VI-f.   Hb H Disease

The functional loss of three of the four normally occurring alpha-globin genes [alphaalpha/alphaalpha to - -/-alpha or - -/alpha(T)alpha or - -/alphaalpha(T)] leads to a condition known as Hb H disease in which excess beta chains combine to form the unstable Hb H or beta4. Its fetal counterpart is Hb Bart's or gamma4 which is seen mainly in newborn babies with this disease; Hb Bart's is considerably more stable than Hb H but both Hb types have an extremely high affinity for oxygen and no Bohr effect, and are, therefore, useless for the transport of oxygen.

Higgs in his recent review (1) reports on the occurrence of the disorder quoting data from WHO reports. It appears that the number of subjects with Hb H disease in Southeast Asia alone approaches 700,000, with some 15,000 newborns with this disorder added each year. Other areas with a relatively high frequency are the Mediterranean countries.

The clinical spectrum varies from a benign disorder to a severe anemia which can be blood transfusion dependent. This heterogeneity at the clinical level can be explained by differences in the molecular defects that have been observed. Four different subclasses can be recognized:

  1. Most common is the deletional type of Hb H disease (or - -/-alpha), a combination of an alpha-thal-1 and a deletional alpha-thal-2. Table XXII lists hematological data for 137 patients with different combinations. Those from Southeast Asia have mainly a combination of the - -(SEA) type of alpha-thal-1 with the -alpha(3.7 kb) or the -alpha(4.2 kb) deletion. Rarer is the occurrence of the larger Filipino and Thai alpha-thal-1 deletions, and the -alpha(2.7 kb) alpha-thal-2 deletion. Patients from the Mediterranean countries are more heterogeneous regarding their alpha-thal-1 type [mainly the 17.5 kb MED-I, the -(alpha)20.5 kb, and the 26.5 kb MED-II deletions]. The alpha-thal-2 deletion is primarily the -alpha(3.7 kb) deletion and only occasionally the -alpha(4.2 kb) allele is present. The table also lists information for patients with the rare South African [- -(SA] deletion together with the -alpha(3.7 kb) or the -alpha(4.2 kb) allele. In all instances a moderate hemolytic anemia is present with severe microcytosis and hypochromia, low levels of Hb A2 (in severe alpha chain deficiencies the formation of the alphabeta dimer is preferred over the alphadelta dimer), and Hb H levels which are usually below 10%. The in vitro alpha/beta chain synthesis ratio is greatly impaired with values as low as 0.2-0.4. Additional diagnostic complications are observed when beta chain (mainly Hb E) or alpha chain variants are present. Reviews by Wasi and Fucharoen (11,12) have detailed these many different conditions present in the Thai population. The combination of an alpha-thal-1 deletion [mainly - -(SEA)] with an -alpha(4.2 kb) determinant which also carries the mutation at codon 74 (GAC->CAC; Asp->His, known as Hb Q-Thailand)] results in the well-defined Hb Q-Thailand-Hb H disease. The only adult Hb in a patient with such a disorder is Hb Q-Thailand [alpha274(EF3)Asp->Hisbeta2] together with a small amount of Hb Q2-Thailand [alpha274(EF3)Asp->Hisdelta2]. Other alpha chain variants which result from mutations in the one remaining alpha-globin gene on a chromosome with the -alpha(3.7 kb) or -alpha(4.2 kb) deletion have been observed in a few patients with the - -/-alpha(X) compound heterozygosity (see also pages 271 and 272).

  2. The second group consists of patients with a deletional alpha-thal-1 and a nondeletional alpha-thal-2 [- -/alpha(T) or - -/alphaalpha(T)]. The alpha-thal-1 alleles are the same as found in the deletional Hb H disease (- -/-alpha). The terminating codon mutation alpha142 (TAA->CAA) leading to the formation of Hb Constant Spring is the most common nondeletional alpha-thal-2 for East Asia, while initiation codon mutations, poly A mutations, the 5 nts frameshift at the IVS-I donor site, are common nondeletional alpha-thal 2 in Mediterranean and Middle East Asian populations (most are mutations in the alpha2-globin gene). Table XXII lists hematological data for 64 patients. In general, these conditions are more severe than the deletional Hb H disease (- -/-alpha); their anemia is more striking, blood transfusion requirements are more frequent, and their Hb H level is usually 15% or higher.

  3. The third group are patients with deletional alpha-thal-1 and a mutation in either the alpha2- or alpha1-globin gene which leads to the formation of a severely unstable Hb. Examples of these rare disorders can be found on pages 240 through 263, where the descriptions of these anomalies are given. Table XXII lists the results for two of these conditions: Hb H disease due to the combination of an alpha-thal-1 allele and the alpha2 mutant Hb Quong Sze [alpha125(H8)Leu->Pro; CTG->CCG] and of an alpha-thal allele and the alpha1 mutant Hb Adana [alpha59(E8)Gly->Asp; GGC->GAC]. Both conditions cause a severe anemia with high levels of Hb H or Hb Bart's.

  4. The fourth group includes patients with a homozygosity for a nondeletional alpha-thal. Most commonly observed are homozygosities for Hb Constant Spring and for one of two poly A mutations. Patients with the alpha(CS)alpha/alpha(CS)alpha genotype have a clinical phenotype closer to the alpha-thal-2 homozygosity (-alpha/-alpha) than to Hb H disease (- -/-alpha). This is not the case however, for subjects with a homozygosity for one of the poly A mutations. Table XXII lists data for 25 such subjects, some with a severe anemia and high levels of Hb H (>15%). This rather surprising observation can be explained by assuming that the abnormal transcript, which is extended because of the mutation in the poly A site, also reduces the expression of the 3' alpha1-globin gene; thus, both alpha-globin genes are down regulated.

Differences between males and females at the pediatric ages are small (Table XXIII), but somewhat more severe anemia is present in the girls. Phenotypical differences between adults and pediatric patients are most marked for the patients with the alpha(PA-1), as can be seen from the data given in the pedigree of Fig. 26.

[Figure not yet available.]

FIG. 26. Pedigree of a family with several members with Hb H disease. The presence of Hb H was detected by electrophoresis and was confirmed by chromatography (from Ref. 8).

The clinical aspects of Hb H disease have been studied in great detail by Galanello et al (10) who compared data for 130 patients with Hb H of the deletional type [128 with - -/-alpha(3.7) and two with - -/-alpha(4.2)] with similar information for 22 Hb H patients with an alpha-thal-1 combined with nondeletional alpha-thal-2 [- -/alpha(T)alpha]. Of these, 66 were children and 86 adults. The clinical phenotypes were vastly different and are summarized in Fig. 27. Patients with the - -/alpha(T)alpha genotype have, more frequently, enlargements of the liver and spleen, jaundice, bone changes, hemolytic crises, and a greater transfusion requirement. The data show that children are often more severely affected than adult patients. Also interesting is the information that of the 58 pregnancies (in 24 women) seven ended in premature interruption, two in premature delivery, while often the anemia of the mother worsened considerably requiring blood transfusions.

[Figure not yet available.]

FIG. 27. Clinical findings in Hb H disease patients according to the genotypes (modified from Ref. 10). A) Children. B) Adults.

       
REFERENCES
1. Higgs, D.R.: in The Haemoglobinopathies, edited by D.R. Higgs and D.J. Weatherall, Bailliere's Clinical Haematology, Vol. 6, page 117, W.B. Saunders Company, London, 1993.
2. Fei, Y-J., Öner, R., Bozkurt, G., Gu, L-H., Altay, Ç., Gürgey, A., Fattoum, S., Baysal, E., and Huisman, T.H.J.: Acta Haematol., 88:82, 1992.
3. Liang, R., Liang, S., Jiang, N.H., Wen, X-J., Zhao, J-B., Nechtman, J.F., Stoming, T.A., and Huisman, T.H.J.: Br. J. Haematol., 86:351, 1994.
4. Öner, C., Gürgey, A., Öner, R., Balkan, H., Gümrük, F., Baysal, E., and Altay, Ç.: Hemoglobin, 21:41, 1997.
5. George, E., Li, H-J., Fei, Y-J., Reese, A.L., Baysal, E., Cepreganova, B., Wilson, J.B., Gu, L-H., Nechtman, J.F., Stoming, T.A., Liu, J-C., Codrington, J.F., and Huisman, T.H.J.: Hemoglobin, 16:51, 1992.
6. Fei, Y-J., Liu, J-C., Jogessar, V.B., Westermeyer, K.R., Bridgemohan, R., and Huisman, T.H.J.: Acta Haematol., 87:11, 1992.
7. Baysal, E., Kleanthous, M., Bozkurt, G., Kyrri, A., Kalogirou, E., Angastiniotis, M., Ioannou, P., and Huisman, T.H.J.: Br. J. Haematol., 89:496, 1995.
8. Adekile, A.D., Gu, L-H., Baysal, E., Haider, M.Z., Al-Fuzae, L., Aboobacker, K.C., Al-Rashied, A., and Huisman, T.H.J.: Acta Haematol., 92:176, 1994.
9. Çürük, M.A., Dimovski, A.J., Baysal, E., Gu, L-H., Kutlar, F., Molchanova, T.P., Webber, B.B., Altay, Ç., Gürgey, A., and Huisman, T.H.J.: Am. J. Hematol., 44:270, 1993.
10. Galanello, R., Aru, B., Dessì, C., Addis, M., Paglietti, E., Melis, M.A., Cocco, S., Massa, P., Giagu, N., Barella, S., Turco, M.P., Maccioni, L., and Cao, A.: Acta Haematol., 88:1, 1992.
11. Wasi, P.: Clin. Haematol., 10:707, 1981.
12. Fucharoen, S. and Winichagoon, P.: Hemoglobin, in press, 1997.

Hb H Disease and Mental Retardation

This new syndrome was first described some 15 years ago (1), while extensive clinical features and the first molecular analyses were detailed in 1990 (2,3). Presently, several families have been discovered where in members the hematological abnormality occurs together with severe mental handicap. Two specific conditions have been recognized:

  1. ATR-16 (ATR = alpha-thalassemia-mental retardation) is characterized by a loss of DNA from the tip of chromosome #16. Truncation, deletion, and translocation (with DNA from the tip of chromosome #1) have been discovered.

  2. ATR-X is characterized by mutations in a gene (XH2) producing a transacting factor regulating gene expression. This gene is located on the X chromosome. Mutations in this X-encoded factor will result in a down regulation in the expression of the alpha-globin gene(s) and of other as yet unidentified genes. The ATR-X syndrome only occurs in males; female heterozygotes do not have the symptoms characteristic for this complex disease except for an occasional Hb H inclusion body.

A detailed description of these disorders is beyond the scope of this syllabus. The interested reader is invited to consult the quoted references.

       
REFERENCES
1. Anneren, G. and Gustavson, K-H.: Acta Paediatr. Scand., 73:281, 1984.
2. Wilkie, A.O.M., Buckle, V.J., Harris, P.C., Lamb, J., Barton, N.J., Reeders, S.T., Lindenbaum, R.H., Nicholls, R.D., Barrow, M., Bethlenfalvay, N.C., Hutz, M.H., Tolmie, J.L., Weatherall, D.J., and Higgs, D.R.: Am. J. Hum. Genet., 46:1116, 1990.
3. Wilkie, A.O.M., Zeitlin, H.C., Lindenbaum, R.H., Buckle, V.J., Fischel-Ghodsian, N., Chui, D.H.K., Gardner-Medwin, D, MacGillivray, M.H., Weatherall, D.J., and Higgs, D.R.: Am. J. Hum. Genet., 46: 1127, 1990.
4. Gibbons, R.J., Picketts, D.J., and Higgs, D.R.: Hum. Mol. Genet., 4:1705, 1995.
5. Villard, L., Toutain, A., Lossi, A-M., Gecz, J., Houdayer, C., Moraine, C., and Fontès, M.: Am. J. Hum. Genet., 58:499, 1996.
6. Gibbons, R.J. and Higgs, D.R.: Medicine, 75:45, 1996.

This material is from the book A Syllabus of Thalassemia Mutations (1997) by Titus H.J. Huisman, Marianne F.H. Carver, and Erol Baysal, published by The Sickle Cell Anemia Foundation in Augusta, GA, USA. Copyright © 1997 by Titus H.J. Huisman. All rights reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, microfilming and recording, or by any information storage and retrieval systems, without permission in writing from the Author.