Acanthocytosis as a predisposing factor for non-ketotic hyperglycaemia induced chorea-ballism.

BACKGROUND: Episodic non-ketotic hyperglycaemia in patients with diabetes may be responsible for a syndrome characterised by hemichorea-hemiballism associated with unique radiological features. OBJECTIVE: To investigate whether factors other than hyperglycaemia may be responsible for the neurological involvement. METHODS: Three patients who developed a persistent chorea-ballism syndrome triggered by a hyperglycaemic crisis were investigated. In these patients, the persistence of the involuntary movements required neuroleptic medication. RESULTS: T1 weighted magnetic resonance imaging revealed bilateral hyperintense lesions involving the striatum. Surprisingly, in these patients, the laboratory investigations revealed peripheral red blood cell acanthocytosis in a significant proportion of cells. CONCLUSION: Compared with the large population of patients with diabetes who do not show abnormal involuntary movements, unrecognised acanthocytosis in diabetes might render patients prone to develop hemichorea-hemiballism.

LPI-labile plasma iron in iron overload.

Labile plasma iron (LPI) represents a component of non-transferrin-bound iron (NTBI) that is both redox-active and chelatable, capable of permeating into organs and inducing tissue iron overload. It appears in various types of hemosiderosis (transfusional and non-transfusional) and in other iron-overload conditions. Sustained levels of LPI could over time compromise organ (e.g. heart) function and patient survival. With the advent of methods for measuring LPI in the clinical setting, it has become possible to assess the implications of LPI in the management of iron overload based on regimens of iron chelation. As LPI is detected primarily in patients with transfusional iron overload and other forms of hemosiderosis, we review here regimens of iron chelation with deferrioxamine and deferiprone (separately or combined) in terms of their efficacy in minimizing daily exposure to LPI in thalassemia major and thalassemia intermedia patients.

Cardiovascular involvement in thalassaemic patients with pseudoxanthoma elasticum-like skin lesions: a long-term follow-up study.

BACKGROUND: Congenital haemolytic anaemia may be associated with pseudoxanthoma elasticum (PXE)-like clinical manifestations. METHODS: The cardiovascular system of 14 homozygous and double heterozygous beta-thalassaemia patients with skin and retinal vessel alterations similar to those in genetic PXE was analysed over a period of 12 years and compared with that of 13 relatives (five sets of parents, one single parent, two thalassaemic brothers), and that of the control group composed of 16, age- and sex-matched, thalassaemic patients. RESULTS: All patients with clinical PXE-like skin lesions exhibited, by light and electron microscopy, dermal alterations and mineralization of elastic fibres identical to those typical of inherited PXE. None of the relatives and none of the control group showed clinical or structural findings of PXE. The follow-up started in 1988. After 12 years of clinical observation, six patients showed dramatic progression of skin involvement, angioid streaks had progressed in two subjects. One patient had recurrent gastrointestinal bleeding and underwent partial stomach removal for gastric artery aneurysm, one underwent colon resection for intestinal infarct, one patient had a transitory ischaemic attack, one died after an intracranial haemorrhage, two patients died from cardiovascular disease and one from neoplasia. CONCLUSIONS: Thalassaemic patients with PXE-like skin lesions also manifest PXE-like vessel alterations that progress with time. Considering the severe outcome of these lesions, accurate monitoring should be routinely performed on the cardiovascular system of thalassaemic patients with PXE-like skin manifestations.

6-Phosphogluconate dehydrogenase deficiency in an Italian family.

A rare case of hereditary erythrocyte enzymopathy, namely 6-phosphogluconate dehydrogenase (6PGD) deficiency, was found in an Italian family. The activity of the enzyme was reduced to 35% in the propositus and her mother, but was normal in the other three members of the family. The 6PGD deficiency was associated with a variable reticulocyte count and recurrent increased unconjugated bilirubinemia without anemia in the propositus, while no clinical or hematological symptoms were evident in her mother. Increased levels of erythrocyte pyruvate kinase (PK) activity and reduced glutathione (GSH) were observed, indicating a slight decrease in mean red blood cell (RBC) age and an activation of reducing systems. The episodic hemolytic events with jaundice observed in the propositus may be the result of a defective RBC ability to counteract conditions of marked oxidative stress. In this report the importance of 6PGD estimation for a proper analysis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is also highlighted. In fact in the present study, the presence of 6PGD deficiency could be mistaken for a partial G6PD deficiency if the assay of G6PD activity was performed without correcting for 6PGD activity.

Hydroxyurea therapy in paraparesis and cauda equina syndrome due to extramedullary haematopoiesis in thalassaemia: improvement of clinical and haematological parameters.

Patients with beta-globin disorders show amelioration of clinical condition by sustained synthesis of fetal haemoglobin in adult life. We report data on a patient with beta(o)-thalassaemia genotype and thalassaemia intermedia clinical phenotype. He received therapy with hydroxyurea (20 mg/kg/d) because of the presence of extramedullary masses causing paraparesis, neurogenic bladder and impotence. During therapy, the patient showed an improved clinical picture and a significant increase in total Hb (from 71.8 to 103.2 g/L) and a gamma/alpha globin synthetic ratio (from 0.39 to 0.68). The myelosuppressive effect of hydroxyurea was revealed by a decrease in CFU-GEMM, BFU-E, and CFU-GM. Therefore hydroxyurea can be effective in the treatment of patients with extramedullary haematopoiesis (EMH) who are not transfusion-dependent and cannot be treated with radiotherapy.

Thalassemic syndromes in Latium: epidemiological evaluation.

BACKGROUND AND OBJECTIVE: After the first National Census of transfusion-dependent thalassemics (1984), in 1992 the Italian Association of Pediatric Hematology and Oncology and the National Health Institute organized its 3rd edition. Here, results concerning Latium are presented and discussed. DESIGN AND METHODS: Data for Latium, as in the rest of Italy, were collected by a single reference center; among all eventual care centers for thalassemia initially contacted, only those with patients were sent data forms. For new cases, a questionnaire was submitted to parents to obtaining social data, and information on their knowledge of thalassemia. RESULTS: Collected data were divided into 2 groups: old cases, before June 30, 1988, and new cases, between July 1, 1988 and December 31, 1992. On the whole, 262 transfusion-dependent thalassemics (127 m., 135 f.) could be counted. Sixteen percent were affected with thalassemia intermedia, severe enough as to need regular transfusions. New patients (last 5 years): the birth of almost 80% of them was due to combined mistakes of parents and doctors. Disease evolution: 19/262 patients had been submitted to BMT (presently transfusion-free). Causes of death: 22 patients died in the considered period, mostly for cardiologic complications. INTERPRETATION AND CONCLUSIONS: Data emerging from censuses on specific pathologies of high social impact (such as thalassemia) may help health plans to rationalize public expenditure, especially by improving working conditions of care centers.

Continuous low-dose subcutaneous desferrioxamine (DFO) to prevent allergic manifestations in patients with iron overload.

In some patients compliance to subcutaneous desferrioxamine therapy is reduced because of allergic symptoms. Effective drug desensitization consists of bringing patients to tolerate the same mode of administration. We evaluated three thalassemic patients with severe allergies to desferrioxamine. Each patient received weekly three prefilled infusors with desferrioxamine 4 g/48 m1/48 h for s.c. therapy. Follow-up was performed for 12 consecutive weeks. During follow-up no allergic events were noted. The s-ferritin levels decreased from 2583 micrograms/l +/- 485 to 1916 micrograms/l +/- 275 (mean decrease 25.8%, p = 0.038). Compliance to the infusional system was excellent. Our results show that continuous infusion of desferrioxamine using a new infusional delivery system is effective in preventing allergic reactions and in reducing iron overload.

[Iron accumulation in the liver of patients with thalassemia major assessed with low field strength magnetic resonance: correlation with clinico-instrumental parameters]. / Accumulo di ferro nel fegato di pazienti con talassemia major valutato mediante risonanza magnetica con bassa intensità di campo: correlazione con i parametri clinico-strumentali.

Eight transfusion dependent patients (3 women and 5 men) with thalassemia major undergoing long-term treatment with Desferoxamine were submitted to MRI, with T2* GE sequences and low field strength. The ratio between liver mean signal intensity and skeletal muscle (L/M) and the ratio between the former and subcutaneous fat (L/F) were calculated in all patients. The results were compared with those of a control group of 7 healthy volunteers (7 men). L/M and L/F ratios were separately correlated with the following parameters: patient's age, transfusion history, serum ferritin, ferritin peak and its onset, transaminases (AST and ALT) and chelation index. The latter is a complex parameter allowing the actual assessment of iron content and of the real efficacy of chelation therapy. In all patients, both the L/M and the L/F ratios decreased significantly (L/M ratio: 0.67 +/- 0.45 vs. 1.2 +/- 0.21, p < 0.02; L/F ratio: 0.39 +/- 0.15 vs. 0.84 +/- 0.11, p < 0.001) relative to the control group. No significant correlation was found between the ratios and any hematochemical parameter, except for r = 0.77 (p < 0.04) between L/F ratio and the chelation index. Our study demonstrates that MRI may play a major role in the examination of thalassemic patients even at low field strength and with GE sequences, which yield good quality images with a relatively short acquisition time. Thus, MRI can be suggested for routine liver studies thanks to its high quality depiction of the liver and to its qualitative and semiquantitative yield. The good correlation between L/F ratio and the chelation index permits MR evaluation of the efficacy of different chelation treatments.

Radiotherapy combined with erythropoietin for the treatment of extramedullary hematopoiesis in an alloimmunized patient with thalassemia intermedia.

We report a patient with thalassemia intermedia who developed a mediastinal syndrome due to the growth of paravertebral hematopoietic masses in the posterior mediastinum. Because the patient did not receive blood transfusions due to alloimmunization, she was first treated with human recombinant erythropoietin (escalating low-moderate doses) to recover hemoglobin levels, then in association with radiotherapy to prevent a worsening of her anemia. The mean Hb level dramatically increased and peaked at week 11, to 83 g/l, and remained unchanged before and after radiotherapy (81 versus 78 g/l). Immediately after radiotherapy extramedullary hematopoiesis volume decreased by 16.4%.

Early detection of nephrotoxic effects in thalassemic patients receiving desferrioxamine therapy.

Nineteen transfusion-dependent beta-thalassemia major patients were included in the study. Six of these patients underwent chelation therapy with desferrioxamine by subcutaneous infusion (50 mg/kg/12 hr) and 13 received intravenous infusion (50 mg/kg/6 hr or 100 mg/kg/24 hr). BUN, creatinine, creatinine clearance, beta 2-microglobulin, urinary beta 2-microglobulin and urinary growth hormone excretion were evaluated during desferrioxamine treatment. Thirteen out of nineteen patients presented tubular damage indicated by increased excretion of urinary beta 2-microglobulin. 85% (11 of 13) of these patients showed more serious tubular damage, as demonstrated by concurrent increased urinary growth hormone excretion. Moreover, a positive correlation between urinary growth hormone excretion and urinary beta 2-microglobulin was observed (P < 0.05).

Beta-thalassemia mutations in Rome. A high frequency of the IVSII-745 allele in subjects of latium origin.

We studied the molecular bases of beta-thalassemia in Rome, a city centrally located in Latium, which is a region with a low incidence of beta-carriers. People also come to Rome from other regions for specific or prenatal diagnostic assessment. Only 11 patients (20%) out of 62 characterized beta-thalassemia subjects were of Latium family origin. They presented five mutations with an uncommonly high frequency of the IVSII-745 allele, that was found in homozygosis in 4 unrelated patients from a southeastern area in the province of Frosinone. These data may indicate a founder effect.

Isolated ultrafiltration in refractory heart failure on patients with Cooley's anemia.

Dilatative cardiomyopathy is a late complication of Cooley's anemia resulting in severe heart failure resistant to conventional medical treatment. Anemia, iron and fluid overload are the main causes of this disease entity. Four male patients (mean age 22.3 +/- 5.4 years) with Cooley's anemia associated heart failure--4th NYHA and fluid overload > 20% body weight--resistant to medical treatment, underwent isolated ultrafiltration (IU). During 90 minutes of treatment an average of 1750 +/- 850 ml of fluid were removed using AN69S plate membrane. Each patient received an average of 7 IU sessions (range 4-13). Cardiac function was assessed before and after each session with echocardiography, venous cardiac catheterization and impedence cardiography. Transient cardiac improvement was observed after each IU session: left ventricular systolic diameter decreased, as did central venous pressure and pulmonary wedge pressure, whereas cardiac index increased. All patients died of unrelated causes. In conclusion IU treatment in dilatative cardiomyopathy resistant to conventional medical treatment in Cooley's anemia patients produces only transient cardiac improvement, but no improvement in overall survival.

Serum erythropoietin levels in thalassemia intermedia.

Serum concentrations of erythropoietin (EPO) were determined by immunoassay in 45 patients with thalassemia intermedia (TI). The mean serum level of EPO was significantly higher in the thalassemic patients than in the controls, but transfused subjects had lower pretransfusional serum concentrations of EPO than untransfused ones. An inverse relationship between the serum values of EPO and total hemoglobin was observed only in the untransfused thalassemic patients. These data suggest that in TI, even a low transfusional regimen may cause a decrease in serum concentration of EPO, independent of the level of total Hb.

PADGEM/GMP-140 expression on platelet membranes from homozygous beta thalassaemic patients.

Thromboembolic events, which are associated with significant morbidity and mortality, occur in beta-thalassaemia. We studied the expression of the platelet selectin PADGEM/GMP-140 on intact cells from thalassaemic patients, as a marker of in vivo platelet activation. The mean of positive cells (%) was 38.143 +/- 20.65 in the patients versus 5.048 +/- 1.8 in the controls, n = 21, P < 0.001. No correlation was found between GMP-140 expression and splenectomy, platelet counts, plasma ferritin and natural coagulation inhibitors. Instead an indirect correlation was found between GMP-140 expression and HDL-cholesterol. Moreover platelet activation was directly correlated with pre-beta lipoproteins. Our data indicate that thalassaemic patients present an in vivo platelet activation, which possibly depends on the dyslipidaemia, which is now regarded as a frequent feature of this disease.

[Clinico-radiological correlation in thalassemia intermedia]. / Correlazioni clinico-radiologiche nella talassemia intermedia.

Fifteen thalassemia intermedia patients were considered, whose clinical and radiological findings were examined and compared. Eight patients underwent regular transfusion therapy. All patients underwent total body CT: the volume of ectopic erythropoiesis foci was calculated by a digital calculation algorithm (ROI volume). This work was aimed at correlating the quantitative measures of ectopic erythropoiesis assessed by CT with serum level of erythropoietin (EPO) and of trasferrin-free receptors (TfR) in both transfused and non-transfused patients, also considering the volume changes of ectopic erythropoiesis and bone changes over 36 months' follow-up. A direct correlation was demonstrated between serum transferrin and ectopic erythropoietic masses in transfusion-dependent patients: in fact, increased values of serum transferrin correspond to the enlargement of these masses and to bone lesion worsening.