Beta-thalassemia

The genetic defects known as thalassemias result from the partial or total absence of one or more a or P chains of hemoglobin. Over 750 different mutations have been identified, but only three are common. Either the a chain (alpha thalassemias) or P chain (beta thalassemias) can be affected. A superscript indicates whether a subunit is completely absent (a or p ) or whether its synthesis is reduced (a or P ). Apart from marrow transplantation, treatment is symptomatic. 

Alpha and beta thalassemias are anemias that result from reduced production of a and P subunits of HbA, respectively. 

Faustino P et al Dominantly transmitted beta-thalassemia arising from the production of several aberrant mRNA species and one abnormal peptide. Blood 1998 91 685. 

The detection of restriction fi agment length polymorphisms (RFLPs) facilitates prenatal detection of hereditary disorders such as sickle cell trait, beta-thalassemia, infant phenylketonuria, and Huntington s disease. Detection of RFLPs involves cleavage of double-stranded DNA by restriction endonucleases, which can detect subtle alterations in DNA that affect their recognized sites. Chapter 40 provides further details concerning the use of PCR and restriction enzymes for diagnosis. 

Zeimer, R, Belkin, M., Leitersdorff, E. and Rachmilewitz, E.A. (1978). A non-invasive method for the evaluation of tissue iron deposition in beta-thalassemia major. J. Lab. Clin. Med. 91, 24-31. 

Case Study 1 Safety Pharmacology Studies for an IND for Beta Thalassemia Susan Perrine, M.D., Professor of Pediatrics, Medicine, Pharmacology, and Experimental Therapeutics, Boston University School of Medicine... 

Summary Thalassemias as a group are the most common genetic diseases in the world. Beta thalassemia is an inherited blood disorder in which the body produces an abnormal form of hemoglobin. The disorder results in excessive destruction of red blood cells, which in a severe form manifests as life-shortening anemia shortly after birth. Short-chain fatty acids had previously been shown to be useful in the... 

Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ (1995) Oral sodium phenylbutyrate therapy in homozygous beta thalassemia a chnical trial. Blood 85 43 9 Collman RG, Perno CF, Crowe SM, Stevenson M, Montaner LJ (2003) HIV and cells of macrophage/dendritic hneage and other non-T cell reservoirs new answers yield new questions. J Leukoc Biol 74 631-634... 

Lu Y, Kham SK, Tan PL et al. Arrayed primer extension a robust and reliable genotyping platform for the diagnosis of single gene disorders beta-thalassemia and thiopurine methyltransferase deficiency. Genet Test 2005 9 212-219. 

Susceptibility factors genetic (unoperated or palliated cyanotic congenital heart disease beta-thalassemia major) sex (conflicting results) altered physiology (iodine intake, conflicting results)... 

Patients with beta-thalassemia major have an increased risk of primary hypothyroidism. In 23 patients with beta-thalassemia amiodarone was associated with a high risk of overt hypothyroidism (33 versus 3% in controls) (43). This occurred at up to 3 months after starting amiodarone. The risk of subclinical hypothyroidism was similar in the two groups. In one case overt hypothyroidism resolved spontaneously after withdrawal, but the other patients were given thyroxine. After 21-47 months of treatment three patients developed thyrotoxicosis, with remission after withdrawal. There were no cases of hyperthyroidism in the controls. The authors proposed that patients with beta-thalassemia may be more susceptible to iodine-induced hypothyroidism, related to an underlying defect in iodine in the thyroid, perhaps associated with an effect of iron overload. 

P. Sutcharitchan, R. Saiki, T.H. Huisman, A. Kutlar, V. McKie, H. Erlich, S.H. Embury, Reverse Dot-Blot Detection of the African-American Beta-thalassemia Mutations , Blood, 86(4), 1580-1585 (1995). 

Lebensburger, J. and Persons, D. A. (2008). Progress toward safe and effective gene therapy for beta-thalassemia and sickle cell disease. Curr. Opin. Drug Discov. Devel. 11 225-232. 

Johnston J, Tazelaar J, Rivera VM, Clackson T, Gao GP, Wilson JM. Regulated expression of erythropoietin from an AAV vector safely improves the anemia of beta-thalassemia in a mouse model. Mol Ther 2003 7 493-497. 

A4. Aksoy, M., The first observation of homozygous hemoglobin S-alpha thalassemia and two types of sickle cell thalassemia disease (a) Sickle cell-alpha thalassemia disease, (b) sickle cell-beta thalassemia disease. Blood 22, 757-769 (1963). 

H9. Heller, P., Yakulis, V. J., Rosenzweig, A. I., Abildgaard, C. F., and Rucknagel, D. L., Mild homozygous beta-thalassemia genes. Further evidence for the heterogeneity of beta-thalassemia genes. Ann. Intern. Med. 64, 52-61 (1966). 

Schwartz, E., Heterozygous beta thalassemia balanced globin synthesis in bone marrow cells. Science 167, 1512-1514 (1970). 

Mariotti S, Loviselli A, Murenu S, Sau F, Valentino L, Mandas A, Vacquer S, Martino E, Balestrieri A, Lai ME. High prevalence of thyroid dysfunction in adult patients with beta-thalassemia major submitted to amiodarone treatment. J Endocrinol Invest 1999 22(l) 55-63. 

Ascorbic acid promotes the absorption of iron, a reason for caution in giving high doses to patients with iron overload (SEDA-9, 324). In particular, patients with hemochromatosis, polycythemia, and leukemia who present with marked iron overload should keep their intake of ascorbic acid to a minimum (42). However, ascorbic acid can also interfere with the distribution of iron in the body in these patients. One consequence is that in patients with iron overload who also have scurvy, iron tends to be deposited in the reticuloendothelial system rather than the parenchymal cells, which may reduce the risks of damage to the liver, heart, or endocrine glands. It has conversely been noted that in beta-thalassemia major... 

Poonkuzhali B, Chandy M, Srivastava A, Dennison D, Krishnamoorthy R. Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation. Drug Metab Dispos 2001 29(3) 264-7. 

Adhikari D, Roy TB, Biswas A, Chakraborty ML, Bhattacharya B, Maitra TK, Basu AK, Chandra S. Efficacy and safety of oral iron chelating agent deferiprone in beta-thalassemia and hemoglobin E-beta thalassemia. Indian Pediatr 1995 32(8) 855-61. 

Pati HP, Choudhry VP. Deferiprone (LI) associated neutropenia in beta thalassemia major an Indian experience. Eur J Haematol 1999 63(4) 267-8. 

Deferoxamine is used in the treatment of acnte iron poisoning and in iron storage diseases, notably beta-thalassemia (1). The usual regimen is 40mg/kg/day as a snbcntaneous infusion over 10-12 honrs, starting at an early age (3 years). During erythrocyte transfusion. 

Neurophysiological evaluation of 40 patients with beta-thalassemia major showed abnormal findings in brain-stem-evoked potentials auditory (25%), visual (15%), and somatosensory (7.5%) some had abnormal nerve conduction velocity (25%) and 15% had involvement of multiple neural pathways (39). Subclinical involvement of the auditory pathway was statistically associated with a higher mean daily dose of deferoxamine and a longer duration of treatment. Abnormalities of the somatosensory pathways were related to old age, a long duration of deferoxamine use, and low serum copper concentrations. Multiple neural pathway involvement was related to the duration of treatment. However, deferoxamine is only partly responsible for the subclinical abnormalities of neural pathways often found in patients with beta-thalassemia major. 

Zafeiriou DI, Kousi AA, Tsantah CT, Kontopoulos EE, Augoustidou-Sawopoulou PA, Tsoubaris PD, Athanasiou MA. Neurophysiologic evaluation of longterm desferrioxamine therapy in beta-thalassemia patients. Pediatr Neurol 1998 18(5) 420-4. 

Gelmi C, Borgna-Pignatti C, Franchin S, Tacchini M, Trimarchi F. Electroretinographic and visual-evoked potential abnormalities in patients with beta-thalassemia major. Ophthalmologica 1988 196(l) 29-34. 

Rinaldi M, Della Corte M, Ruocco V, D Onofrio C, Zanotta G, Romano A. Ocular involvement correlated with age in patients affected by major and intermedia beta-thalassemia treated or not with desferrioxamine. Metab Pediatr Syst Ophthalmol 1993 16(l-2) 23-5. 

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