Prevalence of the NPHS2 variants p.R229Q, p.A242V, and p.R138Q in patients with focal segmental glomerulosclerosis.

BACKGROUND: NPHS2 gene variants are associated with focal segmental glomerulosclerosis (FSGS) and steroid-resistant nephrotic syndrome (SRNS). In this study, the prevalence of NPHS2 variants p.R229Q, p.A242V, and p.R138Q was investigated in patients with familial or sporadic FSGS. MATERIALS AND METHODS: The sample consisted of 40 children and 70 adults diagnosed with FSGS confirmed by renal biopsy. Clinical and laboratory parameters were evaluated. Genotyping for the three single nucleotide polymorphisms (SNPs) was performed by real-time polymerase chain reaction: two variants in exon 5 (p.R229Q and p.A242V) and one in exon 3 (p.R138Q). Variants were correlated with ethnicity, clinical presentation, treatment response, and renal outcomes. RESULTS: Among the 40 children analyzed, 20% had familial and 80% sporadic FSGS and among adults, 4.3% had familial and 95.7% sporadic FSGS, respectively. Overall, SRNS was found in 70% of adults and 90% in children. Among children, variants were detected in 2 (5%) with sporadic FSGS, p.R229Q and p.A242V in 1 each. Among adults, variants were present in 9 (12.9%) patients, all with sporadic FSGS, p.R229Q in 4 and p.A242V in 5. No patient had the p.R138Q variant. Among adults, a trend of higher proteinuria at the end of follow-up (p = 0.06) was found in patients carrying a variant. There was no significant association between NPHS2 variants with the clinical presentation, dependence on immunosuppressive treatment, or renal outcomes. Regarding ethnicity, all patients carrying the p.R229Q variant were White, while 67% of carriers of the p.A242V variant were Black. CONCLUSION: In these patients with familial or sporadic FSGS, the prevalence of p.R229Q and p.A242V variants in children was 5% and in adults 12.9%. More studies of patients with FSGS could better define a strategy for genetic analysis and therapeutic management.

NR3C1, ABCB1, TNF and CYP2C19 polymorphisms association with the response to the treatment of erythema nodosum leprosum.

Aim: To evaluate the effects of gene polymorphisms in the treatment of erythema nodosum leprosum with prednisone/thalidomide. Patients & methods: A total of 152 patients from different regions of Brazil were included. Generalized estimating equation was used to evaluate the influence of polymorphisms and haplotypes on the drug dose variation throughout the treatment. Results: An association between the genotype tuberculoid of polymorphism ABCB1 3435C>T (rs1045642; p = 0.02) and prednisone dose was found in the recessive model. An association between the haplotypes 1031T/-863C/-857C/-308A/-238G (p = 0.006) and 1031T/-863C/-857T/-308A/-238G (p = 0.040) of the TNF gene and the CYP2C19*2 polymorphism were also identified, in relation to thalidomide dosage variation over the course of treatment. Conclusion: This work presents the first pharmacogenetic report of association between gene polymorphisms and erythema nodosum leprosum treatment with prednisone/thalidomide.

The impact of thalidomide use in birth defects in Brazil.

Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed.

Pharmacoepidemiology and thalidomide embryopathy surveillance in Brazil.

INTRODUCTION: Thalidomide causes congenital defects in children, such as limb reduction defects. Currently, it is used for a few indications; in Brazil, where leprosy is endemic, thalidomide is used for the treatment of erythema nodosum leprosum, and recent cases of thalidomide embryopathy have been reported. METHODS: We analyzed the frequency of births with phenotypes consistent with thalidomide embryopathy (TEP) and correlated this with the distribution of thalidomide and the prevalence of leprosy between 2005 and 2010 in Brazil. RESULTS: A total of 5,889,210 thalidomide tablets were distributed; the prevalence of limb reduction defects was 1.60 (CI95%: 1.54-1.66) and TEP was 0.11 (CI95%: 0.10-0.13) per 10,000 births. Poisson regression showed an increase in cases of TEP and limb reduction defects per 100,000 tablets dispensed. Clusters and geographical isolates were identified in several regions. CONCLUSIONS: There is a correlation between thalidomide and TEP showing that thalidomide embryopathy should be monitored in countries where this medication is available.