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Thalassemias are a heterogeneous group of genetic diseases based on a quantitative disorder of globin chain synthesis. They are among the most frequent monogenic hereditary diseases worldwide. Migration during recent years led to a profoundly increasing number of patients in countries where the indigenous population has not been affected. The complex treatment of the patients represents a medical and socioeconomic challenge with the need for structured interdisciplinary clinical care and close collaboration among healthcare providers, regulatory authorities, and health care insurance companies. The following article provides an overview of the causes, pathogenesis, clinical presentation, and treatment of alpha- and beta-thalassemias.

Glycine transporter-1 (GlyT1) inhibition has been extensively studied both in pharmaceutical companies and academic institutions primarily as a potential new approach to treat schizophrenia, a severe and chronic mental illness. More recently, preclinical results have suggested that this approach could also have therapeutic potential for CNS disorders beyond schizophrenia as well as for non-CNS indications. Over the past 17 years, Roche has been a key player in the GlyT1 field with the discovery and development of bitopertin, the most advanced GlyT1 inhibitor to date and the only one which completed Phase III clinical studies for schizophrenia. In this article, we relate the eventful journey of the discovery and development of bitopertin, from project initiation in 2001 to its evaluation today in patients suffering from beta-thalassemia, a monogenic hereditary haematological disorder.

In Germany and Central Europe, congenital disorders leading to secondary hemochromatosis are rare. The majority of these patients are treated in peripheral medical institutions. As a consequence, the experience of each institution in the treatment of secondary hemochromatosis in patients with congenital anemia is limited. Recent developments concerning new chelating agents, their combination for intensified chelation and new possibilities to diagnose and monitor iron overload have important consequences for the management of patients with secondary hemochromatosis and increase its complexity enormously. Therefore, the development of a guideline for rational and efficient diagnostics and treatment was necessary. The new guideline was developed within a formal consensus process and finally approved by a consensus conference with participants from both the pediatric and adult German hematology societies (GPOH and DGHO). Apart from general information and recommendations, the guideline contains 9 consensus statements on diagnostics (iron status, siderotic complications, chelator side-effects), the start of chelation, indications for intensified chelation, iron elimination in specific disorders, and iron elimination after stem cell transplantation. Here, these consensus statements are presented and discussed in detail. For the complete text of the guideline, please visit the AWMF homepage at http://www.leitlinien.net .

We discuss the case of a 32 year-old male with severe microcytic anemia (hemoglobin 2,9 g/dl) and megaloblastic changes in the bone marrow. The patient reported of substantial dietary weight loss. The family history was positive for beta-thalassemia. Previous blood work showed iron deficiency with mild anemia. Further work-up verified beta-thalassemia minor and revealed severely decreased vitamin B12 levels with positive anti intrinsic-factor antibodies, pathognomonic for autoimmune pernicious anemia. The paradoxon therefore dissolved as a pernicious anemia with megaloblastic changes with microcytic erythrocytes due to beta-thalassemia.

We present the case of a young Italian woman with thalassemia major and describe a series of complications such as infertility, fetal growth restriction, difficult intubation, and cardiac decompensation that occurred in the course of family planning, pregnancy, and the puerperal period. By review of the literature and based on own experiences, we show how the preconceptional consultation and the care during a pregnancy, especially the individualized planning of delivery, can be optimized. The intensive and interdisciplinary care by obstetricians and internists is very important.

Longtime outcome in case of thalassemia depends on the patients' adherence in home treatment to reduce hemosiderosis. This study describes the patients' perspective, their typical coping strategies, health related locus-of-control-beliefs and psychosocial influences on adherence.A battery of questionnaires was employed to 43 patients with thalassemia major (3 to 26 years old) treated in Germany according to the german multicenter study respectively their parents: the Ulm Thalassemia Inventory, the KIDCOPE, the Multidimensional Health Locus of Control Scales and the Giessen Complaint List. Clinical symptoms of hemosiderosis were correlated with psychosocial variables.The patients feel more distressed from their treatment than from their illness itself. They react to disease-related distress with a variety of coping strategies. Some of the most frequent coping strategies are maladaptive, indicating feelings of helplessness. Internal locus-of-control-beliefs were low and fatalistic locus-of-control-beliefs were high compared with other clinical groups. The self-reported adherence to the iron chelation treatment is correlated with age, gender, age at the start-point of the treatment and emotional distress. Complaints, coping strategies and locus of control are independent from adherence as well as from hemosiderosis.Patients with thalassemia major need more information about their disease and about the benefits of iron chelation therapy. Additional psychosocial support should reduce emotional distress, strengthen coping competence and lead to a better integration of therapy in daily life.

The prognosis and therewith the quality of life of patients with beta-thalassaemia major is decisively influenced by the compliance with the therapy of the patients and their families, who are massively burdened with this lifelong and much time requiring treatment. To improve the compliance with therapy a group of 10 afflicted adolescents and young adults aged between 15 and 27 years was founded in 1992. The aims are to get to know the reasons for the unsatisfactory compliance with therapy, to promote the exchange of experience how to deal with the disease and its treatment, to give comprehensive medical informations and to improve in this way the own responsibility and the compliance with therapy. At the monthly meetings aspects of interaction between parents and the child with a hereditary disease are discussed. Also the themes of self-image and body image of these adolescents are set who are stigmatized by thalassaemia and grow up in uncertainty about the development of their disease and often suffer from mortal fear. Possibilities and limits of integration of these chronically ill patients within school and profession, and not at last within the clinique are debated. Although two members of this group have died, our patients show more interest in their disease, their therapy and their prospects since the beginning of this psychosocial care. The compliance with therapy has become better in the majority of patients.

Surgical therapy of the acute abdomen often allows only limited time for differential diagnosis to confirm the indication for surgery. Under consideration of clinical aspects and case history both common and rare causes of an acute abdomen should be investigated without undue loss of time. Differential diagnostic considerations and eventual therapy are presented in the following case of a 25-year-old Afro-american who developed multiorgan failure after an initial course of lower-back pain. In addition to the clinical setting of an acute abdomen the patient presented with acute respiratory failure and laboratory signs of severe hemolysis in combination with newly detected splenomegaly. The indication for splenectomy was made following CT-proven complete splenic infarction due to repeated acute squestration. Histologic examination of the spleen together with hemoglobin electrophoresis confirmed the clinical assumption of unusually late primary manifestation of a sickle cell crisis. In the underlying case, the hemoglobinopathy was in fact the less common form of combined sickle-cell-beta-thalassemia. A ten-day course of intensive care therapy was necessary to treat ongoing multiorgan failure due to persistent sickle cell crisis. Current diagnostic and therapeutic procedures in connection with sickle cell crisis as a rare cause of an acute abdomen with the necessity for surgical intervention are presented.

A 25-year-old Turkish patient presented with a "swelling" of the ankles which now persisted for 5 years. He had previously been diagnosed as having HLA-B27 negative spondylarthropathy with peripheral joint involvement. The symptoms failed to respond to different therapies. Serological markers and radiological procedures revealed beta-thalassemia minor.Symptoms, diagnostic procedures and differential diagnostic options are discussed.

At present, about 300 patients with thalassemia major are living in Germany. Starting in 1991, a multicenter study in Germany has concentrated on identifying all patients suffering from thalassemia as well as on establishing a uniform therapy protocol including follow-up diagnostic procedures. After six years of study, the data of 198 patients suffering from thalassaemia major were analysed. The majority of these patients originate from endemic regions around the Mediterranean Sea. The patient's median age is 13.8 years (range 1-37.5 yrs.). At present, about 20% of patients are older than 21 years. Regarding transfusion therapy, a shortening of the average transfusion interval to 3 weeks in most cases occurred. Throughout the entire period, median baseline haemoglobin concentrations of 10.0 g/dl could be observed. The evaluation of serum ferritin levels revealed considerable differences depending on patients age. 60% of patients in the first decade of life showed good therapeutic results with serum ferritin levels below 1800 ng/ml. In contrast, 52% of patients older than ten years presented with ferritin levels above 2500 ng/ml. During the observation, a decreasing number of patients with ferritin levels above 2500 ng/ml was observed in patients aged 15 to 21 years of age. The situation of patients aged 9 to 15 years proved to be more problematic. More than half of all treated patients presented with siderotic complications as cardiac disease in 13%, liver disease in 21%, impaired glucose metabolism in 14%, hypothyroidism in 24% and hypogonadism in 59% of all patients. These values did not change considerably during the observation apart from an increase of cardiac disorders to 20%. Since the situation concerning siderosis and the lack of compliance proved to be particularly difficult in adolescent patients, further efforts has to concentrate on this age group.

Red cell haemolysates of 627 patients with mainly microcytic anaemia were subjected to HPLC for diagnosis of thalassaemia (thal) or haemoglobinopathy during 1998. Thalassaemia was diagnosed in 16.3% (95 beta-thal minor, 1 beta-thal major, 2 delta beta-thal heterozygote, 4 alpha-thal1), haemoglobinopathies in 3.5% (10 Hb S including 3 Hb S-alpha-thal, 1 homozygote, 1 Hb SC and 1 Hb SE; 6 Hb E including 3 homozygotes; 3 Hb Lepore heterozygotes; 1 Hb K; 1 Hb O-Arab*; 1 Hb K-Ibadan* [* = confirmed by DNA sequencing]). In 10.7% of patients severe iron-deficiency (ferritin7 micrograms/l) was the cause of microcytosis (MCV 72.1 +/- 2.6 fl) and anaemia (Hb 97.2 +/- 9.8 g/l). The beta-thal minor group showed prominent microcytosis (MCV 66.9 +/- 2.6 fl) but only mild anaemia (Hb 114.1 +/- 12.9 g/l). Variant Hb K-Ibadan und Hb O-Arab were found during quantification of HbA1c. Patients with beta-thal minor or severe iron-deficiency anaemia were identified with equal frequency in adult females, children and adolescents of both sexes; however, in adult males beta-thal minor was the most frequent aetiology (90%) of microcytic anaemia. Our results demonstrate the diagnostic value of red cell lysate HPLC and ferritin determination when evaluating unclear microcytic anaemia. This approach, together with die HbA1c-quantification by HPLC, will render possible detailed diagnosis of thalassaemia and haemoglobinopathies.

Superficial leptomeningeal hemosiderosis is a rare disease of the central nervous system. Chronic bleeding into the subarachnoid space causes deposition of hemosiderin in glial cells and subsequent damage to adjacent brain tissue. There is a characteristic predilection for the cerebellum and eighth cranial nerve. Accordingly, among a variety of symptoms, cerebellar ataxia and sensorineural hearing loss progressing to total deafness commonly occur. To date, the hearing loss has been believed to be purely neural. We present a case of superficial hemosiderosis in a patient with total deafness who was successfully provided with a cochlear implant. Audiometry demonstrated total bilateral cochlear hearing losses but with preserved function of the eighth cranial nerve. These findings make us conclude that in contrast to current opinion, superficial hemosiderosis can initially damage the cochlea alone. Thus, patients with total deafness due to this disorder may benefit from cochlear implantation. All patients require careful audiometric assessment, including promontory stimulation.

In Germany there are about 300-400 patients with homozygous beta-thalassaemia who immigrated from endemic regions mostly in the Mediterranean. In the non-immigrant population beta-thalassaemia is rare with only single case reports of homozygous patients. Heterozygous beta-thalassaemia, however, is more common and must be considered in the differential diagnosis of hypochromic anemia.Here, clinical and molecular data of 221 homozygous patients from immigrant families and 256 non-immigrant German heterozygous individuals are presented.Clinically, 87% (n = 192) of the homozygotes are regularly transfused and classified as thalassaemia major (TM). The other 13% (n = 29) are not (regularly) transfused and thus classified as thalassaemia intermedia (TI). There is a wide spectrum of 39 beta-globin gene mutations and even the most common three, IVSI-110G-A, NS 39, and IVSI-6 T-C occur with relatively low frequencies of 28%, 22%, and 9%, respectively. In 17/29 (58%) TI patients "mild" mutations are found that inactivate the affected gene incompletely. In 16/29 (55%) there are mutations that are associated with increased gamma-globin gene activity. alpha-Thalassaemia is rare and only found in 3/29 TI-patients. In the 256 Germans with heterozygous beta-thalassaemia there are 27 different beta-globin gene mutations. The 3 most common are Mediterranean mutations together accounting for 61%. Also-relatively common (5%; n = 13) is an otherwise rare frameshift mutation of codon 83 (FS83 delta G). The other mutations occur in10 individuals only. Two mutations described here are novel. One of them affects position-2 of the intron 1 splice acceptor site (IVSI-129 A-G) and the other is a deletion of a single G in codon 15/16 (FS 15/16 delta G).Taken together, a plausible molecular pathogenesis for the observed phenotype (TM vs. TI) can be identified in most homozygous patients thus allowing for rational counselling of the affected families. In heterozygous Germans beta-thalassaemia has probably been imported from the Mediterranean in about 2/3 of the cases whereas in the remaining 1/3 it has probably originated locally.

Regular blood transfusions in patients with beta-thalassaemia major lead to secondary hemochromatosis in the majority of cases. As a consequence of chronic iron overload, many endocrinopathies may occur. The most frequent endocrine dysfunction is hypogonadotropic hypogonadism, which is mainly responsible for osteopenia in as much as 80% of thalassemic patients. The frequencies of other endocrine disorders (hypothyroidism, diabetes mellitus and hypoparathyroidism) are lower. We investigated 5 female patients aged 22-25 years for endocrine dysfunction and bone density. All presented with hypogonadotropic hypogonadism and amenorrhea (four primary and one secondary). 4 patients showed absent or delayed pubertal development and short stature (below 10th percentile). In all five, hypogonadism is the most relevant cause of osteopenia as demonstrated by osteodensitometry. Endocrine disorders, especially absent pubertal development, should be detected in good time and treated with hormonal replacement. Established osteopenia is treated hormonally and with vitamin D3 and calcium.

Our experience of beta-thalassemia during pregnancy is limited to 2 rare cases. The first patient suffered from beta(0)/beta(+) thalassemia, and therapy consisted of 300 ml of concentrated red cells every month and deferoxamine. During pregnancy the patient received 300 ml of concentrated red cells every week, and a healthy child was born by cesarean section. The second patient suffered from Cooley's disease till 1985. She received many transfusions but was allergic to deferoxamine. Later, bone marrow transplantation was successful. Her normal full-term pregnancy concluded with the birth of a healthy child.

Desferrioxamine (DFO) is the most important drug in the treatment of thalassemia major and other hematological diseases requiring regular transfusion. It eliminates excessive ferritin by building up chelate complexes. Different mechanisms of possible DFO toxicity are induction of oxidation, damage of the blood-retina barrier, or reduction in other metalloions (Cu2+, Zn2+). The objective of the present study was to evaluate the ocular side effects of DFO treatment. We prospectively examined 17 patients aged 5 to 25 years, all of them treated with DFO. Visual acuity, pupillary reaction, anterior segment, lens and fundus were checked. If possible, visual fields, color vision, dark adaptation, stereoscopic vision, and contrast sensitivity were investigated. Lens opacities were found in 41% (7/17), changes in the retinal pigment epithelium in 35% (6/17), tortuosity of retinal vessels in 24% (4/17), dilation and sheathing of the retinal vessels in 18% (3/17), defects in color vision in 29% (5/17), and abnormal dark adaptation in 18% (3/17) of the patients. The oculotoxicity of DFO is dose-dependent. Major side effects like depression of the visual acuity are partially reversible after discontinuing the therapy. Regular ophthalmological check-ups are therefore necessary.

Patients with beta-thalassemia develop a specific osteoarthropathy as they approach the second life decade. Radiological changes included osteopenia, widened medullary spaces, thin cortices with coarse reticulations, evidence of microfractures, premature epiphysiodesis of long bones and skeletal deformations. The fact that currently patients with beta-thalassemia have a longer life expectancy may explain the recent observations in this case report of this entity, which should become more familiar to orthopaedic surgeons who treat thalassemia patients in the future.

The case of a 14-year-old-boy with homozygotic beta-Thalassemia in which an intraspinal extension of the extramedullary focal hemopoiesis gave rise to spinal compression with partial paraplegia is reported. A rapid improvement was observed after blood transfusions.

At the present time, about 3.5 million people from Turkey, Greece, Italy, the Middle East, Africa and Asia are living in Germany. They are potential carriers of beta-thalassaemia and haemoglobinopathies such as sickle cell disease. These diseases are new for most of us and represent a challenge to physicians, taking care of these patients. Not only do we have to learn about the clinical problems of homozygous patients and how to handle them, we also have to become acquainted with the problems related to the heterozygous carrier stage. The large number of asymptomatic pregnant carriers of beta-globin anomalies is a particular challenge for obstetricians. They need to identify carriers through haemoglobin electrophoresis screening, inform the carrier about the meaning of being a carrier, screen the woman's partner, refer for genetic counselling and suggest and explain prenatal diagnosis in case the partner is also a carrier. There is as yet no cure for thalassaemia and sickle cell disease, except for bone marrow transplantation in a few selected cases. Therefore, prenatal diagnosis presents a valuable method of preventing severe chronic diseases. Screening does not only allow genetic counselling, the information gained has also clinical implications for carriers of beta-thalassaemia. In this paper a summary is given of the pathophysiological and clinical features of thalassaemia and sickle cell disease and molecular biology methods to diagnose thalassaemias and sickle cell disease are discussed. In addition, a screening programme for pregnant women from countries at risk is suggested to enable physicians to give optimal care and initiate prenatal diagnosis.

A now 42-year-old Thai woman was known to have been anaemic since childhood. When aged 33 years she was diagnosed as having beta zero/HBE thalassaemia. Computed tomography demonstrated a tumour in the posterior mediastinum, histologically found to be an extramedullary haematopoietic focus. Subcutaneous infusion of deferoxamine (2 g five times weekly), initiated because of massive iron overload, reduced the serum ferritin level from 3,460 ng/ml to less than 500 ng/ml. The haemoglobin level in the subsequent years was between 6 and 8 g/dl. Five years later sensory deficits were noted from the 5th thoracic vertebra downwards. Magnetic resonance imaging demonstrated a tumour which compressed the spinal cord: it, too, was an ectopic haematopoietic focus. The neurological symptoms disappeared after radiotherapy with 3,000 cGy, but they recurred 4 years later. Because of the low radiation reserve of the spinal cord, hypertransfusion treatment was initiated, namely 16 RBC concentrates within 4 months and afterwards two transfusions every 3 months. By this means the haemoglobin level was kept at about 9 g/dl. The tumour had regressed 4 months after onset of treatment. For 2 years since the beginning of the hypertransfusion treatment the patient has remained free of neurological symptoms.

A method is described in which allele-specific oligonucleotides (ASO) are labeled non-enzymatically with digoxigenin (DIG). The ASOs were synthesized in a DNA synthesizer. A primary C6-alkylamine was incorporated at the 5'end of the ASO. The derivative was coupled to digoxigenin-3-0-methylcarbonyl-epsilon-aminocaproic acid-N-hydroxy-succinimide ester. The DIG-ASO probes were isolated from the crude preparation and hybridized with amplified genomic DNA. The annealed probes were detected with an ELISA test. The DIG-ASO probes were successfully used for the identification of sickle cell disease genotypes and the most common beta-thalassemia mutations.