The 5, 10 methylenetetrahydrofolate reductase C677T mutation and risk of fetal loss: a case series and review of the literature

<p>Abstract</p> <p>Background</p> <p>The true relationship between methylenetetrahydrofolate reductase C677T homozygosity and risk of recurrent spontaneous abortion is unknown, and it is unclear if women with these mutations should be anticoagulated during pregnancy.</p> <p>Objectives</p> <p>We report a series of 8 patients with this issue and review the current literature.</p> <p>Methods</p> <p>8 patients (3 of whom were actively pregnant) were referred with histories of spontaneous fetal loss; hypercoaguability work-ups revealed each were homozygous for the MTHFR C677T mutation without other thrombophilias.</p> <p>Results</p> <p>In the 3 women who have conceived, treatment with LMW heparin during pregnancy led to two full-term births and one additional pregnancy without complication. For the 5 who have not, we recommended treatment with LMW heparin upon conception.</p> <p>Conclusion</p> <p>We provide evidence to support the relationship between MTHFR C677T mutations and recurrent fetal loss, and to suggest that anticoagulation of these patients during pregnancy can lead to a successful pregnancy outcome.</p

Phenotypic Expressions of CCR5-Δ32/Δ32 Homozygosity

Objective: As blockade of CC-chemokine receptor 5 (CCR5) has been proposed as therapy for HIV-1, we examined whether the CCR5-Δ32/Δ32 homozygous genotype has phenotypic expressions other than those related to HIV-1. Design: Study subjects were white homosexual men or men with hemophilia who were not infected with HIV-1. In this study, 15 CCR5-Δ32/Δ32 homozygotes were compared with 201 CCR5 wild-type (+/+) subjects for a wide range of clinical conditions and laboratory assay results ascertained during prospective cohort studies and routine clinical care. CCR5-Δ32 genotype was determined by polymerase chain reaction, followed by single-stranded conformational polymorphism analysis. Results: Hypertension and conditions attributable to hemophilia were the only diagnoses frequently found in clinical records of CCR5-Δ32/Δ32 study subjects. Based on blood pressure measurement and treatment history, CCR5-Δ32/Δ32 homozygotes had a 2.8-fold higher prevalence of hypertension than age-matched CCR5-+/+ study subjects (95% confidence interval [CI], 1.2-6.4; p = .01); none of the homozygotes had severe hypertension. Hematologic measures were generally similar across the genotypes, but total lymphocyte counts were ~20% higher in CCR5-Δ32/Δ32 study subjects than in CCR5-+/+ study subjects (p \u3c .05). Among patients with hemophilia who were infected with hepatitis C virus (HCV), mean alanine aminotransferase levels were 117% higher among CCR5-Δ32/Δ32 homozygotes (p \u3c .05), but serum HCV levels did not differ by CCR5-Δ32 genotype. CCR5-Δ32/Δ32 homozygous study subjects had a lower prevalence of antibodies to measles virus than those with other genotypes, but this association was not confirmed in a group of blood donors. The prevalence of antibodies to nine other common viruses, HBV, and HCV was not related to CCR5 genotype. Conclusions: CCR5-Δ32/Δ32 homozygotes are generally similar to wild-type persons. Confirmatory investigations are required to determine whether hypertension, increased lymphocyte counts, and higher hepatic enzyme levels in the presence of HCV infection represent true phenotypic expressions of this genotype. CCR5-Δ32/Δ32 homozygosity does not provide broad protection against viral infections

Will gene therapy trump factor treatment in hemophilia?

Hemophilia treatment is entering a new phase, with the exciting possibility of gene therapy promising a cure. Novel gene transfer strategies are being considered for patients with inhibitors.Improvement of factor-replacement therapy is being aggressively pursued with long-acting factor concentrates, many of which are in clinical trials. Whether gene therapy will be safe and cost effective to eventually supersede factor-replacement therapy is yet to be determined. It is hoped that with the profusion of clinical trial programs in hemophilia care, it will eventually provide affordable treatment to many patients who currently cannot access adequate treatment in the developing countries.</p