Think About Hemoglobinopathies Orna Steinberg Shemer MD Msc and Hannah Tamary MD

Home , Hemoglobinopathy, Sulfhemoglobinemia

IMAJ • VOL 16 • December 2014 EDITORIALS

Think about Hemoglobinopathies Orna Steinberg Shemer MD MSc and Hannah Tamary MD

Department of Hematology-Oncology, Schneider Children’s Medical Center of Israel, Petah Tikva, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

senting with dyspnea, who was eventually arterial blood was later described [6]. Low Key words: Titusville hemoglobin, diagnosed with Titusville hemoglobin- oxygen affinity hemoglobinopathies can hemoglobinopathies, cyanosis, low opathy. Hb Titusville was first described also cause a mild anemia, as was shown oxygen affinity hemoglobin by Schneider et al. in 1975 [3]. An addi- in a murine model of Hb Titusville [7]. In IMAJ 2014; 16: 785–786 tional two families with Hb Titusville were the first case described by Schneider et al. described almost two decades later [4,5]. [3], no cyanosis was detected, and indeed The clinical presentation varied between most cases are asymptomatic. The patient low oxygen saturation that was clinically described here by Marcus and colleagues asymptomatic, dyspnea and peripheral [2] probably had contributing factors, such emoglobin (Hb) is one of the most cyanosis. A Scandinavian patient who pre- as heavy smoking, which exacerbated the H studied human structures, and nu- sented with shortness of breath, low oxy- clinical presentation. merous point mutations have been dis- gen saturation measured by pulse oxime- Hb Titusville results from a point muta- covered in the globin genes. Mutations try, low oxygen saturation in arterial blood, tion causing a G to A change at codon 94 in leading to a decrease in the alpha or beta but normal partial pressure of oxygen in the alpha globin gene, leading to a change globin protein levels will result in thalas- semia; however, many point mutations Figure 1. A induce clinical consequences due to al- [A] The hemoglobin tered hemoglobin function; the most well- molecule is a tetramer known example is sickle cell hemoglo- of two alpha globin and bin. Other hemoglobinopathies can be two beta globin chains. Normally, there is an divided into a few types: equilibrium between • High oxygen affinity hemoglobinopa- oxyhemoglobin and thies causing erythrocytosis deoxyhemoglobin. In Hb • Low oxygen affinity Hb mutants. These Titusville, as well as in hemoglobinopathies can cause dyspnea Hb Kansas and Hb Beth or cyanosis, especially when the oxygen Israel, the interaction between alpha1 and dissociation curve is shifted extremely beta2 is disrupted, to the right and when the variant hemo- and the equilibrium globin is abundant is shifted towards the • M hemoglobins causing pseudocya- deoxyhemoglobin state nosis. [B] Oxygen dissociation curves B 100 Physiologically, a steady state exists of normal and low oxygen affinity hemoglobin. “Normal” represents between the oxygenated hemoglobin, 80 also called the R (relaxed binding) state the oxygen dissociation curve for normal adult hemoglobin, and “Low and deoxyhemoglobin, called the T (tight Oxygen Affinity” represents the mildly 60 binding) state, as shown in Figure 1A. right shifted oxygen dissociation

This steady state is influenced by the levels curve found in disorders causing low Saturation 40 of 2,3-DPG and CO, pH, and the partial oxygen affinity, such as Hb Titusville pressure of oxygen. Some point mutations 20 in any of the globin genes can influence this steady state [1]. 0 0 10 20 30 40 50 60 70 80 90 100 In this issue of IMAJ, Marcus et al. [2] pO2 describe the case of a young patient pre-

785 EDITORIALS IMAJ • VOL 16 • December 2014

from aspartic acid to aspargine. This site is firmed by DNA sequencing. A bedside References involved in the contact area between alpha1 test that can rule out the presence of met- 1. Steinberg MH, Nagel RL. Unstable hemoglobin, hemoglobins with altered oxygen affinity, hemo- and beta2 globins. The effect manifests as hemoglobin, sulfhemoglobin and hemoglobin M, and other variants of clinical and a stabilization of the T state and lowering globin M can be performed by exposing biological interest. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, eds. Disorders of Hemo- the affinity of the hemoglobin to oxygen the blood of the patient to oxygen. In globin: Genetics, Pathophysiology and Clinical Man- [Figure 1A]. Interestingly, mutations in low oxygen affinity hemoglobinopathies, agement. Cambridge, UK: Cambridge University the beta globin, involving the same contact blood will turn from purple to bright red Press, 2009: 589-606. 2. Marcus R, Shiloh E, Mizrahi A, Gerah-Yehoshua O, area, have also been described, including upon exposure to oxygen, while the color Rapoport MJ. Titusville hemoglobinopathy pres- Hb Kansas [8] and Hb Beth Israel [9], both will not change in methemoglobinemia, enting as new-onset dyspnea in a young soldier. involving residue 102 of the beta globin. sulfhemoglobinemia and hemoglobin M IMAJ 2014; 16: 799-800. 3. Schneider RG, Atkins RJ, Hosty TS, et al. Asn102, in the beta globin, is connected disease. This test cannot, however, rule Haemoglobin Titusville: alpha94 Asp replaced by to asp94 in the alpha globin by a hydrogen out cardiopulmonary diseases that will Asn. A new haemoglobin with a lowered affinity bond. Thus, Hb Kansas, Hb Beth Israel and give the same effect. for oxygen. Biochim Biophys Acta 1975; 400: 365-73. 4. Luo HY, Irving I, Prior J, et al. Hemoglobin Hb Titusville all cause an interruption to In summary, low affinity hemoglo- Titusville, a low oxygen affinity variant hemoglobin, the alpha1-beta2 interface. Similarly, in Hb bin variants are usually benign, caus- in a family of Northern European background. F-Sarajevo, amino acid 102 of the gamma ing no or mild symptoms. However, Am J Hematol 2004; 77: 384-6. 5. Deyell R, Jackson S, Spier S, Le D, Poon MC. globin is involved [10], leading to cyanosis they should be considered in the dif- Low oxygen saturation by pulse oximetry may be appearing early in life and subsiding after ferential diagnosis of any patient with associated with a low oxygen affinity hemoglobin variant, hemoglobin Titusville. J Pediatr Hematol the neonatal period. All of the described unexplained low oxygen saturation, Oncol 2006; 28: 100-2. cases of Hb Titusville are heterozygous to dyspnea or cyanosis, especially when 6. Avellan-Hietanen H, Aittomaki J, Ekroos H, et al. the mutation, and no known homozygotes there is no evidence of cardiopulmonary Decreased oxygen saturation as a result of haemoglobin Titusville. Clin Respir J 2008; 2: 242-4. have been found as this is most likely a abnormalities. Correct diagnosis of low 7. Shirasawa T, Izumizaki M, Suzuki Y, et al. Oxygen lethal defect. oxygen affinity hemoglobinopathies is affinity of hemoglobin regulates O2 consumption, In Hb Titusville, as in other hemoglo- important, as it can eliminate the need metabolism, and physical activity. J Biol Chem 2003; 278: 5035-43. binopathies causing low oxygen affinity, for an expensive and invasive workup 8. Bonaventura J, Riggs A. Hemglobin Kansas, a the oxygen dissociation curve is shifted and is relatively simple, when these human hemoglobin with a neutral amino acid to the right [Figure 1B] and the oxygen abnormalities are properly considered substitution and an abnormal oxygen equilibrium. J Biol Chem 1968; 243: 980-91. extraction to the tissues is enhanced [7]. in the differential diagnosis. 9. Nagel RL, Lynfield J, Johnson J, Landau L, Bookchin The p50 of Hb Titusville is higher than RM, Harris MB. Hemoglobin Beth Israel. A mutant normal. Oxygen saturation measured by causing clinically apparent cyanosis. N Engl J Med Correspondence 1976; 295: 125-30. Dr. H. Tamary pulse oximetry is low; however, the partial 10. Zimmermann-Baer U, Capalo R, Dutly F, et al. pressure of oxygen in the arterial blood Head, Hematology Unit, Schneider Children’s Neonatal cyanosis due to a new (G)γ-globin variant Medical Center of Israel, Petah Tikva 49202, Israel causing low oxygen affinity: Hb F-Sarajevo [(G) is normal. The diagnosis can be made Phone: (972-3) 925-3669 γ102(G4)Asn→Thr, AAC>ACC]. Hemoglobin by hemoglobin electrophoresis and con- email: [email protected] 2012; 36: 109-13. Capsule

How the common cold can worsen asthma Rhinoviruses – the main cause of the common cold – can make tion triggered IL-25 production, and blocking the IL-25 receptor asthma attacks worse. Now Beale and co-workers report that eased the increased asthma symptoms. Thus, as the cold one reason may be because rhinoviruses cause lung epithelial season approaches, blocking IL-25 may be a promising thera- cells to make the cytokine interleukin-25 (IL-25). More peutic strategy in asthmatics. IL-25 is produced in people with asthma than in those who Sci Transl Med 2014; 6: 256ral134 are healthy. In mice with allergic “asthma,” rhinovirus infec- Eitan Israeli

“Patience is also a form of action” Auguste Rodin (1840-1917), French sculptor. Many of his most notable sculptures were criticized during his lifetime as they clashed with the predominant figure sculpture tradition that was decorative and formulaic. Rodin’s work departed from traditional themes of mythology and allegory, modeled the human body with realism, and celebrated individual character and physicality. He was sensitive to the controversy surrounding his work but refused to change his style. Successive works brought increasing favor from the government and the artistic community and his reputation grew. By 1900, he was a world-renowned artist. Among others, his most well-known works are The Thinker, The Kiss, and The Gates of Hell.

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