Changing trends in the prevalence of heart failure impairment with Thalassemias over three decades.

BACKGROUND: To assess the prevalence trend and contributing factors of heart failure (HF) impairment with thalassemias at global, regional and national levels. METHODS: Data on HF impairment with thalassemias was collected from the Global Burden of Disease study. The absolute number and prevalence of the disease were systematically collected for each year, and the estimated annual percentage changes (EAPC) in HF impairment were calculated by gender, region and country to measure temporal trends. RESULTS: Thalassemias have caused a significant global burden since 1990, and the case number of HF related to thalassemias has been steadily increasing. The highest case number of HF impairments with thalassemias is observed in China (7739 cases) and the highest prevalence is in Pakistan (1.61 per 100,000) currently. Besides, the middle sociodemographic index (SDI) region carries the highest burden of comorbid disease yet exhibits the most evident trend for improvement across the five regions (EAPC = -.98). The burden of thalassemias and comorbid HF is generally higher in males than females with the gender gap growing chasm in the future. Besides, the hotspots of HF impairment with thalassemias have gradually shifted to low SDI regions, though middle SDI regions still hold a relatively higher prevalence (.37 per 100,000) across different regions. CONCLUSIONS: The burden of thalassemias and accompanying HF, as well as their temporal trends, vary greatly across countries and regions. These findings can improve understanding of these conditions and guide policymakers in developing appropriate policies to address disparities between countries.

Incidence Trends of Inherited Anemias at the Global, Regional, and National Levels Over Three Decades.

Inherited anemia continues to pose a significant public health concern on a global scale, owing to its extensive geographical prevalence, substantial patient population, and profound ramifications. Here, we investigated detailed information on inherited anemias (including thalassemias, thalassemias trait, sickle cell disease, sickle cell trait, G6PD deficiency, and G6PD trait) for the period 1990-2019 from the Global Burden of Disease study. Over the course of three decades, there has been a persistent rise in the incidence of inherited anemias worldwide, culminating in a total of 44,896,026 incident cases in 2019. However, the prevalence of inherited anemias has exhibited a consistent downward trend over successive years. Significantly, these inherited anemias primarily impact females, exhibiting a male-to-female ratio of 1:1.88. Among males, the most prevalent inherited anemia is G6PD deficiency, whereas G6PD trait prevails among females. The incidence rates of inherited anemias and their temporal trend exhibited significant variations across different regions, with Central Sub-Saharan Africa displaying the highest incidence rates and Central Latin America experiencing the most substantial decline. The findings of this study suggest a significant correlation between the Socio-Demographic index (SDI) and incidence rates of inherited anemias, particularly in regions with lower SDI levels such as Africa and South Asia. These results contribute valuable insights for the analysis of global trends in the burden of inherited anemias.

Thalassemia, a human blood disorder / Talassemia, uma doença do sangue humano

A group of inherited blood defects is known as Thalassemia is among the world's most prevalent hemoglobinopathies. Thalassemias are of two types such as Alpha and Beta Thalassemia. The cause of these defects is gene mutations leading to low levels and/or malfunctioning α and β globin proteins, respectively. In some cases, one of these proteins may be completely absent. α and β globin chains form a globin fold or pocket for heme (Fe++) attachment to carry oxygen. Genes for alpha and beta-globin proteins are present in the form of a cluster on chromosome 16 and 11, respectively. Different globin genes are used at different stages in the life course. During embryonic and fetal developmental stages, γ globin proteins partner with α globin and are later replaced by β globin protein. Globin chain imbalances result in hemolysis and impede erythropoiesis. Individuals showing mild symptoms include carriers of alpha thalassemia or the people bearing alpha or beta-thalassemia trait. Alpha thalassemia causes conditions like hemolytic anemia or fatal hydrops fetalis depending upon the severity of the disease. Beta thalassemia major results in hemolytic anemia, growth retardation, and skeletal aberrations in early childhood. Children affected by this disorder need regular blood transfusions throughout their lives. Patients that depend on blood transfusion usually develop iron overload that causes other complications in the body systems like renal or hepatic impairment therefore, thalassemias are now categorized as a syndrome. The only cure for Thalassemias would be a bone marrow transplant, or gene therapy with currently no significant success rate. A thorough understanding of the molecular basis of this syndrome may provide novel insights and ideas for its treatment, as scientists have still been unable to find a permanent cure for this deadly disease after more than 87 years since it is first described in 1925.

Um grupo de defeitos sanguíneos hereditários é conhecido como talassemia e está entre as hemoglobinopatias mais prevalentes do mundo. As talassemias são de dois tipos, como talassemia alfa e beta. As causas desses defeitos são as mutações genéticas que levam a níveis baixos e/ou proteínas de globina com mau funcionamento, respectivamente. Em alguns casos, uma dessas proteínas pode estar completamente ausente. As cadeias de globina α e β formam uma dobra ou bolsa de globina para a fixação de heme (Fe ++) para transportar oxigênio. Os genes das proteínas alfa e beta globina estão presentes na forma de um cluster nos cromossomos 16 e 11, respectivamente. Diferentes genes de globina são usados em diferentes estágios do curso de vida. Durante os estágios de desenvolvimento embrionário e fetal, as proteínas γ globina se associam à α globina e, posteriormente, são substituídas pela proteína β globina. Os desequilíbrios da cadeia de globina resultam em hemólise e impedem a eritropoiese. Indivíduos que apresentam sintomas leves incluem portadores de talassemia alfa ou as pessoas com traços de talassemia alfa ou beta. A talassemia alfa causa condições como anemia hemolítica ou hidropsia fetal fatal, dependendo da gravidade da doença. A beta talassemia principal resulta em anemia hemolítica, retardo de crescimento e aberrações esqueléticas na primeira infância. As crianças afetadas por esse distúrbio precisam de transfusões de sangue regulares ao longo da vida. Os pacientes que dependem de transfusão de sangue geralmente desenvolvem sobrecarga de ferro que causa outras complicações nos sistemas do corpo, como insuficiência renal ou hepática, portanto as talassemias agora são classificadas como uma síndrome. A única cura para as talassemias seria um transplante de medula óssea ou terapia genética sem atualmente uma taxa de sucesso significativa. Uma compreensão completa da base molecular dessa síndrome pode fornecer novos insights e ideias para seu tratamento, [...].

Thalassemia, a human blood disorder

Abstract A group of inherited blood defects is known as Thalassemia is among the worlds most prevalent hemoglobinopathies. Thalassemias are of two types such as Alpha and Beta Thalassemia. The cause of these defects is gene mutations leading to low levels and/or malfunctioning and globin proteins, respectively. In some cases, one of these proteins may be completely absent. and globin chains form a globin fold or pocket for heme (Fe++) attachment to carry oxygen. Genes for alpha and beta-globin proteins are present in the form of a cluster on chromosome 16 and 11, respectively. Different globin genes are used at different stages in the life course. During embryonic and fetal developmental stages, globin proteins partner with globin and are later replaced by globin protein. Globin chain imbalances result in hemolysis and impede erythropoiesis. Individuals showing mild symptoms include carriers of alpha thalassemia or the people bearing alpha or beta-thalassemia trait. Alpha thalassemia causes conditions like hemolytic anemia or fatal hydrops fetalis depending upon the severity of the disease. Beta thalassemia major results in hemolytic anemia, growth retardation, and skeletal aberrations in early childhood. Children affected by this disorder need regular blood transfusions throughout their lives. Patients that depend on blood transfusion usually develop iron overload that causes other complications in the body systems like renal or hepatic impairment therefore, thalassemias are now categorized as a syndrome. The only cure for Thalassemias would be a bone marrow transplant, or gene therapy with currently no significant success rate. A thorough understanding of the molecular basis of this syndrome may provide novel insights and ideas for its treatment, as scientists have still been unable to find a permanent cure for this deadly disease after more than 87 years since it is first described in 1925.

Resumo Um grupo de defeitos sanguíneos hereditários é conhecido como talassemia e está entre as hemoglobinopatias mais prevalentes do mundo. As talassemias são de dois tipos, como talassemia alfa e beta. As causas desses defeitos são as mutações genéticas que levam a níveis baixos e/ou proteínas de globina com mau funcionamento, respectivamente. Em alguns casos, uma dessas proteínas pode estar completamente ausente. As cadeias de globina e formam uma dobra ou bolsa de globina para a fixação de heme (Fe ++) para transportar oxigênio. Os genes das proteínas alfa e beta globina estão presentes na forma de um cluster nos cromossomos 16 e 11, respectivamente. Diferentes genes de globina são usados em diferentes estágios do curso de vida. Durante os estágios de desenvolvimento embrionário e fetal, as proteínas globina se associam à globina e, posteriormente, são substituídas pela proteína globina. Os desequilíbrios da cadeia de globina resultam em hemólise e impedem a eritropoiese. Indivíduos que apresentam sintomas leves incluem portadores de talassemia alfa ou as pessoas com traços de talassemia alfa ou beta. A talassemia alfa causa condições como anemia hemolítica ou hidropsia fetal fatal, dependendo da gravidade da doença. A beta talassemia principal resulta em anemia hemolítica, retardo de crescimento e aberrações esqueléticas na primeira infância. As crianças afetadas por esse distúrbio precisam de transfusões de sangue regulares ao longo da vida. Os pacientes que dependem de transfusão de sangue geralmente desenvolvem sobrecarga de ferro que causa outras complicações nos sistemas do corpo, como insuficiência renal ou hepática, portanto as talassemias agora são classificadas como uma síndrome. A única cura para as talassemias seria um transplante de medula óssea ou terapia genética sem atualmente uma taxa de sucesso significativa. Uma compreensão completa da base molecular dessa síndrome pode fornecer novos insights e ideias para seu tratamento, já que os cientistas ainda não conseguiram encontrar uma cura permanente para essa doença mortal depois de mais de 87 anos desde que foi descrita pela primeira vez em 1925.

Thalassemia, a human blood disorder / Talassemia, uma doença do sangue humano

Abstract A group of inherited blood defects is known as Thalassemia is among the world's most prevalent hemoglobinopathies. Thalassemias are of two types such as Alpha and Beta Thalassemia. The cause of these defects is gene mutations leading to low levels and/or malfunctioning α and β globin proteins, respectively. In some cases, one of these proteins may be completely absent. α and β globin chains form a globin fold or pocket for heme (Fe++) attachment to carry oxygen. Genes for alpha and beta-globin proteins are present in the form of a cluster on chromosome 16 and 11, respectively. Different globin genes are used at different stages in the life course. During embryonic and fetal developmental stages, γ globin proteins partner with α globin and are later replaced by β globin protein. Globin chain imbalances result in hemolysis and impede erythropoiesis. Individuals showing mild symptoms include carriers of alpha thalassemia or the people bearing alpha or beta-thalassemia trait. Alpha thalassemia causes conditions like hemolytic anemia or fatal hydrops fetalis depending upon the severity of the disease. Beta thalassemia major results in hemolytic anemia, growth retardation, and skeletal aberrations in early childhood. Children affected by this disorder need regular blood transfusions throughout their lives. Patients that depend on blood transfusion usually develop iron overload that causes other complications in the body systems like renal or hepatic impairment therefore, thalassemias are now categorized as a syndrome. The only cure for Thalassemias would be a bone marrow transplant, or gene therapy with currently no significant success rate. A thorough understanding of the molecular basis of this syndrome may provide novel insights and ideas for its treatment, as scientists have still been unable to find a permanent cure for this deadly disease after more than 87 years since it is first described in 1925.

Resumo Um grupo de defeitos sanguíneos hereditários é conhecido como talassemia e está entre as hemoglobinopatias mais prevalentes do mundo. As talassemias são de dois tipos, como talassemia alfa e beta. As causas desses defeitos são as mutações genéticas que levam a níveis baixos e/ou proteínas de globina com mau funcionamento, respectivamente. Em alguns casos, uma dessas proteínas pode estar completamente ausente. As cadeias de globina α e β formam uma dobra ou bolsa de globina para a fixação de heme (Fe ++) para transportar oxigênio. Os genes das proteínas alfa e beta globina estão presentes na forma de um cluster nos cromossomos 16 e 11, respectivamente. Diferentes genes de globina são usados ​​em diferentes estágios do curso de vida. Durante os estágios de desenvolvimento embrionário e fetal, as proteínas γ globina se associam à α globina e, posteriormente, são substituídas pela proteína β globina. Os desequilíbrios da cadeia de globina resultam em hemólise e impedem a eritropoiese. Indivíduos que apresentam sintomas leves incluem portadores de talassemia alfa ou as pessoas com traços de talassemia alfa ou beta. A talassemia alfa causa condições como anemia hemolítica ou hidropsia fetal fatal, dependendo da gravidade da doença. A beta talassemia principal resulta em anemia hemolítica, retardo de crescimento e aberrações esqueléticas na primeira infância. As crianças afetadas por esse distúrbio precisam de transfusões de sangue regulares ao longo da vida. Os pacientes que dependem de transfusão de sangue geralmente desenvolvem sobrecarga de ferro que causa outras complicações nos sistemas do corpo, como insuficiência renal ou hepática, portanto as talassemias agora são classificadas como uma síndrome. A única cura para as talassemias seria um transplante de medula óssea ou terapia genética sem atualmente uma taxa de sucesso significativa. Uma compreensão completa da base molecular dessa síndrome pode fornecer novos insights e ideias para seu tratamento, já que os cientistas ainda não conseguiram encontrar uma cura permanente para essa doença mortal depois de mais de 87 anos desde que foi descrita pela primeira vez em 1925.

Thalassaemia Registries: A Call for Action. A Position Statement from the Thalassaemia International Federation.

Disease registries can be extremely powerful evidence generating tools while providing a central meeting point for all implicated stakeholders, facilitating their networking and interaction. Registries can play a major role in addressing the challenges that the care of thalassemia patients is currently facing. By collecting updated and representative data on disease burden, features, management and outcomes at local, national, regional and global level, thalassemia registries can allow the evaluation and bench marking of provided healthcare services, the detection of unmet clinical needs and the identification of inequalities in healthcare delivery. A total of 17 thalassemia registries has been in place since 1984, being characterized by heterogeneity and incomplete geographic coverage. Representativeness, interoperability, harmonization, quality assurance and sustainability are important features that thalassemia registries should pursue. The Thalassaemia International Federation (TIF) aims at promoting the coordination and collaboration in existing thalassemia registries and the establishment of new ones, with a particular focus on areas of emerging economies. In this regard, TIF has undertaken the design, development and implementation of a web-based platform to host a global thalassemia registry.

Coordinated ß-globin expression and α2-globin reduction in a multiplex lentiviral gene therapy vector for ß-thalassemia.

A primary challenge in lentiviral gene therapy of ß-hemoglobinopathies is to maintain low vector copy numbers to avoid genotoxicity while being reliably therapeutic for all genotypes. We designed a high-titer lentiviral vector, LVß-shα2, that allows coordinated expression of the therapeutic ßA-T87Q-globin gene and of an intron-embedded miR-30-based short hairpin RNA (shRNA) selectively targeting the α2-globin mRNA. Our approach was guided by the knowledge that moderate reduction of α-globin chain synthesis ameliorates disease severity in ß-thalassemia. We demonstrate that LVß-shα2 reduces α2-globin mRNA expression in erythroid cells while keeping α1-globin mRNA levels unchanged and ßA-T87Q-globin gene expression identical to the parent vector. Compared with the first ßA-T87Q-globin lentiviral vector that has received conditional marketing authorization, BB305, LVß-shα2 shows 1.7-fold greater potency to improve α/ß ratios. It may thus result in greater therapeutic efficacy and reliability for the most severe types of ß-thalassemia and provide an improved benefit/risk ratio regardless of the ß-thalassemia genotype.

Anemias hemolíticas hereditarias por defectos en la síntesis de globina / Hereditary hemolytic anemias due to defective globin synthesis

Introducción: Los defectos genéticos en la molécula de hemoglobina se dividen en aquellos que tienen una tasa reducida de producción de una o más cadenas de globina, las talasemias; y en los que se producen cambios estructurales que conducen a inestabilidad o transporte anormal de oxígeno. Objetivo: Explicar los diferentes mecanismos por los cuales ocurren las talasemias y otras alteraciones en la síntesis de las cadenas de globina, así como las características moleculares, fisiopatogénicas y los cambios hematológicos. Métodos: Se realizó una revisión de la literatura, en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google académico de artículos publicados en los últimos 10 años. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: Las talasemias son un grupo heterogéneo de defectos genéticos en la síntesis de hemoglobina, que causa una disminución en la tasa de producción de una o más cadenas de la molécula. De acuerdo a la cadena de globina que presenta el defecto se dividen en α-β-, δβ- o γδβ-talasemias. Conclusiones: Las talasemias y las hemoglobinopatías son las enfermedades hemolíticas hereditarias más comunes en muchas partes del mundo, caracterizadas por complejas interacciones entre anemia, eritropoyesis ineficaz y alteraciones del metabolismo del hierro(AU)

Introduction: Genetic disorders in the hemoglobin molecule are divided into those that have a reduced rate of production of one or more globin chains, thalassemias; and those in which structural changes occur that lead to instability or abnormal oxygen transport. Objective: To explain the different mechanisms by which thalassemias and other alterations in the synthesis of globin chains occur, as well as molecular, physiopathogenic and hematological changes. Methods: A review of the literature in English and Spanish was carried out through the PubMed website and the Google Scholar search engine, searching for articles published in the last ten years. The revised bibliography was analyzed and summarized. Information analysis and synthesis: Thalassemias make up a heterogeneous group of genetic defects in the synthesis of hemoglobin, which causes a decrease in the rate of production of one or more chains of the molecule. According to the globin chain that presents the defect, they are divided into α-β-, δβ- or γδβ-thalassemias. Conclusions: Thalassemias and hemoglobinopathies are the most common hereditary hemolytic diseases in many parts of the world. They are characterized by complex interactions between anemia, ineffective erythropoiesis, and alterations in iron metabolism(AU)

For Debate: Assessment of HbA1c in Transfusion Dependent Thalassemia Patients.

At present, assessment of haemoglobin A1c (HbA1c) is widely used for the diagnosis and monitoring of treatment in diabetes mellitus (DM). However, the HbA1c level is affected by many factors such as those influencing the lifespan of red blood cells and the structure, function and amount of normal HbA. Therefore, the clinical significance of HbA1c assessment in thalassemia patients needs careful consideration, especially in transfusion dependent thalassemia patients (TDT) in whom circulating Hb is that of blood donors. Preliminary reports have documented that HbA1c estimation in efficiently transfused patients seems valuable in diagnosis and monitoring of treatment in DM and other glucose disturbances in TDT patients. Herein, a short review of HbA1c measurement in anemias, blood transfusions and hemoglobinopathies, and the debate of the credibility of Hb A1c assessment in TDT patients is reported.

Frequency of thyroid nodules in patients with ß-thalassemias in Southern Iran.

BACKGROUND: Although thyroid nodules are a common finding in the general population, determining the clinically important nodules is essential. We investigated thyroid nodules or cysts by thyroid ultrasonography (US) in patients with ß-thalassemia major (ß-TM) and intermedia (ß-TI). We also report a ß-TI patient who was diagnosed with thyroid cancer six months before our screening. METHODS: In this cross-sectional study, 178 patients with ß-thalassemias referred to the Thalassemia Clinic in a tertiary hospital affiliated to Shiraz University of Medical Sciences were investigated, from January to June 2016, by US. RESULTS: Thyroid nodules or cysts were detected in 11 patients [total: 6.17 %; 8 patients with ß-TM (8.2%) and 3 patients with ß-TI (3.7%)]. All nodules were < 1 cm in diameter and were not suspicious of malignancy. All patients, after 1 year of thyroid US follow-up, did not show any significant change in favor of malignancy. CONCLUSION: Based on our results, the frequency of thyroid nodules was similar to what was reported in the general population. However, a long-term follow-up of these patients is recommended because of the potential carcinogenic effects of iron and hepatitis C infection (HCV). To achieve more precise information, collaborative multicenter studies should be considered.

Investigating the suitability of high-resolution mass spectrometry for newborn screening: identification of hemoglobinopathies and ß-thalassemias in dried blood spots.

A fast and reliable method for the determination of hemoglobinopathies and thalassemias by high-resolution accurate mass spectrometry (HRAM/MS) is presented. The established method was verified in a prospective clinical study (HRAM/MS vs. high-pressure liquid chromatography [HPLC]) of 5335 de-identified newborn samples from the Hamburg area. The analytical method is based on a dual strategy using intact protein ratios for thalassemias and tryptic digest fragments for the diagnosis of hemoglobinopathies. Due to the minimal sample preparation and the use of flow injection, the assay can be considered as a high-throughput screening approach for newborn screening programs (2 min/sample). Using a simple dried blood spot (DBS) extraction (tryptic digest buffer), the following results were obtained: (1) a carrier incidence of 1:100 newborns (35 FAS, nine FAC, eight FAD and two FAE), and (2) no homozygous affected patient was detected. Using the HRAM/MS protocol, an unknown Hb mutation was identified and confirmed by genetic testing. In addition to greater specificity toward rare mutations and ß-thalassemia, the low price/sample (1-2€) as well as an automated data processing represent the major benefits of the described HRAM/MS method.

Nondeletional α-Thalassemia: Two New Mutations on the α2 Gene.

About 10.0% of α-thalassemia (α-thal) cases are due to point mutations, small deletions, or insertions of one or more bases on the α genes that can alter mRNA processing at the transcription, translation, or post-translation level; these cases are called nondeletional α-thalassemias (α-thal). Most occur within the domain of the α2 gene without changes in the expression of the α1 gene. We present two new frameshift mutations on the HBA2 gene, associated with a nondeletional α-thal phenotype. The probands were referred to our clinic because of persistent microcytosis and hypochromia. The molecular characterization was performed by automatic sequencing of the α-globin genes. Two new mutations were detected on the HBA2 gene; HBA2: c.85delG, p.(Ala29fs*21), and HBA2: c.268_280delCACAAGCTTCGGG, p.(His90Trpfs*9). These new mutations cause a change of the reading frame, the first on codon 28 and the second from codons 89 to 93. In the first mutation, the result is an altered amino acid sequence and a premature termination codon at position 87, while the elimination of 13 bp generates a protein of 95 residues and in this case, the premature termination codon is at position 96. These types of mutation are among the most damaging changes to the coding of a protein. Not only do they lead to changes in the length of the polypeptide, but they also vary the chemical composition, which would result in a nonfunctional protein. The importance of identifying these new mutations lies in their possible association with α0-thal, which could lead to a severe thalassemia.

A Concise Review on the Frequency, Major Risk Factors and Surveillance of Hepatocellular Carcinoma (HCC) in ß-Thalassemias: Past, Present and Future Perspectives and the ICET-A Experience.

Due to the recent alarming increase in the incidence of hepatocellular carcinoma (HCC) in thalassemias, the present report reviews briefly the frequency, the major risk factors, and the surveillance of HCC in ß-thalassemias. Over the past 33 years, 153 cases of HCC were reported in patients with thalassemia, mainly in Italy and Greece. Among HCV-infected patients, additional factors promoting the development of HCC included: advanced age, male sex, chronic hepatitis B (CHB) co-infection, and iron overload. For early diagnosis of HCC, sequential ultrasound screening is recommended especially for thalassemia patients with chronic hepatitis C (CHC), which coincides with (one or more) additional risk factors for HCC. Here we report also the preliminary data from thalassemic patients, above the age of 30 years, followed in 13 ICET-A centers. The total number of enrolled patients was 1,327 (males: 624 and 703 females). The prevalence of HCC in thalassemia major patients [characterized by transfusion-dependency (TDT)] and thalassemia intermedia [characterized by nontransfusion dependency (NTDT)] was 1.66 % and 1.96 %, respectively. The lowest age at diagnosis of HCC was 36 years for TDT and 47 years for NTDT patients. We hope that this review can be used to develop more refined and prospective analyses of HCC magnitude and risk in patients with thalassemia and to define specific international guidelines to support clinicians for early diagnosis and treatment of HCC in thalassemic patients.

Thyroid Disorders in Homozygous ß-Thalassemia: Current Knowledge, Emerging Issues and Open Problems.

Changes in thyroid function and thyroid function tests occur in patients with ß-thalassemia major (TM). The frequency of hypothyroidism in TM patients ranges from 4% to 29 % in different reports. The wide variation has been attributed to several factors such as patients' genotype, age, ethnic heterogeneity, treatment protocols of transfusions and chelation, and varying compliance to treatment. Hypothyroidism is the result of primary gland failure or insufficient thyroid gland stimulation by the hypothalamus or pituitary gland. The main laboratory parameters of thyroid function are the assessments of serum thyroid-stimulating hor-mone (TSH) and serum free thyroxine (FT4). It is of primary importance to interpret these measurements within the context of the laboratory-specific normative range for each test. An elevated serum TSH level with a standard range of serum FT4 level is consistent with subclinical hypothyroidism. A low serum FT4 level with a low, or inappropriately normal, serum TSH level is consistent with secondary hypothyroidism. Doctors caring for TM patients most commonly encounter subjects with subclinical primary hypothyroidism in the second decade of life. Several aspects remain to be elucidated as the frequency of thyroid cancer and the possible existence of a relationship between thyroid dysfunction, on one hand, cardiovascular diseases, components of metabolic syndrome (insulin resistance) and hypercoagulable state, on the other hand. Further studies are needed to explain these emerging issues. Following a brief description of thyroid hormone regulation, production and actions, this article is conceptually divided into two parts; the first reports the spectrum of thyroid disease occurring in patients with TM, and the second part focuses on the emerging issues and the open problems in TM patients with thyroid disorders.

The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center.

INTRODUCTION: The hemoglobinopathies pose a significant health burden in India. Apart from the ß thalassemias and sickle cell disorders, α thalassemias and structural hemoglobin variants are also common. Here we have reviewed the phenotypic and molecular diversity of hemoglobinopathies encountered at a referral center in western India over a period of 15 years. MATERIALS AND METHODS: Screening for hemoglobinopathies was done using HPLC and cellulose acetate electrophoresis. Molecular characterization was done using Covalent Reverse Dot Blot Hybridization (CRDB), Amplification Refractory Mutation System (ARMS), GAP PCR and direct DNA sequencing. RESULTS: The study includes 31 075 individuals who were referred for diagnosis of hemoglobinopathies and prenatal diagnosis. Of these 14 423 individuals showed various hemoglobin abnormalities. Beta genotyping in 5615 individuals showed the presence of 49 ß thalassemia mutations. 143 ß thalassemia heterozygotes had normal or borderline HbA2 levels. We identified three δ gene mutations (HbA2 Pellendri, HbA2 St.George, HbA2 Saurashtra) in ß thalassemia heterozygotes leading to normal HbA2 levels. The commonest defects among the raised Hb F determinants were Gγ(Αγδß)0 Indian inversion and the HPFH-3 Indian deletion. A total of 312 individuals showed the presence of α thalassemia, of which 12.0% had a single α gene deletion (-α/αα). HbH disease was identified in 29 cases with 10 different genotypes. Alpha globin gene triplication was seen in 2.1% of ß thalassemia heterozygotes with a thalassemia intermedia phenotype. Seven unusual α chain variants and eight uncommon ß chain variants were identified. CONCLUSION: The repertoire of molecular defects seen in the different globin genes will be valuable for management and control of these disorders both in India as well as in other countries where there is a huge influx of migrant populations from India.

[Epidemiological profile of hemoglobinopathies: a cross-sectional and descriptive index case study]. / Profil épidémiologique des hémoglobinopathies: étude transversale descriptive autour du cas index.

Hemoglobinopathies are congenital disorders resultimg from hemoglobin abnormalities. Major forms are often severe, their management is difficult and associated with a great psychosocial impact on patients and their families. They are classified as rare diseases and are still insufficiently known by health professionals. This lack of knowledge is at the origin of diagnostic errors, delay in their management and therefore high morbidity and mortality rate for these patients. In 2008, the World Health Organization (WHO) has published data on hemoglobinopathies epidemiology: more than 330.000 cases of hemoglobinopathy occur each year (83% of cases of sickle cell anemia, 17 % of cases of thalassemia). Hemoglobin disorders are responsible for approximately 3.4% of deaths among people under the age of 5. At the global level, approximately 7% of pregnant women would be carriers of a form of thalassemia and 1% of couples are at risk. However, they are relatively frequent in some regions of the globe where consanguineous marriages are common. We conducted a descriptive cross-sectional study based on two surveys, the first in May 2015 and the second in June of the same year. It was performed in the immunization days to deliver pneumococcal vaccine to the index cases and it was aimed to describe the epidemiological features of families at risk of hemoglobinopathies (index case study), whose index cases were treated in the Department of Pediatrics at the Provincial Hospital El Idrisi, Kenitra, Morocco. After having collected the epidemiological data from patients, laboratory tests were performed including: blood count with red blood cells morphological assessment using the MGG assay and automatic numbering of reticulocytes; hemoglobin electrophoresis at alkaline pH (8.8) and then at acid pH (5.4) on agarose gel and densitometric integration. 275 patients had laboratory profiles compatible with hemoglobinopathy. The majority of these patients were born to consanguineous marriages (83.1%) and came from the north regions of Morocco. This family survey allowed to identify families at risk with a high frequency of sickle cell anemia. Our results confirm the existence of hemoglobinopathies variants among Moroccan population.

Gene Therapy for ß-Hemoglobinopathies.

ß-Thalassemia and sickle cell disease (SCD) are the world's two most widely disseminated hereditary hemoglobinopathies. ß-Thalassemia originated in the Mediterranean, Middle Eastern, and Asian regions, and SCD originated in central Africa. However, subsequent population migration means that these two diseases are now global and thus constitute a growing health problem in many countries. Despite remarkable improvements in medical care for patients with ß-hemoglobinopathies, there is still only one definitive treatment option: allogeneic hematopoietic stem cell (HSC) transplantation. The development of gene therapy for ß-hemoglobinopathies has been justified by (1) the limited availability of human leukocyte antigen (HLA)-identical donors, (2) the narrow window of application of HSC transplantation to the youngest patients, and (3) recent advances in HSC-based gene therapy. The huge ongoing efforts in translational medicine and the high number of related publications show that gene therapy has the potential to become the treatment of choice for patients who lack either an HLA genoidentical sibling or an alternative, medically acceptable donor. In this dynamic scientific context, we first summarize the main steps toward clinical translation of this therapeutic approach and then discuss novel lentiviral- and genome editing-based treatment strategies for ß-hemoglobinopathies.

The Present and Future Global Burden of the Inherited Disorders of Hemoglobin.

The inherited disorders of hemoglobin represent the most common monogenic diseases. This article provides a brief description of the main inherited disorders of hemoglobin and their classification, and summarizes progress made in the last decade toward a better awareness and recognition of these disorders as a global health problem. Also presented are the main demographic, genetic, and environmental factors that influence the present and future health burden of these disorders. The strengths and limitations of existing estimates and current health policies in high-, low-, and middle-income countries are discussed.

The Molecular Spectrum of ß- and α-Thalassemia Mutations in Non-Endemic Umbria, Central Italy.

The aim of this study was to describe the mutational spectrum of hemoglobinopathies during the period 1988-2015 in Umbria, Central Italy, which has never been considered endemic for these conditions. Twenty-four different ß-globin gene mutations were identified in 188 patients and eight different α-globin gene mutations in 74 patients. Sixty percent ß-thalassemia (ß-thal), 85.0% sickle cell disease, 44.0% Hb S (HBB: c.20A>T)/ß-thal and 85.0% compound heterozygotes for hemoglobin (Hb) variant-carrying patients were diagnosed or molecularly characterized in the last 3 years. Moreover, most homozygous or compound heterozygous patients (84.5%) came from foreign countries, while only 15.5% were of Italian origin. These data are in accordance with the increasing foreign resident population in Umbria, which has nearly doubled in 10 years (2004-2014). Different from ß-globin gene variations, no increasing trend in α defects was observed in our study cohort. Consistently, 58.0% of patients have an Italian origin, suggesting no broad influence of foreign migration in the α-globin genes genetic background. As few defects are prevalent in each country of origin or ethnic group, their knowledge may provide a proper strategy for the identification of mutations in immigrant individuals in a non-endemic region and be important for carrier identification and prenatal screening.

Molecular Basis of ß-Thalassemia in the Population of the Aegean Region of Turkey: Identification of A Novel Deletion Mutation.

ß-Thalassemia (ß-thal) is the most common monogenic disorder in Turkey. The aim of this study was to investigate the spectrum of ß-thal mutations in the Aegean region of Turkey. The data was derived from 1171 unrelated ß-thal subjects, detected in a regional reference hospital between November 2004 and December 2013. Screening for the 22 common mutations was performed using the polymerase chain reaction (PCR)-reverse dot-blot method, and direct automated DNA sequencing for the unknown samples. Thirty-one different ß-thal alleles were identified. Seven mutations, namely IVS-I-110 (G > A) (41.7%), IVS-I-1 (G > A) (8.9%), IVS-II-745 (C > G) (8.6%), codon 8 (-AA) (7.7%), IVS-II-1 (G > A) (7.2%), IVS-I-6 (T > C) (6.6%), codon 39 (C > T) (4.6%) accounted for 85.3% of the mutated alleles. Frequencies of the remaining 24 ß-thal mutations were less than 2.2%; these included one novel mutation [HBB: c.206_212del (p.Leu69Profs*19)], and four others [-56 (G > C), codon 16 (-C), IVS-I (-3) (C > T) (codon 29), codon 76 (-C)] found in Turkey for the first time. The results will help to prevent severe ß-thal through genetic counseling and prenatal diagnosis (PND) in the Aegean region of Turkey.