The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil.

High levels of fetal hemoglobin (HbF) reduce sickle cell anemia (SCA) morbidity and mortality. HbF levels vary considerably and there is a strong genetic component that influences HbF production. Genetic polymorphisms at three quantitative trait loci (QTL): Xmn1-HBG2, HMIP-2 and BCL11A, have been shown to influence HbF levels and disease severity in SCA. Hydroxyurea (HU) is a drug that increases HbF. We investigated the influence of single nucleotide polymorphisms (SNPs) at the Xmn1-HBG2 (rs7482144); BCL11A (rs1427407, rs4671393 and rs11886868); and HMIP-2 (rs9399137 and rs9402686) loci on baseline and HU-induced HbF levels in 111 HbSS patients. We found that both BCL11A and HMIP-2 were associated with increased endogenous levels of HbF. Interestingly, we also found that BCL11A was associated with higher induction of HbF with HU. This effect was independent of the effect of BCL11A on baseline HbF levels. Additional studies will be needed to validate these findings and explain the ample inter-individual variations in HbF levels at baseline and HU-induced in patients with SCA.

Enzyme Replacement Therapy in a Patient with Gaucher Disease Type III: A Paradigmatic Case Showing Severe Adverse Reactions Started a Long Time After the Beginning of Treatment.

INTRODUCTION: There are three recombinant enzymes available for the treatment of Gaucher disease (GD): imiglucerase, velaglucerase alfa, and taliglucerase alfa. CASE REPORT: A male GD type III patient, 14 years old, genotype p.L444P/L444, diagnosed at 2 years old. He had been treated with imiglucerase for 9 years since the diagnosis. In 2008, however, he presented a severe adverse reaction to imiglucerase, characterized by cough, laryngeal stridor, and periorbital edema. The infusions were suspended for 3 months when imiglucerase was restarted with premedication and a slower infusion rate. After 5 months, he presented a new adverse reaction with vomiting, tachypnea, cough, and periorbital edema. Intradermal testing confirmed IgE-mediated reaction but serological tests were negative. After 2 years and 10 months with no specific treatment and a significant worsening of the clinical picture, taliglucerase alfa was prescribed, with premedication and a slower infusion rate. At the first infusion, he presented moderate adverse reaction and the infusions were suspended. After 2 months, velaglucerase alfa was initiated uneventfully. He maintains day-hospital infusions without premedication and shows improvement of clinical and laboratory parameters. CONCLUSION: This is the first report of the use of velaglucerase alfa in patients with GD type III. The use of recombinant enzymes is safe for the majority of GD patients, but severe reactions may occur even many years after the beginning of the treatment. Premedication and slower infusion rate reduce the incidence of adverse reactions but may not solve the problem. This case report further demonstrates the different safety profile among all the recombinant enzymes available for the treatment of GD.