found. Each of the patient's transferrin genes contains one mutation, ie, the patient is a compound heterozygote for these mutations, because one was found in each of her parents. In addition to these mutations, which we regard to be causative in the patient's atransferrinemia, a silent polymorphism at cDNA 1572 G-->C was found in exon 13 as well as 2 previously unreported polymorphisms at IVS8 + 62 c-->t and IVS14-4 c-->a. The mutation in nt 1572 and that in intron 8 were common in the general population; the intron 14 mutation is rare.
Assuntos
Substituição de Aminoácidos , Anemia/genética , Duplicação Gênica , Sobrecarga de Ferro/genética , Deleção de Sequência , Transferrina/deficiência , Adulto , Amenorreia/etiologia , Anemia/terapia , Terapia Combinada , Análise Mutacional de DNA , DNA Complementar/genética , Éxons/genética , Feminino , Humanos , Hipotireoidismo/etiologia , Illinois , Íntrons/genética , Ferro/metabolismo , Ferro/farmacocinética , Ferro/uso terapêutico , Sobrecarga de Ferro/complicações , Mutagênese Insercional , Osteoporose/etiologia , Flebotomia , Plasma , Recidiva , Transferrina/química , Transferrina/genéticaRESUMO
Published data from Europe and North America indicate that for non-iron-deficient adult Caucasian males, the normal mean packed cell volume (PCV) is 0.46 and the 2.5-97.5 percentile interval is 04.0-0.53. Corresponding values for adult Caucasian females are: mean PCV 0.42; 2.5-97.5 percentile interval 0.36-0.48. It is not usually appropriate to undertake studies of polycythemia in adult Caucasian males with PCV < 0.55 (Hb Conc. < 180 g/L) or in adult Caucasian females with PCV < 0.50 (Hb Conc. < 16.5 g/L). Application of this principle will reduce the number of inappropriate and costly studies that would otherwise be performed in patients whose PCV values are only in the upper percentiles of the normal range, and will help to avoid misdiagnoses and therapeutic misadventures.
Assuntos
Hematócrito/normas , Hemoglobinas/metabolismo , Adolescente , Adulto , Idoso , Técnicas de Laboratório Clínico/economia , Técnicas de Laboratório Clínico/normas , Feminino , Hemoglobinas/normas , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia/sangue , Policitemia/diagnóstico , Policitemia/economia , Valores de Referência , População BrancaRESUMO
OBJECTIVE: The HFE gene contains two mutant alleles; C282Y and H63D. The C282Y mutation occurs in 55-100% of patients with hereditary hemochromatosis. The aim of our study was to re-examine the frequencies of the C282Y and H63D mutations in patients with mild and marked iron overload and in normal subjects. METHODS: A total of 82 patients with iron overload were included in this study and had hepatic iron index determination and/or quantitation of iron stores by phlebotomy. The control group consisted of 81 healthy blood donors. HFE mutation analysis was performed on leukocyte DNA using PCR-amplified genomic DNA. RESULTS: Of patients with iron overload, 70/82 (85%) were homozygous for C282Y versus 2/81 (2.5%) in the control population. Four patients had no HFE mutations despite significant iron overload, including a sister and brother (brother not included in the study group) with hepatic iron concentrations >500 micromoles/g dry weight. CONCLUSIONS: In all, 85% of our patients with iron overload were C282Y homozygotes, although a few had no HFE gene mutations. Pooled data and analysis of chromosomes considered to be at risk for H63D indicate that H63D is associated with iron overload.
Assuntos
Análise Mutacional de DNA , Antígenos HLA/genética , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana , Idoso , Alelos , Feminino , Frequência do Gene/genética , Proteína da Hemocromatose , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
We determined that the molecular defect of 2 patients with hemoglobin (Hb) M-Kankakee [Hb M-Iwate, alpha87 (F8) His --> Tyr] resides in the alpha1-globin gene. The proportion of Hb M observed is higher than that predicted for an alpha1-globin variant. Our evidence suggests that the greater-than-expected proportion of Hb M-Kankakee results from preferential association of the electronegative beta-globin chains with the alpha(M)-globin chains that are more electropositive than normal alpha-globin chains.
Assuntos
Hemoglobina M/genética , Mutação Puntual , Feminino , Hemoglobina M/química , Histidina , Humanos , Eletricidade Estática , TirosinaRESUMO
Hereditary hemochromatosis (HHC) is the most common inherited single gene disorder in people of northern European descent. Hereditary hemochromatosis is characterized by increased intestinal absorption of iron leading to its deposition into multiple organs. The classic description of HHC is bronze diabetes in a patient with cirrhosis. Hereditary hemochromatosis is increasingly being diagnosed at an earlier, less symptomatic stage. Diagnosis is based on an elevated fasting early morning transferrin saturation. Treatment is by phlebotomy, which, if initiated before the development of cirrhosis or diabetes, is associated with a normal life expectancy. Recently, a gene associated with HHC was discovered and named HFE. Two point mutations of this gene have been referred to as C282Y and H63D. Several US and European studies have found that 60% to 93% of patients with suspected HHC are homozygous for C282Y. Positive results of HFE gene testing may eliminate the need for a liver biopsy in selected cases. The greatest utility of HFE gene testing will likely be in screening family members of an identified proband and in helping to resolve ambiguous cases.
Assuntos
Antígenos HLA/genética , Hemocromatose/diagnóstico , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana , Mutação Puntual , Diagnóstico Diferencial , Europa (Continente) , Hemocromatose/sangue , Hemocromatose/complicações , Hemocromatose/terapia , Proteína da Hemocromatose , Homozigoto , Humanos , Flebotomia , Transferrina/metabolismoRESUMO
Among the causes of life-long cyanosis are congenital methemoglobinemia due to M hemoglobins, congenital methemoglobinemia due to methemoglobin reductase deficiency, a small number of low oxygen affinity hemoglobins, and a small number of unstable hemoglobins that spontaneously form methemoglobin in vivo at an accelerated rate. We report an unstable hemoglobin with these characteristics that was observed in a family of indigenous (native American) origin living near Santiago, Chile. This variant has the substitution beta28(B10)Leu-->Met, unambiguously corresponding to the DNA mutation of CTG-->ATG in beta-globin gene codon 28.
Assuntos
Anemia Hemolítica/sangue , Hemoglobinas Anormais/genética , Metemoglobinemia/sangue , Anemia Hemolítica/induzido quimicamente , Anemia Hemolítica/genética , Hemoglobinas Anormais/metabolismo , Humanos , Leucina , Masculino , Metemoglobinemia/genética , Metionina , Azul de Metileno , Pessoa de Meia-Idade , Mutação Puntual , SulfonamidasRESUMO
Since the first systematic blood volume studies of polycythemia in the 1920s, measurement of blood volume and red cell mass (RCM) has become routine. However, the radionuclide-labeling methods promulgated by the International Committee for Standardization in Haematology (ICSH) remain complex and poorly understood. Many hematologists and other clinicians err in the belief that these methods permit "direct measurement" of RCM, whereas the ICSH method is indirect: it requires calculation of RCM from (PCV) X (whole blood volume). The use of an elevated value of PCV to calculate RCM in order to evaluate the same elevated value of PCV is a curiously circular logic that is embraced by most clinicians and most hematologists. Analysis of published data in 186 cases of polycythemia vera indicates that RCM is an exponential function of PCV. In most cases, PCV alone suffices to document normal or increased RCM. Relative polycythemia results from dehydration, not from stress. Clinicians need to be aware of the range of physiologic fluctuations that normally occur in plasma volume. Realistic criteria for normal ranges of PCV, Hb concentration and RCM should be adopted in clinical laboratories so that clinicians will not be misled to undertake futile and costly investigations of results that are in the upper percentiles of the normal distribution, as exemplified by the Ulysses Syndrome.
RESUMO
OBJECTIVE: To determine the nature and characteristics of a unique hemoglobin variant that causes a spurious increase in glycated hemoglobin (HbA1c). MATERIAL AND METHODS: Blood specimens from four unrelated persons with this hemoglobin variant were examined by conventional laboratory methods, including electrophoresis, high-performance ion-exchange chromatography, and isoelectric focusing; by amino acid sequence analysis, polymerase chain reaction-based DNA sequence analysis, and electrospray ionization mass spectrometry, to establish the molecular structure; and by studies of oxygen affinity under varied conditions, to define the functional characteristics of the hemoglobin variant. RESULTS: The unique hemoglobin variant observed in these four cases is due to the mutation CAC-->TAC, at beta-globin gene codon 143, corresponding to beta 143 (H21) His-->Tyr. This amino acid substitution affects an important 2,3-diphosphoglycerate binding site and slightly increases the oxygen affinity of the hemoglobin variant. CONCLUSION: A hitherto unrecognized hemoglobin variant, encountered in four unrelated persons of Irish or Scots-Irish ancestry, hemoglobin Old Dominion/Burton-upon-Trent, beta 143 (H21) His-->Tyr, has now been characterized at the molecular, structural, and functional levels. Although it is associated with a slight increase in oxygen affinity, it is without hematologic effect, and its only clinical significance is that it coelutes with HbA1c on ion-exchange chromatography and thereby causes a spurious increase in HbA1c and compromises the use of this analyte to monitor the treatment of diabetes mellitus.
Assuntos
Diabetes Mellitus/sangue , Hemoglobinas Glicadas , Adulto , Idoso , Diabetes Mellitus/etnologia , Feminino , Hemoglobinas Glicadas/genética , Humanos , Irlanda/etnologia , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Escócia/etnologiaRESUMO
Among the causes of congenital methemoglobinemia, Hb M-Milwaukee-2 was one of the earliest described, in a patient who also had Hb E trait. The structure of Hb M-Milwaukee-2 has been elusive. DNA sequence analysis, as here reported, proves that this hemoglobin variant is due to the mutation CAC-->TAC at codon 92 of the beta-globin gene, corresponding to the substitution of tyrosine for histidine. This mutation is identical with that presumed to be the cause of Hb M-Hyde Park and Hb M-Akita. In addition, the DNA mutation of Hb E, GAG-->AAG at codon 26, was confirmed in this case.
Assuntos
Códon , Globinas/genética , Hemoglobina M/genética , Mutação Puntual , Adulto , Idoso , Feminino , Globinas/química , Hemoglobina M/química , Humanos , Análise de Sequência de DNARESUMO
Hemoglobin variants in which a frameshift results in chain elongation are unusual and also have a low population frequency. Hb Tak was previously characterized by amino acid analysis, and it was assumed to be due to an insertion of the dinucleotide CA into codon 146 [CAC-->CA(CA)C] which abolishes the normal stop codon at position 147. This insertion causes a frameshift which results in elongation of the beta chain by 11 amino acids. This variant has previously been described in a few Thai families. We report the DNA sequence of Hb Tak in an individual of Cambodian descent who is a Hb E/Hb Tak compound heterozygote. In contrast with extended variants of the alpha-globin chain that are expressed as alpha-thalassemias, the hematologic effect of Hb Tak/Hb E is a mild polycythemia. The combination of Hb Tak/Hb E is not expressed as a thalassemia.
Assuntos
Triagem de Portadores Genéticos , Hemoglobina E/genética , Hemoglobinas Anormais/química , Hemoglobinas Anormais/genética , Análise de Sequência de DNA , Talassemia/sangue , Talassemia/genética , Adulto , Substituição de Aminoácidos/genética , Camboja/etnologia , Ácido Glutâmico/genética , Hemoglobina A/genética , Hemoglobinas Anormais/isolamento & purificação , Humanos , Lisina/genética , Masculino , MutaçãoRESUMO
We report a new hemoglobin variant which we have named Hb Silver Springs. This variant results from a substitution CAG-->CAC (Gln-->His) at codon 131 of the beta chain. It was detected only by cation exchange high performance liquid chromatography. This is the fifth reported substitution at codon 131. This variant does not appear to have any clinical or hematologic manifestations.
Assuntos
Substituição de Aminoácidos/genética , Hemoglobinas Anormais/genética , Hemoglobinas Anormais/isolamento & purificação , Adulto , População Negra/genética , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Variação Genética , Glutamina/genética , Hemoglobinas Anormais/química , Histidina/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To assess the incidence and clinical spectrum of anemia among older people. DESIGN: Inception cohort assembled and followed by medical records linkage until death or last clinical contact through January 1994. SETTING: Population-based study in Olmsted County, Minnesota. PARTICIPANTS: All 618 Olmsted County men and women aged 65 years or more with anemia by World Health Organization criteria that was first recognized in 1986. MEASUREMENTS: Age- and sex-adjusted incidence rates, corrected for prevalent anemia, and survival estimates using the Kaplan-Meier method, with calculation of standardized mortality ratios for specific causes of death. RESULTS: The corrected annual incidence of anemia rose with age, and rates were higher in men (90.3 per 1000; 95% CI, 79.2-101.4) than women (69.1 per 1000; 95% CI, 62.3-75.8). In 465 cases (75%), anemia was detected in conjunction with a hospitalization, but admission was due to anemia in only 57 instances. Half of the cases were caused by blood loss, two-thirds of these as a result of surgery. The cause of anemia was uncertain in 102 cases (16%). One-third of the patients were transfused with a median of 3 units each. Overall survival was worse than expected but was better among those with anemia caused by blood loss. Mortality attributable to malignancy, mental disorders, circulatory and respiratory diseases, ill-defined conditions, and injuries was significantly increased among these older patients with anemia. CONCLUSIONS: The incidence of anemia among older people is 4 to 6 times greater than that suspected clinically, rises with age, and is higher in men than in women. The apparent cause in half the cases is blood loss. Even mild anemia is associated with reduced survival, especially during the first year, but this could relate to underlying comorbid conditions.
Assuntos
Anemia/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/etiologia , Anemia/terapia , Estudos de Coortes , Feminino , Hemoglobinas/análise , Humanos , Incidência , Masculino , Minnesota/epidemiologiaRESUMO
We have identified a new, slightly unstable alpha chain hemoglobin variant, present in a Mexican-American family. Amino acid sequencing and mass spectral analysis of the aberrant peptide (alpha T-9) of the variant revealed that the aspartic acid is deleted either at position 74 or 75 of one of the alpha-globin chains. Sequencing of the amplified alpha 2- or alpha 1-globin genes revealed a trinucleotide deletion (GAC) at codon 74 or 74 of the alpha 2 gene. Although the aspartic acid residues of 74 and 75 of the alpha chain are neither a heme nor an inter chain contact, the slight instability of Hb Watts may be due to disturbance of the central cavity of hemoglobin by the deletion of an aspartic acid residue in the EF helix. Hb Watts is the first example of a trinucleotide deletion in the alpha 2-globin gene.