Phenotypic and Genetic Discordance in Monozygotic Twins with Sickle Anemia and ð-Thalassemia.

Abstract

Abstract 5084 IntroductionDiscordant monozygotic twins with sickle cell anemia (SCA) are rare. In the present study we describe current clinical and laboratory data in a set of 49 year old discordant monozygotic twins with coexistent SCA and α-/αα thalassemia. We compare the current findings to their previously described data (Hemoglobin 1991;15:247-56). MethodsEvaluations of painful episode frequency, episode severity, frequency of the acute chest syndrome, standard blood counts and chemistries, hemolysis, pulmonary hypertension, irreversibly sickled cells (ISC) and RBC rheology were obtained. DNA from peripheral blood was genotyped using Illumina 610K SNP (single nucleotide polymorphism) beadchip allowing analysis of SNP genotypes and DNA copy number variations (CNVs). ResultsTwin I is right handed and Twin II is left handed. Frequency of hospitalized painful episodes examined over 34 years were similar (approximately 1 episode per year) and were asynchronous. Prior to approximately 25-27 years of age, the painful episodes in Twin I were moderately severe with decreasing severity as ageing occurred. In contrast, Twin II, who also had moderately severe painful episodes during early years, showed marked worsening of severity as ageing occurred. Episodes of acute chest syndrome were asynchronous with similar frequency (Twin I had 2 episodes in 18 years; Twin II had 2 episodes in 21 years). Systemic blood pressures were similar. Osteonecrosis, leg ulcers, priapism, stroke were absent.Laboratory results (Current)*Twin ITwin IIHb(gm/dl)9.238.76Reticulocytes (%)9.111.4Fetal Hb (%)5.04.5Plasma Hb(uM) (Normal <2uM)3.727.79Total GPA(+)CD71, RBC-derived vesicles x 105/l blood2.986.32Total Bilirubin(mg/dl)5.356.83- Indirect Bilirubin (mg/dl)4.635.7RBC survival(51Cr T1/2 days)(Hemoglobin1991;15:247-56)1312.3Irreversibly sickled cells(%)24.417.5Plasma nitrite (nM)(Normal 114 ± 11)84.52100.04Tricuspid regurgitant velocity(m/sec)2.512.51Rheology- Extent of RBC aggregation (Normal 16.3 ± 0.34)9.8811.58- Strength of RBC aggregation (Normal 78 ± 3.6)49134- T1/2 time for RBC aggregation (Normal 2.8 ± 0.09)4.755.33- RBC deformabilityIdentical maximum deformation indexCT scanGallstones, Aortic aneurysmGallstonesLDH-T1(u/l)254248LDH-1(%)3435Blood group phenotype, Chance of monozygosity(%)99.4005399.005*Levels of Hb, Reticulocytes, Hb F, Total and Indirect bilirubin are the Means of 3 samplesConcordance of SNP genotypes confirmed that the twins are monozygotic. Analysis of the entire genome for CNVs revealed a number of candidate loci that differ. Most differences in CNVs occurred in Twin II. ConclusionsClinical and laboratory findings in these twins include differences and similarities. Clinical differences have been observed in handedness, asynchronism of painful episodes and differences in episode severity with ageing. Similarity was observed in the frequency of the painful episodes. Laboratory differences indicate that the degree of intravascular hemolysis is greater in Twin II than in Twin I, as shown by the differences in plasma Hb and RBC-derived vesicle levels (Brit J Haematol 2008;142:126-35). In contrast, the current pulmonary pressures and the current and previous rheologic studies are similar. Ageing contributes to the extent of intravascular hemolysis, as noted when the current findings are compared to those observed in the earlier study. Levels of ISC,which are related to the life span of sickle RBC (Am J Med 1978;64:253-7, Brit J Haemat 1969;17:527-533), appear to be inversely associated with indicators of intravascular hemolysis, such as plasma Hb and RBC-derived vesicles (Twin I, ISC 24.4%, Pl Hb 3.72, RBC-vesicles 2.98; Twin II, ISC 17.5%, Pl Hb 7.79, RBC-vesicles 6.32). The difference in CNVs between the twins, which is greater in Twin II, may explain the phenotypic discordance (Amer J Human Genetics 2008;82:763-71). The loci showing the differences will require further study. To what extent genetic differences in handedness in the twins are associated with the phenotypic differences have not been examined (Mol Psychiatry 2007;12:1129-39). DisclosuresNo relevant conflicts of interest to declare.