RESUMEN
BACKGROUND: Hb Chapel Hill [Alpha2 74(EF3) Asp > Gly] results from an GAC > GGC substitution at codon 74 of the HBA1 or HBA2 genes. Hb Chapel Hill has not been reported since 1986. METHODS: A heterozygous mutation, HBA2: c.224A > G, was identified in the proband, her father and sister. We compared the haematological and clinical data of this family with the data reported in the limited number of individuals. RESULTS: Having excluded iron deï¬ciency, the Hb Chapel Hill was asymptomatic in heterozygous state. The cases presented here characterize cases in new techniques including capillary electrophoresis (CE). Two aberrant peaks were identified by CE, a major peak migrating in the zone 7 that correspond to Hb Chapel Hill (αChapel Hill 2ß2) and a minor peak migrating in the zone 1 that correspond to Hb Chapel Hill2 (αChapel Hill 2δ2). Focusing on the variant expression, the Hb Chapel Hill plus Hb A2 variant were around 18.9-20.6% of total Hb in three members. CONCLUSION: This data will be useful for providing up-to-date and high quality information on the Hb Chapel Hill.
Asunto(s)
Hemoglobinas Anormales , Talasemia alfa , Femenino , Humanos , Globinas alfa/genética , Talasemia alfa/genética , Pueblos del Este de Asia , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Heterocigoto , Mutación , MasculinoRESUMEN
A 37-year-old Chinese man complained of recurrent dyspnea, with low pulse oximetry (SpO2) and normal partial pressure of oxygen (PaO2) by blood gas analysis. The patient's P50 was elevated at 47.3â mmHg, while hemoglobin fraction by capillary electrophoresis revealed an abnormal HbD quantified at 43.2%. Further DNA analysis by whole exome sequencing (WES) identified heterozygosity for a mutation in exon 2 at codon 38 (HBB: c.112T>A, p.Trp38Arg), which decodes to a substitution of the amino acid tryptophan (Try) by arginine (Arg), known as Hb Rothschild. The patient's mother and daughter were also diagnosed to have low SpO2 readings and his daughter was confirmed to carry Hb Rothschild. This is the first known familial case of Hb Rothschild in China. As Hb Rothschild may be underdiagnosed in Asian descent, better understanding in this area would help avoid unnecessary cardiorespiratory interventions.
Asunto(s)
Hemoglobinas Anormales , Masculino , Humanos , Adulto , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Oximetría , Codón , Oxígeno , Mutación , Globinas beta/genéticaRESUMEN
We describe a first Dutch case of Hb M Saskatoon (HBB:c.190C > T p.His64Tyr) in a 47-year-old female Dutch patient who presented with cyanosis, hemolysis, and abnormal co-oximetry. A mean corpuscular volume (MCV) of 105â fL caused by reticulocytosis (160 × 109/L) and low red blood cell count (3.6 × 1012/L) suggested an increased erythrocyte turnover. An HPLC glyco-globin analysis revealed a decreased HbA1c fraction of 12.3â mmol/mmol, HbA0 of 93.3% and an additional unidentified fraction at 1.2â min. DNA sequencing revealed a missense mutation in the HBB gene, (HBB:c.190C > T p.His64Tyr), known as Hb M Saskatoon, a variant which has been previously identified as an unstable hemoglobin variant leading to methemoglobinemia and anemia. In this report, we describe the clinical and remarkable laboratory aspects of our patient with Hb M Saskatoon, and the consequences for treatment and drug use.
Asunto(s)
Anemia/sangre , Anemia/genética , Cianosis/sangre , Cianosis/genética , Hemoglobina Glucada/metabolismo , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Alelos , Sustitución de Aminoácidos , Anemia/diagnóstico , Biomarcadores , Cianosis/diagnóstico , Análisis Mutacional de ADN , Índices de Eritrocitos , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Oximetría , FenotipoRESUMEN
OBJECTIVE: To evaluate the effectiveness of placental volume measured by virtual organ computer-aided analysis (VOCAL) at 12 to 14 weeks of gestation in predicting fetal hemoglobin (Hb) Bart's disease among pregnancies at risk. METHODS: This study involves 3-dimensional ultrasound (3D-US) volume datasets derived from pregnancies at risk of fetal Hb Bart's disease at 12 to 14 weeks of pregnancy. VOCAL technique was used to measure and calculate placental volume by the authors, who did not know the fetal diagnosis. Placental thickness was also measured. The diagnostic values of placental volume and placental thickness in prediction of fetal Hb Bart's disease were calculated. RESULTS: Sixty-five volume datasets, including 22 datasets of the affected fetuses and 43 unaffected fetuses, were included. The mean placental volume (±SD) of the affected cases was significantly higher than that of the unaffected ones, 85.35 ± 20.84 cm3 vs 52.24 ± 19.01 cm3 (Student's t test, P < .001). In predicting Hb Bart's disease, placental volume and placental thickness had sensitivities of 77.3% and 72.7% respectively as well as specificities of 88.37% and 76.7% respectively. CONCLUSION: Of fetuses at risk of Hb Bart's disease, 3D-US VOCAL placental volume may be useful in early detection of affected fetuses. Its effectiveness is superior to that of conventional placental thickness measurement.
Asunto(s)
Diagnóstico por Computador , Hemoglobinas Anormales/metabolismo , Placenta/patología , Primer Trimestre del Embarazo , Diagnóstico Prenatal , Femenino , Humanos , Tamaño de los Órganos , EmbarazoRESUMEN
BACKGROUND: Severe fetal anemias can cause high output cardiac failure. Mitochondria are key regulators of cardiac function. However, the effects of an early phase of fetal anemia on the fetal heart and cardiac mitochondrial function are not known. OBJECTIVE: The aim of this study is to compare mitochondrial function and cardiac biochemical alterations in the fetal cardiac tissue between anemic and non-anemic fetuses. MATERIALS AND METHODS: A cross-sectional study was conducted in Fetuses affected by Hb Bart's disease (n=18) and non-anemic fetuses (n=10) at 17-20 weeks. Echocardiograms had been carried out in all cases to assess prenatal cardiac function. Cardiac tissues were collected after pregnancy termination for the determination of cardiac iron accumulation, mitochondrial function, including mitochondrial ROS production, mitochondrial depolarization and mitochondrial swelling, mitochondrial dynamics, inflammation, and apoptosis. RESULTS: Prenatal cardiac function evaluated by ultrasound was comparable between the Hb Bart's and non-anemic groups. In Bart's group, the levels of cardiac mitochondrial depolarization and swelling, and the TNF-α level were significantly higher, compared to the non-anemic group. On the contrary, anti-inflammatory (IL-10) levels were significantly lower in the Hb Bart's group. Additionally, active caspase-3 and Bcl-2 expression were also significantly higher (P= 0.001, P=0.035) in Bart's group. The mitochondrial fission protein expression, including p-DRP1/total DRP1, was significantly higher in Bart's group. However, there was no difference in cardiac iron accumulation levels between these two groups. CONCLUSION: Despite equivalent prenatal cardiac function and comparable cardiac iron accumulation in the Bart's and non-anemic groups, fetal anemia is significantly associated with cardiac mitochondrial dysfunction, increased mitochondrial fission, and increased inflammation and apoptosis. These findings indicate that an early phase of fetal anemia without cardiac iron overload can lead to cardiac mitochondrial dysfunction in fetuses with Hb Bart's.
Asunto(s)
Anemia/complicaciones , Enfermedades Fetales/patología , Corazón Fetal/patología , Insuficiencia Cardíaca/patología , Hemoglobinas Anormales/metabolismo , Mitocondrias Cardíacas/patología , Anemia/diagnóstico por imagen , Anemia/patología , Apoptosis , Estudios de Casos y Controles , Estudios Transversales , Femenino , Enfermedades Fetales/diagnóstico por imagen , Enfermedades Fetales/etiología , Corazón Fetal/diagnóstico por imagen , Corazón Fetal/metabolismo , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/etiología , Hemoglobinas Anormales/análisis , Humanos , Mediadores de Inflamación/metabolismo , Hierro/metabolismo , Mitocondrias Cardíacas/metabolismo , Estrés Oxidativo , Embarazo , Ultrasonografía PrenatalAsunto(s)
Hemoglobinas Anormales/genética , Mutación , Policitemia/diagnóstico , Policitemia/genética , Globinas alfa/genética , Alelos , Sustitución de Aminoácidos , Análisis de los Gases de la Sangre , Genotipo , Hemoglobinas Anormales/metabolismo , Humanos , Oxígeno/metabolismo , Policitemia/sangre , Unión Proteica , Globinas alfa/metabolismo , Talasemia alfa/sangre , Talasemia alfa/diagnóstico , Talasemia alfa/genéticaRESUMEN
OBJECTIVES: With improved access to intrauterine transfusion (IUT), more fetuses with haemoglobin Bart's hydrops fetalis (HBHF; homozygous α0-thalassaemia) will survive. DESIGN: To evaluate the long-term outcome of affected fetuses with and without IUT in Ontario, Canada, we retrospectively collected data on IUTs and pregnancy outcomes in all cases of HBHF, from 1989 to 2014. Clinical outcome and neurocognitive profiles of long-term survivors were also collected and compared with data from 24 patients with transfusion-dependent ß-thalassaemia (TDT-ß). RESULTS: Of the 99 affected pregnancies (93 prenatally diagnosed), 68 resulted in miscarriage or elective termination of pregnancy. Twelve mothers (12%) continued their pregnancies without IUT, and none of those newborns survived the first week of life. All 13 fetuses that received IUT(s) were live-born, but 3 died due to severe hydrops at birth and 1 died due to infection. The remaining nine survivors, in comparison with TDT-ß patients, had earlier iron overload requiring iron chelation therapy. Endocrinopathies and short stature were more frequent in these patients. Neurocognitive outcome was not significantly affected in five patients who were assessed, and none were diagnosed with intellectual impairment. In three patients, MRI studies demonstrated brain white matter changes in keeping with 'silent' ischaemic infarcts. CONCLUSIONS: In patients with HBHF, IUT is associated with improved survival. While acceptable neurocognitive outcome can be expected, these patients have more clinical complications compared with their TDT-ß counterparts. The clinical and neurocognitive outcomes of HBHF should be discussed in detail when counselling and offering IUT for patients.
Asunto(s)
Transfusión de Sangre Intrauterina/métodos , Hemoglobinas Anormales/metabolismo , Hidropesía Fetal/fisiopatología , Hidropesía Fetal/terapia , Aborto Inducido/estadística & datos numéricos , Aborto Espontáneo/epidemiología , Femenino , Humanos , Hidropesía Fetal/mortalidad , Sobrecarga de Hierro/epidemiología , Ontario , Embarazo , Diagnóstico Prenatal , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
We identified two unstable variants in the third exon of α-globin genes: Hb Bernalda/Groene Hart (HBA1:c.358C>T), and Hb Caserta (HBA2:c.79G>A) in cis to Hb Sun Prairie (HBA2:c.391G>C), also named Hb Southern Italy. These mutations occurred in the H helix of the α-globin that is involved in heme contacting, specific recognition of α-hemoglobin-stabilizing protein (AHSP), and α1ß1 interactions. The carriers showed α-thalassemia phenotype, but one also jaundice and cholelithiasis. Molecular identification of clusters of families in Southern Italy encouraged molecular characterization of mRNA, globin chain analyses, molecular modeling studies, and comparison with globin variants to understand the mechanisms causing the α-thalassemia phenotype. A normal amount of Hb Bernalda/Groene Hart mRNA were found, and molecular modeling highlighted additional H bonds with AHSP. For Hb Southern Italy, showing an unexpected α/ß biosynthetic ratio typical of the ß-thalassemia type, two different molecular mechanisms were shown: Reduction of the variant mRNA, likely due to the No-Go Decay for the presence of unused triplet ACG at cod 26, and protein instability due to the impairment of AHSP interaction. The UDP glucuronosyltransferase 1A (UGT1A1) genotyping was conclusive in the case of jaundice and cholelithiasis. Multiple approaches are needed to properly identify the mechanisms leading to unstable variants and the effect of a mutation.
Asunto(s)
Hemoglobina A/genética , Hemoglobinas Anormales/genética , Mutación , Talasemia/genética , Adolescente , Adulto , Anciano , Sitios de Unión , Proteínas Sanguíneas/metabolismo , Células Cultivadas , Niño , Femenino , Glucuronosiltransferasa/genética , Hemoglobina A/química , Hemoglobina A/metabolismo , Hemoglobinas Anormales/química , Hemoglobinas Anormales/metabolismo , Humanos , Italia , Masculino , Persona de Mediana Edad , Chaperonas Moleculares/metabolismo , Fenotipo , Unión Proteica , Estabilidad Proteica , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Talasemia/patologíaRESUMEN
We report the case of a 61-year-old Canadian male of Maltese descent investigated for unexplained polycythemia. Decreased p50 suggested the presence of a high oxygen affinity hemoglobin (Hb) variant. Molecular genetic testing demonstrated that he carries a novel missense mutation (HBB: c.258T>G), resulting in a PheâLeu substitution at position 85 of the ß chain. The novel Hb variant has been designated Hb Kennisis in recognition of where the proband resides. Two other missense mutations have been reported at this position [Hb Bryn Mawr or Hb Buenos Aires, ß85(F1)PheâSer (HBB: c.257T>C); Hb Grantham, ß85(F1)PheâCys; (HBB: c.257T>G)], both of which have increased oxygen affinity.
Asunto(s)
Hemoglobinas Anormales/genética , Mutación Missense , Oxígeno/metabolismo , Policitemia/genética , Globinas beta/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Hemoglobinas Anormales/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Policitemia/sangre , Policitemia/diagnóstico , Policitemia/fisiopatología , Unión Proteica , Globinas beta/metabolismoRESUMEN
Hb Dompierre [ß29(B11)GlyâArg, HBB: c.88G>C] is a rare ß-globin gene variant that was previously described in the heterozygous state in a 24-year-old female patient. It is defined in the HbVar database as being clinically and biologically asymptomatic. A few years after the first description, we had an opportunity of reassessing the index case because she presented with splenomegaly and clinical and biological manifestations of hemolysis. After ruling out the most common causes of hemolysis, further analyses on the variant hemoglobin (Hb) using brilliant cresyl blue staining, indicated that it showed mild instability, which may explain the clinical and biological manifestations. A structural bioinformatic analysis on the Hb variant suggested that the amino acid replacement may be deleterious to the integrity of the Hb. This report confirms the importance of completely characterizing all new Hb variants in order to guide the patients' clinical management and follow-up, as well as to provide the probands and their family members with appropriate genetic counseling.
Asunto(s)
Dolor Abdominal/genética , Hemoglobinopatías/genética , Hemoglobinas Anormales/genética , Mutación Missense , Esplenomegalia/genética , Globinas beta/genética , Dolor Abdominal/sangre , Dolor Abdominal/diagnóstico , Dolor Abdominal/fisiopatología , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Femenino , Asesoramiento Genético , Hemoglobinopatías/sangre , Hemoglobinopatías/diagnóstico , Hemoglobinopatías/fisiopatología , Hemoglobinas Anormales/metabolismo , Hemólisis , Humanos , Modelos Moleculares , Fenotipo , Estabilidad Proteica , Esplenomegalia/sangre , Esplenomegalia/diagnóstico , Esplenomegalia/fisiopatología , Globinas beta/metabolismoRESUMEN
A continuous supply of oxygen is essential for the survival of multicellular organisms. The understanding of how this supply is regulated in the microvasculature has evolved from viewing erythrocytes (red blood cells [RBCs]) as passive carriers of oxygen to recognizing the complex interplay between Hb (hemoglobin) and oxygen, carbon dioxide, and nitric oxide-the three-gas respiratory cycle-that insures adequate oxygen and nutrient delivery to meet local metabolic demand. In this context, it is blood flow and not blood oxygen content that is the main driver of tissue oxygenation by RBCs. Herein, we review the lines of experimentation that led to this understanding of RBC function; from the foundational understanding of allosteric regulation of oxygen binding in Hb in the stereochemical model of Perutz, to blood flow autoregulation (hypoxic vasodilation governing oxygen delivery) observed by Guyton, to current understanding that centers on S-nitrosylation of Hb (ie, S-nitrosohemoglobin; SNO-Hb) as a purveyor of oxygen-dependent vasodilatory activity. Notably, hypoxic vasodilation is recapitulated by native S-nitrosothiol (SNO)-replete RBCs and by SNO-Hb itself, whereby SNO is released from Hb and RBCs during deoxygenation, in proportion to the degree of Hb deoxygenation, to regulate vessels directly. In addition, we discuss how dysregulation of this system through genetic mutation in Hb or through disease is a common factor in oxygenation pathologies resulting from microcirculatory impairment, including sickle cell disease, ischemic heart disease, and heart failure. We then conclude by identifying potential therapeutic interventions to correct deficits in RBC-mediated vasodilation to improve oxygen delivery-steps toward effective microvasculature-targeted therapies. To the extent that diseases of the heart, lungs, and blood are associated with impaired tissue oxygenation, the development of new therapies based on the three-gas respiratory system have the potential to improve the well-being of millions of patients.
Asunto(s)
Dióxido de Carbono/sangre , Fenómenos Fisiológicos Cardiovasculares , Hemoglobinas/metabolismo , Óxido Nítrico/sangre , Oxígeno/sangre , Regulación Alostérica , Animales , Transfusión Sanguínea , Secuencia Conservada , Cisteína/metabolismo , Células Endoteliales/fisiología , Eritrocitos/metabolismo , Hemoglobinas/genética , Hemoglobinas Anormales/metabolismo , Humanos , Hipoxia/fisiopatología , Mamíferos/sangre , Microcirculación , Modelos Cardiovasculares , Oxihemoglobinas/metabolismo , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/fisiopatología , S-Nitrosotioles/análisis , S-Nitrosotioles/sangre , Vasodilatación/fisiologíaRESUMEN
Haemoglobin (Hb) H-constant spring (CS) alpha thalassaemia (- -/-αCS) is the most common type of nondeletional Hb H disease in southern China. The CRISPR/Cas9-based gene correction of patient-specific induced pluripotent stem cells (iPSCs) and cell transplantation now represent a therapeutic solution for this genetic disease. We designed primers for the target sites using CRISPR/Cas9 to specifically edit the HBA2 gene with an Hb-CS mutation. After applying a correction-specific PCR assay to purify the corrected clones followed by sequencing to confirm the mutation correction, we verified that the purified clones retained full pluripotency and exhibited a normal karyotype. This strategy may be promising in the future, although it is far from representing a solution for the treatment of HbH-CS thalassemia now.
Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Hemoglobinas Anormales , Células Madre Pluripotentes Inducidas/metabolismo , Talasemia alfa , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/patología , Talasemia alfa/genética , Talasemia alfa/metabolismo , Talasemia alfa/terapiaRESUMEN
Healthy human blood contains only a trace amount of methemoglobin (Hb M), less than 1%. In Hb M iron is present in the oxidized ferric state (Fe3+) not in the reduced ferrous form (Fe2+) and this reduces the ability of hemoglobin to bind oxygen. The described rare hemoglobin variant Hb MHyde Park (also known as Hb M-Akita) results from the substitution of amino acid tyrosine by histidine at position 93 of the beta-globin chain of hemoglobin. The rare Hb variant Hb MHyde Park (Hb MAkita) is mainly inherited autosomal dominant and causes methemoglobinemia. Due to the low frequency of inherited Hb M variants, the diagnosis is challenging. Here, we here report on a family with Hb MHyde Park (Hb MAkita) whose members demonstrated Hb Mâ¯> 10%, but were, asymptomatic except for chronic cyanosis. Due to human mobility and migration other hemogobin variants, such as beta-thalassemia minor have spread to Austria . A genetic combination of two different hemoglobin variants may result in severe anemia. Genetic counseling for patients with hemoglobin variants, including Hb MHyde Park (Hb MAkita) and beta-thalassemia minor, is essential.
Asunto(s)
Hemoglobina M/genética , Metahemoglobinemia , Austria , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Humanos , Metahemoglobinemia/sangre , Metahemoglobinemia/diagnóstico , Metahemoglobinemia/genética , Oxihemoglobinas/metabolismo , Talasemia beta/genéticaRESUMEN
We report two cases of hemoglobin Sendagi in a Romanian family residing in Spain: a four-year-old boy and his mother, who had been previously diagnosed with another type of congenital hemolytic anemia and had undergone splenectomy in her country during childhood. The unstable hemoglobin variant, hemoglobin Sendagi, is characterized by decreased oxygen affinity caused by replacement of one of the critical amino acid residues, phenylalanine beta 42 (CD1) of the beta-chain, with valine in the heme pocket, resulting in methemoglobin formation. As a result of migratory movements in Europe, new disease-causing hemoglobin variants are emerging in our country. Here, capillary electrophoresis enabled the identification of the variant and a molecular study was used to establish an accurate diagnosis.