Elisabeth Kohne

Hemoglobinopathies: Clinical Manifestations, Diagnosis, and Treatment

BACKGROUND Hemoglobinopathies are among the most common inherited diseases around the world. They have become much more common recently in northern and central Europe, including Germany, due to immigration. METHOD Selective review of the literature with consideration of national guidelines. RESULTS The hemoglobinopathies encompass all genetic diseases of hemoglobin. They fall into two main groups: thalassemia syndromes and structural hemoglobin variants (abnormal hemoglobins). α- and β-thalassemia are the main types of thalassemia; the main structural hemoglobin variants are HbS, HbE and HbC. There are many subtypes and combined types in each group. The highly variable clinical manifestations of the hemoglobinopathies range from mild hypochromic anemia to moderate hematological disease to severe, lifelong, transfusion-dependent anemia with multiorgan involvement. Stem-cell transplantation is the preferred treatment for the severe forms of thalassemia. Supportive, rather than curative, treatment consists of periodic blood transfusions for life, combined with iron chelation. Drugs to treat the symptoms of sickle-cell disease include analgesics, antibiotics, ACE inhibitors and hydroxyurea. Blood transfusions should be given only when strictly indicated. More than 90% of patients currently survive into adulthood. Optimally treated patients have a projected life span of 50 to 60 years. CONCLUSION Hemoglobinopathies are a public health issue in todays multiethnic German population. Adequate care of the affected patients requires a wide variety of diagnostic and therapeutic measures.

Rapid and non-radioactive prenatal diagnosis of β thalassaemia and sickle cell disease: application of the polymerase chain reaction (PCR)

The standard method for the prenatal diagnosis of the haemoglobinopathies is by restriction enzyme mapping of chorionic villus DNA using Southern blotting and radioactively labelled gene probes. An improvement of the procedure which involves the selective amplification of DNA fragments by the polymerase chain reaction allows one to visualize restriction fragments directly without the use of radioactivity and within 2 d after obtaining the sample.

The excretion of diamines in human urine. II. Cadaverine, putrescine, 1,3-diaminopropane, 2,2′-dithiobis(ethylamine) and spermidine in urine of patients with cystinuria and cystinlysinuria☆

Abstract The urinary excretion of non-substituted aliphatic di-and polyamines in cystinuria and cystinlysinuria were studied. The following substances were identified: cadaverine, putrescine, 2,2′-dithiobis (ethylamine) and, for the first time in human urine, 1,3-diaminopropane, and spermidine. The excretion of these substances is usually very small compared to the respective amino acids. During collection of the urines conditions were maintained to avoid bacterial contamination. A method for separation and estimation of aliphatic di- and polyamines in biological material using an amino acid analyzer is described.

Beta‐thalassaemia in the immigrant and non‐immigrant German populations

In Germany homozygous β‐thalassaemia mainly occurs in the immigrant population from endemic regions. In non‐immigrants β‐thalassaemia is rare. Heterozygous β‐thalassaemia minor, however, is more common and must be considered in the differential diagnosis of hypochromic anaemia. The clinical and molecular data of 221 homozygous patients and 256 non‐immigrant German heterozygous individuals are presented. Clinically, 87% (n =192) of the homozygotes are classified as thalassaemia major (TM) and the other 13% as thalassaemia intermedia (TI). There is a wide spectrum of 39 thalassaemia mutations which occur with relatively low frequencies in individual cases. In 17/29 TI patients ‘mild’ mutations have been found and in 16/29 there are mutations that are associated with increased γ‐globin gene activity. α‐Thalassaemia is rare and found only in 3/29.

Cardiac and extracardiac complications in infants of diabetic mothers and their relation to parameters of carbohydrate metabolism

Abstract Despite the current improvement of diabetes care in pregnancy, neonatal complications are still more frequent than in the general population. Even in fetuses of well controlled diabetic mothers, myocardial hypertrophy can be demonstrated although it is not related to maternal metabolic control. The objective of this study was to determine perinatal complications and the course of myocardial hypertrophy in newborns who had been prenatally monitored and to relate the findings to neonatal parameters of carbohydrate metabolism. Perinatal complications and echocardiographic evidence of myocardial hypertrophy were determined in 104 neonates of closely followed diabetic mothers. Cord blood was obtained for determination of insulin, C-peptide and glycosylated fetal haemoglobin (HbF1c). In cases of myocardial hypertrophy, the echocardiographic examinations were repeated until normalisation of the myocardial wall thickness. The most striking finding was myocardial hypertrophy in 25% of the 104 neonates, which predominantly involved the interventricular septum. This is in contrast to the prenatal symmetrical hypertrophy of the ventricular walls and may be explained by perinatal changings of ventricular geometry. There was no sign of outflow tract obstruction, and myocardial hypertrophy resolved within 6 months. Insulin and C-peptide were elevated in the majority of the newborns, whereas HbF1c was significantly decreased. Neither the maternal type of diabetes nor neonatal metabolic data were related to the somatic findings. Conclusion Myocardial hypertrophy still occurs in infants of diabetic mothers despite their good met abolic control reflected by the decreased fraction of glycosylated fetal hemoglobin which points to low fetal blood sugar levels during the last intra-uterine weeks.

Frequency of congenital dyserythropoietic anemias in Europe

Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders characterized by ineffective erythropoiesis and striking abnormalities of erythroblast morphology. The mutated genes are known for the most frequent types, CDA I and II, but data about their frequency do not exist. The objective of this retrospective study was to estimate the frequency of CDA I and II, based on all cases reported in the last 42 yr in publications and identified registries or surveys. Reports were collected of 124 and 377 confirmed cases of CDA I and CDA II cases, respectively. The cumulated incidence of both types combined varied widely between European regions, with minimal values of 0.08 cases/million in Scandinavia and 2.60 cases/million in Italy. CDA II is more frequent than CDA I, with an overall ratio of approximately 3.2, but the ratio also varied between different regions. The most likely explanations for the differences are both differences in the availability of advanced diagnostic procedures and different levels of the awareness for the diagnosis of the CDAs. The estimations reported here are most probably below the true incidence rates, because of failure to make the correct diagnosis and to underreporting. Limited data do not suggest differing levels of risk in identified ethnic groups.

Hemoglobinopathies: a longitudinal study over four decades.

BACKGROUND Hemoglobinopathies are among the most common hereditary diseases worldwide, with high prevalence in the Mediterranean basin, Africa, and Asia. Although they are rare in the indigenous central European population, they have become much more common in Germany recently through the immigration of millions of people from endemic regions. METHODS In a long-term study (1971-2007), 100,621 hemoglobin analyses were performed and retrospectively evaluated. Basic clinical and hematological information were provided by the participating physicians. The hemoglobin defects were characterized with hematological and biochemical methods, as well as by DNA analysis in selected cases (from the mid-1980s onward). 73% of the analyses were performed in patients with an immigration background, 27% in patients of German ethnic origin. RESULTS 34,228 persons, or 34% of those studied, were found to have a hemoglobinopathy. Most cases involved thalassemia syndromes (25,798 cases, 25.6%); the second most common type was a structural abnormality of hemoglobin (8,430 cases, 8.4%). This study provides the first broad overview of the occurrence, spectrum, and geographical distribution of hemoglobinopathies in Germany. CONCLUSIONS These data show that hemoglobinopathies are a relevant health problem in the population of Germany today. This is not an epidemiological study, and thus it is unknown to what extent these data are representative. Because hemoglobin defects are of widely diverse genetic and clinical types, specialized laboratory analysis is needed to diagnose them correctly and provide a basis for proper therapeutic decisions.

DNA-polymorphic patterns linked to the β-globin genes in German families affected with hemoglobinopathies and thalassemias: a comparison to other ethnic groups

SummaryDNA haplotype constellations of the β-globin gene cluster have been analyzed in German families with hemoglobinopathies (Hb Freiburg, Hb Köln, Hb Presbyterian) and β-thalassemias. The polymorphis patterns obtained were compared to those found in families from Greece, Italy, and Turkey affected by β-thalassemia syndromes. With the combined analysis of seven restriction site polymorphisms a DNA-diagnostic prediction for additional offspring could be made with an overall frequency of 75% in the four ethnic groups.

Familial polycythemia vera with Budd–Chiari syndrome in childhood

Summary. Polycythemia vera is a myeloproliferative disorder that, in most cases, occurs sporadically with a median age at presentation of 60 years. Familial cases are very rare and usually manifest in elderly family members. The Budd–Chiari syndrome, characterized by the obstruction and occlusion of the suprahepatic veins, is a rare typical complication in polycythemia vera patients. To date, only two children or adolescents with polycythemia vera and Budd–Chiari syndrome have been described. Here, we report an 11‐year‐old girl with Budd–Chiari syndrome as the initial symptom of familial polycythemia vera, which was also found in the girls grandmother. Details of the diagnostic procedures used and the clinical course are reported. The patient underwent orthotopic liver transplantation and is being treated with hydroxyurea. The available literature on familial polycythemia vera and polycythemia vera in childhood with and without Budd–Chiari syndrome is reviewed.

Disproportionately elevated fasting proinsulin levels in normoglycemic patients with thalassemia major are correlated to the degree of iron overload

Objective: To analyze the secretion of the insulin precursor proinsulin in patients with β-thalassemia and its possible relation to iron overload. Methods: We assessed fasting proinsulin, insulin, C-peptide and glucose levels from 34 patients with β-thalassemia and 33 healthy controls. The correlation to age, body mass index, hepatic iron concentration, serum ferritin and serum AST was analyzed. Results: Fasting proinsulin (p < 0.002) and proinsulin-to-insulin ratio (p < 0.02) were significantly increased in patients with thalassemia irrespective of the degree of glucose tolerance. They correlated positively to serum ferritin, liver iron, patient age and serum AST (all p < 0.05). Conclusions: Disproportionately elevated proinsulin levels in thalassemic patients indicate early β-cell dysfunction due to siderosis. An additional biological significance of hyperproinsulinemia and its possible ability to predict long-term iron toxicity in these patients remain to be clarified.