Marta Polo

Frequency of the C282Y and H63D mutations of the hemochromatosis gene (HFE) in a cohort of 1,000 neonates in Madrid (Spain).

For centuries in Europe, population movements have contributed to ethnic groups, cultures, and consequently, inheritance mixing. There are certain genetic diseases such as hereditary hemochromatosis whose distribution is directly related to the population movements. The objective of the present investigation was to determine the C282Y and H63D mutation frequency of the HFE gene in a cohort study of 1,000 neonates in the Community of Madrid (Spain), thus contributing to the HFE gene mutations distribution research in Europe and establishing the origin of the mutations in Spain. The allelic frequency of C282Y mutation was 1.7% (CI 95% 1.1–2.3) and the H63D allele was present in 16.4% of chromosomes (CI 95% 14.8–18). In Spain, the presence of C282Y mutation and its distribution could be due more to Celtic than to Viking legacy, whereas it is assumed that the one in relation to the H63D variant occurred in the Basque Country during the Paleolithic Period.

THE FIRST CASE OF Hb E-SASKATOON ASSOCIATED WITH Hb LEPORE-BALTIMORE FOUND IN SPAIN

Hb E-Saskatoon [β22(B4)Glu→Lys] does not cause any clinical symptoms in the heterozygous state. The homozygous state shows moderate phenotype expression. It has also been detected in association with β-thalassemia. We present the first case of Hb E-Saskatoon associated with Hb Lepore-Baltimore. This unusual combination of mutations does not aggravate the clinical picture, as only microcytosis and hypochromia have been observed. Hb E-Saskatoon can only be correctly characterized by ion exchange high performance liquid chromatography (HPLC) or by DNA sequencing.

Hemoglobina Stanleyville II [ α78(EF7)Asn → Lys]. Primer caso descrito en España

Resumen Fundamento y objetivo Las hemoglobinopatias estructurales son el resultado de mutaciones en los genes de globina que determinan una alteracion cualitativa en la expresion de dichos genes. En la mayoria de ellas la alteracion estructural no condiciona ningun cambio significativo, por lo que cursan de forma silente o asintomatica. En este trabajo presentamos un nuevo caso de hemoglobina (Hb) Stanleyville II. Pacientes y metodo El probando es una mujer de 72 anos, raza blanca y origen canario. En la analitica presentaba Hb de 14,3 g/dl, hematocrito del 44,4%, volumen corpuscular medio de 85,8 fl, Hb corpuscular media de 27,7 pg y concentracion de Hb corpuscular media de 32,2 g/l; el indice de anisocitosis era del 15,1%, reticulocitos del 1,2%, HbA2 del 3,1% y HbF del 1,6%. En la electroforesis en acetato de celulosa a pH alcalino y en el isoelectroenfoque se separo una Hb anormal a la altura de la HbS. En agar citrato a pH acido la Hb anormal no se separaba de la HbA. Por cromatografia liquida de alta resolucion de fase reversa se eluyo una cadena anormal mas precoz que la normal. Resultados En el analisis molecular, que se completo con la secuenciacion de los productos de amplificacion por reaccion en cadena de la polimerasa de los genes α 1 y α 2 , se demostro la mutacion AAC → AAA en el codon 78 del segundo exon del gen 2 en estado heterocigoto, que determina un cambio de asparagina por lisina. Conclusiones La sustitucion de un aminoacido con carga neutra, como la asparagina, por otro con carga muy positiva, como la lisina, en el segmento EF, que corresponde a la superficie externa de la estructura terciaria de la cadena de globina, determina un cambio neto en la carga de la cadena. Esto permite su facil diferenciacion por metodos electroforeticos y cromatograficos. Sin embargo, como la localizacion no es fundamental para la estabilidad, solubilidad y afinidad por el oxigeno del tetramero, cursa de forma silente o asintomatica. La Hb Stanleyville II se habia descrito hasta ahora en familias de raza negra del Congo, Uganda, Zaire, EE.UU., Alsacia y Brasil. Este caso representa el primero descrito en Espana.

A Novel Mutation of the α2-Globin causing α+-Thalassemia: Hb Plasencia [α125(H8)Leu→Arg (α2)

We describe, in a Spanish family with moderate microcytosis and hypochromia, a novel nondeletional α-thalassemia (thal) mutation localized on the α2-globin gene. DNA sequencing revealed a point mutation at codon 125 (CTG→CGG) in the heterozygous state, that was confirmed by restriction analysis. The resulting variant, which causes a nondeletional α-thal, was named Hb Plasencia [α125(H8)Leu→Arg (α2)] after the place of residence of the affected family.

Incidence of the HFE gene mutations in a cohort of non-Spanish origin neonates in Madrid

Dear Editor, Hereditary Hemochromatosis (HH) is a potentially serious disease due to the build up of iron excess and attendant cells damage in several organs [4] that issues from the irongreedy bowels. Unless it is early diagnosed and treated, HH can lead to liver cirrhosis and hepatocellular carcinoma, diabetes mellitus, infertility, heart disease, and arthropathy [8]. However, an early diagnosis, before irreversible injuries become established, can prevent all associated disorders and re-establish a life expectancy similar to that of the general population [4, 8]. The disease is passed on as an autosomal recessive trait associated to C282Y (Cys282Tyr) and H63D (His63Asp) mutations of the hemochromatosis (HFE) gene, located on the short arm of chromosome 6 [5, 9]. Geographical distribution of HH is quite irregular. Both mutations are frequent in Europe. However, H63D has also been found in northern Africa, the Middle East, and Asia, whereas C282Y seems to affect, only, European populations, particularly in the Scandinavian countries, where seemingly this mutation on the HFE gene was originated and spread with the Vikings [14]. In these countries, the prevalence ranges from 5 to 10%, and the mutation has been found to be homozygous in 1:100 to 1:400 of the overall population [12, 15]. In recent years, migratory movements have changed the demographic, cultural, and social characteristics of Spanish cities. At this time, 12.1% of the Madrid population was not born in Spain. And even more significant, in 2005, the increase in children born to non-Spanish parents reached 17.37% [10]. Given this demographic shift, the aim of this study is to determine the incidence of C282Y and H63D mutations in a cohort of neonates born from non-Spanish parents in the Madrid Autonomous Community territory. And in this way, the knowledge of the genotype of these new populations could be helpful for planning future health policy strategies related to HH. In a cross-sectional study, parents of all 1,000 neonates born in the Hospital Clínico San Carlos of Madrid, from February 1st to May 31st, 2006, were asked to answer a socio-demographic questionnaire, but the study was limited to 449 neonates who issued from non-Spanish parents. The study was submitted to the Institutional Ethics and Research Committee for approval, and an informed consent was secured, always, from the parents. The HFE gene was studied using polymerase chain reaction amplification primed with previously described oligonucleotides [2, 9, 13]. Data on genotype and allele frequency, in all neonates, are shown with the respective count, percentage, and 95% confidence interval. The Hardy–Weinberg test was applied to determine the population genetics equilibrium. Allelic frequency was 0.9% for the C282Y mutation and 11.5% in the H63D variant. None of the neonates presented homozygosity for the C282Y mutation, whereas in eight neonates, the mutation was present in a single allele (1.8%). As for mutation H63D, homozygosity was identified in ten neonates (2.2%), and heterozygosity was found in 83 neonates (18.5%). Double heterozygosity was not identified. Ann Hematol (2007) 86:459–462 DOI 10.1007/s00277-007-0264-z

Hb LA Coruña [β38(C4)Thr→Ile]: A New Hemoglobin Variant Leading to Familial Polycythemia

Hb La Coruña [β38(C4)Thr → Ile] is a new hemoglobin (Hb) variant that has an increased oxygen affinity. Clinically, this Hb leads to erythrocytosis. Hb La Coruña is an electrophoretically silent variant that can be detected by reversed phase high performance liquid chromatography (HPLC) and characterized by DNA sequencing. The patient was a 22-year-old Spanish male whose family lived in La Coruña, in the northwest of Spain. His mother was also a carrier.

First Spanish Case Of Thalassemia Major Due to a Compound Heterozygosity for the IVS-II-848 (C→A) And Codon 39 (C→T) Mutations Of The β-Globin Gene

This report describes the first case in Spain of a severe form of β-thalassemia (thal) due to a compound heterozygosity for the IVS-II-848 (C→A) and the nonsense codon 39 (C→T) mutations. Five members of a family from Cadiz (southern Spain) were studied. The proband was an 8-year-old girl diagnosed as anemic at the age of 13 months. Her father had the codon 39 (C→T) mutation and her mother the C→A change at nucleotide (nt) 848 of IVS-II. Haplotype analysis showed that the proband was a compound heterozygote for haplotypes I [+ − − − − + +] and VII [+ − − − − − +]. This is the first description in Spain of the IVS-II-848 (C→A) mutation. It appears, from restriction fragment length polymorphism (RFLP) analysis, that this mutation has a different origin in the various populations, where it was found. This observation shows that in this case the association of a β0- and a β+-thal mutation does not lead to a thalassemia intermedia but to a severe thalassemia with very low hemoglobin (Hb) levels. From a therapeutic point of view, early introduction of a transfusion regimen may improve the clinical picture of these children, allowing for better development and growth.