Marcial Francis Galera

Mutations, Clinical Findings and Survival Estimates in South American Patients with X-Linked Adrenoleukodystrophy

In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. Methods X- ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. Results We identified thirty-six different mutations (twelve novel). This population had an important allelic heterogeneity, as only p.Arg518Gln was repeatedly found (three families). Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD). The mean (95% CI) ages at onset and at death of the CALD were 10.9 (9.1–12.7) and 24.7 (19.8–29.6) years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. Conclusions This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.

Ethical issues related to the access to orphan drugs in Brazil: the case of mucopolysaccharidosis type I

Background/Aims Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disorder treated with bone marrow transplantation or enzyme replacement therapy with laronidase, a high-cost orphan drug. Laronidase was approved by the US Food and Drug Administration and the European Medicines Agency in 2003 and by the Brazilian National Health Surveillance Agency in 2005. Many Brazilian MPS I patients have been receiving laronidase despite the absence of a governmental policy regulating access to the drug. Epidemiological and treatment data concerning MPS I are scarce. This study aims to present a demographic profile of Brazilian patients with MPS I, describe the routes of access to laronidase in Brazil, and discuss associated ethical issues relating to public funding of orphan drugs. Methods In this cross-sectional observational study, data were collected nationwide between January and September 2008 from physicians, public institutions and non-governmental organisations involved with diagnosis and treatment of MPS I, using two data collection instruments specifically designed for this purpose. Results The minimum prevalence of MPS I in Brazil was estimated at 1/2u2008700u2008000. Most patients (69.8%) were younger than 15u2005years; 60 (88.2%) received laronidase. The most common route of access to the drug was through lawsuits (86.6%). Conclusions In Brazil, MPS I is predominantly a paediatric illness. Even though the cost of laronidase treatment is not officially covered by the Brazilian government, most MPS I patients receive the drug, usually through litigation. This gives rise to major ethical conflicts concerning drug access in a low-resource context. The Brazilian health policy framework lacks evidence-based clinical protocols for the distribution of orphan drugs.

Características clínicas e citogenéticas da síndrome de Turner na região Centro-Oeste do Brasil

PURPOSEnto examine the association between cytogenetic characteristics and clinical and epidemiological changes in patients with Turner syndrome (TS).nnnMETHODSnForty-two patients were included. Data were collected using a standardized questionnaire in interviews conducted with the responsible person and, when possible, with the patient. A detailed physical examination was performed. The association between karyotype, stigmata and clinical disorders were examined using the χ2 test.nnnRESULTSnSixty-four percent of TS patients were 45,X; 26,2% 45,X/46,X;7% 45,X/46Xi(Xq), and 2,3% 45,X/46,X,Del(Xq). Regardless of the karyotype, all patients had short stature. Low hair implantation was more frequent in patients with 45,X (p=0.03). Cardiovascular abnormalities (45%), otitis (43%), thyroid dysfunction (33%) and hypertension (26.6%) were the most frequent clinical disorders, but without correlation with the karyotype. Anthropometric measurements revealed a positive linear correlation of waist and hip circumference with age (r=0.9, p=0.01). Thirty-one patients (74%) were using or had previously used growth hormone (43%), sex steroids (30%), thyroxine (11.9%) or oxandrolone (9.5%). Comparison between gestational age at birth and learning difficulties showed a prevalence ratio of 1.71 (p>0.05).nnnCONCLUSIONnLow hair implantation is the most prevalent stigma in patients with a 45,X karyotype and the most common clinical changes were cardiovascular problems, otitis, thyroid dysfunction and hypertension; however, they did not show any correlation with the karyotype.

Molecular identification of chromosome Y sequences in Brazilian patients with Turner syndrome

The investigation of Y-specific sequences in patients with Turner Syndrome (TS) with karyotype 45,X or mosaic, has a fundamental role in the clinical management of these patients. The relationship between the presence of Y chromosome fragments and a higher risk of gonadoblastoma in TS has already been established. The aim of the study was to investigate the presence of Y-chromosome fragments in a population of 42 female Brazilian patients with TS from Mato Grosso state. Cytogenetic analysis has shown the karyotypes 45,X in 27 of them (64.3%) and mosaic in 15 (35.7%). The presence of the Y-primers SRY, DYZ3, ZFY, DYZ1, DYS1 and PABY was investigated in all patients. These markers were amplified by polymerase chain reaction (PCR) technique, using DNA genomic from peripheral blood lymphocytes. None of these patients had shown any Y-chromosome fragments when they were analysed only by the classic cytogenetic technique. The PCR analysis with the Y-specific sequences ZFY and DYZ3 were identified in two different patients (4.8%), both with karyotype 45,X. It was concluded that PCR is efficient in the investigation of hidden Y-fragments in TS patients. Therefore, this method should be included in the routine assistance of these patients.

Prevalence of Hyposalivation in Patients with Systemic Lupus Erythematosus in a Brazilian Subpopulation

Background. Systemic lupus erythematosus (SLE) is a chronic inflammatory, multisystem, and autoimmune disease. Objective. The aim of this study was to describe the prevalence of hyposalivation in SLE patients and evaluate factors associated. Methods. This is a cross-sectional study developed at the Cuiaba University General Hospital (UNIC-HGU), Mato Grosso, Brazil. The study population consisted of female SLE patients treated at this hospital from 06/2010 to 12/2012. Unstimulated salivary flow rates (SFRs) were measured. Descriptive and inferential analyses were performed in all cases using a significance level P < 0.05. Results. The results showed that 79% of patients with systemic lupus erythematosus suffered from hyposalivation and that the disease activity and age in years were the factors that resulted in statistically significant differences. Conclusion. The activity of the disease, age >27 years, and the drugs used were factors associated with hyposalivation, resulting in a statistically significant decrease in saliva production.

Qualificação e provimento de médicos no contexto da Política Nacional de Atenção Integral às Pessoas com Doenças Raras no Sistema Único de Saúde (SUS)

Este ensaio teorico reflete sobre a qualificacao e o provimento de medicos no contexto da Politica Nacional de Atencao Integral as Pessoas com Doencas Raras no SUS. Para isso, apresentamos a Politica e suas diretrizes, e situamos a discussao em torno de duas estrategias integradas: o provimento e a fixacao de medicos geneticistas; e a capacitacao de profissionais da Atencao Primaria a Saude em relacao as doencas geneticas e aos defeitos congenitos. Finalmente, considerando as Diretrizes Curriculares Nacionais do Curso de Graduacao em Medicina, apresentamos uma proposta de perfil de competencia minimo em Genetica, elaborada para instrumentalizar os cursos de graduacao da area da Saude, em particular os cursos de Medicina. Assim, oferecemos um referencial teorico para apoiar o delineamento de programas de educacao e formacao em Saude, contribuindo para inclusao do cuidado em Genetica no SUS.Este ensaio teorico reflete sobre a qualificacao e o provimento de medicos no contexto da Politica Nacional de Atencao Integral as Pessoas com Doencas Raras no SUS. Para isso, apresentamos a Politica e suas diretrizes, e situamos a discussao em torno de duas estrategias integradas: o provimento e a fixacao de medicos geneticistas; e a capacitacao de profissionais da Atencao Primaria a Saude em relacao as doencas geneticas e aos defeitos congenitos. Finalmente, considerando as Diretrizes Curriculares Nacionais do Curso de Graduacao em Medicina, apresentamos uma proposta de perfil de competencia minimo em Genetica, elaborada para instrumentalizar os cursos de graduacao da area da Saude, em particular os cursos de Medicina. Assim, oferecemos um referencial teorico para apoiar o delineamento de programas de educacao e formacao em Saude, contribuindo para inclusao do cuidado em Genetica no SUS.

Glutathione S-transferase M1 and T1 gene polymorphisms in Brazilian women with endometriosis.

PurposeThe glutathione family (GST) genes appear to play a role in the genesis of endometriosis. This case–control study aimed to compare the frequencies of GSTM1 and GSTT1 polymorphisms in women with endometriosis and women without endometriosis.MethodsPolymerase chain reaction was performed to analyze the GSTM1 and GSTT1 genotypes among women with surgically and histologically confirmed endometriosis (case group nu2009=u2009121) and in women without evidence of endometriosis confirmed by laparoscopy for investigation the infertility or for laparoscopic tubal sterilization (control group nu2009=u200997).Result(s)No differences in the frequencies of GSTM1 polymorphism (null genotype) were observed between the cases and controls: odds ratio (OR)u2009=u20091.13; 95xa0% CI 0.656–1.93 (pu2009=u20090.659). The GSTT1 polymorphism (null genotype) was more prevalent in the endometriosis group than in the control group (ORu2009=u20090.53; 95xa0% CI 0.94–0.29 (pu2009=u20090.039). No relationship between menstrual cycle interval and GSTM1 null genotype frequency was observed in either cases or controls (pu2009=u20090.370 and pu2009=u20090.664, respectively). In addition, no relationship between menstrual cycle interval and GSTT1 null genotype was observed in cases (pu2009=u20090.797) or controls (pu2009=u20090.052).ConclusionsGSTM1 null genotype frequency was similar between cases and controls. The GSTT1 null genotype was more frequent in the control group.