Biotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients

[EN] The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity. Methods All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed. Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.- 183G>A and c.-514C>T were also present in 10/37 concordant patients. The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.SIThis study received financial support from Fundo de Incentivo à Pesquisa e Eventos/Hospital de Clínicas de Porto Alegre (FIPE-HCPA) for research materials and publication fee. Post Graduate Program in Genetics and Molecular Biology (Universidade Federal do Rio Grande do Sul) funded the translation. ECN has a commercial affiliation (CTN Diagnósticos) which did not have any role or financial contribution to this research. TB have fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes). FS had fellowship from the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS). IVDS, MRSC and PASF have fellowships from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). HB receives a research grant of Orphan Europe. The funders did no provide support in the form of salaries for any author, and did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section

Mucopolysaccharidosis I, II, and VI: Brief review and guidelines for treatment

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions

Bioethical conflicts arising out of access to orphan drugs in Brazil: the example of laronidase for treating mucopolysaccharidosis type I

Submitted by Gilvan Almeida ([email protected]) on 2016-08-10T18:30:49Z No. of bitstreams: 2 891.pdf: 5555282 bytes, checksum: 4967cf80e2f0f12e343be4ff4e9e02f8 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Approved for entry into archive by Maria Arruda ([email protected]) on 2018-02-08T12:21:29Z (GMT) No. of bitstreams: 2 891.pdf: 5555282 bytes, checksum: 4967cf80e2f0f12e343be4ff4e9e02f8 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)Made available in DSpace on 2018-02-08T12:21:29Z (GMT). No. of bitstreams: 2 891.pdf: 5555282 bytes, checksum: 4967cf80e2f0f12e343be4ff4e9e02f8 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2011Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.Esta pesquisa busca, como seu objetivo principal, discutir conflitos morais decorrentes do acesso e da alocação de recursos públicos, a medicamentos órfãos, tomando como exemplo a laronidase, medicamento pleiteado para o tratamento de uma doença órfã denominada mucopolissacaridose tipo I. A partir da obtenção de dados empíricos para análise, realizamos uma elaboração teórica acerca dos conflitos morais que permearam a prescrição, o acesso ou a negativa ao medicamento órfão pleiteado, em reflexões que se distribuíram em três artigos distintos:No primeiro artigo, ao caracterizarmos o acesso à laronidase, ponderamos acerca da judicialização da assistência farmacêutica. A necessidade de políticas focalizadoras que contemplem a necessidade de minorias versus a crescente preocupação com o financiameno público de medicamentos órfãos, em que pese os princípios do SUS, foram colocados, utilizando-se como base de discussão pensadores que lidam com a bioética principialista e teorias da justiça no contexto das instituições de saúde. No segundo artigo, ao caracterizarmos os argumentos processuais, discutimos os conflitos associados nas suas diversas esferas. Observamos a necessidade de trazer à tona a questão da transparência acerca das tomadas de decisões alocativas em saúde, visto que o critério de publicidade é uma dimensão ética do processo político, de acordo com um dos critérios definidos como accountability for reasonableness . No terceiro artigo, ao caracterizarmos as justificativas médicas para a prescrição da laronidase contidas nos laudos obtidos dos processos judiciais refletimos sobre os argumentos morais observados. Estes foram discutidos à luz dos princípios de beneficência e não maleficência e das ponderações de pensadores acerca das decisões alocativas em saúde e suas formas de racionamento.The main objective of this research project was to discuss the moral conflicts associated with public resource allocation and access to orphan drugs, based on the example of laronidase, a medication used in the treatment of the orphan disease mucopolysaccharidosis type I. After collecting empirical data for analysis, we constructed a theoretical framework of the moral conflicts that permeated prescription of and granting or denial of access to the requested drug, with reflections spanning three distinct article: In the first article, we sought to characterize access to laronidase and reflect on the judicialization of pharmaceutical assistance. We discuss the need for focal policies that take into account the needs of minorities versus a growing concern with public funding for orphan drugs, considering the principles of the Brazilian Unified Health System, using the work of principlist bioethicists and several theories of justice in the context of health care as a foundation. In the second article, we characterize arguments advanced in lawsuits and discuss the associated conflicts at various levels. We note the need to address the issue of transparency in resource allocation decisions in health care, as publicity is an ethical dimension of the political process, according to one of the criteria defined as “accountability for reasonableness”. In the third article, we characterize physicians’ rationales for prescribing laronidase, as contained in medical reports filed in support of lawsuits, and reflect on the moral arguments contained in these rationales, which are then discussed from the standpoint of the principles of beneficence and nonmaleficence and in light of the reflections of several thinkers as to resource allocation decisions and forms of rationing in health care

Principle of protection and treatment of rare genetic diseases in Brazil: the case of lysosomal storage disorders

Submitted by Regiane Silva ([email protected]) on 2018-11-28T16:37:40Z No. of bitstreams: 1 Bioética da proteção e tratamento de doenças genéticas raras no Brasil.pdf: 101034 bytes, checksum: c9784b5373d31cf09f45c253e096512b (MD5)Approved for entry into archive by Regiane Silva ([email protected]) on 2018-12-04T15:35:02Z (GMT) No. of bitstreams: 1 Bioética da proteção e tratamento de doenças genéticas raras no Brasil.pdf: 101034 bytes, checksum: c9784b5373d31cf09f45c253e096512b (MD5)Made available in DSpace on 2018-12-04T15:35:02Z (GMT). No. of bitstreams: 1 Bioética da proteção e tratamento de doenças genéticas raras no Brasil.pdf: 101034 bytes, checksum: c9784b5373d31cf09f45c253e096512b (MD5) Previous issue date: 2009Universidade do Estado do Rio de Janeiro. Faculdade de Ciências Médicas. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Escola Nacional de Saúde Pública Sergio Arouca. Rio de Janeiro, RJ, Brasil.Este trabalho tem como objetivo discutir a moralidade do financiamento público das drogas órfãs, de altíssimo custo, para o tratamento de doenças genéticas raras, utilizando as ferramentas da Bioética, em especial o princípio da proteção, aplicável a indivíduos e populações vulneradas. Com base neste princípio, e considerando o contexto normativo constituído pelo Sistema Único de Saúde (SUS), argumenta-se sobre a obrigação moral do Estado de prover políticas públicas que assistam ao indivíduo portador de uma doença genética - como a de depósito lisossômico - e que pode, portanto, ser considerado, "vulnerado", bem como são sugeridas medidas que possam implementar e dar sustentabilidade a tais políticas com ênfase em questões de alocação de recursos, focalização e equanimidade.This study aimed to discuss the morality of public funding for highly expensive orphan drugs for treatment of rare genetic diseases, using tools from bioethics, especially the principle of protection, applicable to vulnerable individuals and populations. Based on this principle, and considering the provisions of the Unified National Health System (SUS), the article argues for the state's moral obligation to provide public policies to ensure care for individuals with genetic diseases like lysosomal storage disorders, who can thus be viewed as "injured", besides suggesting measures to implement and ensure the sustainability of policies with an emphasis on resource allocation, targeting, and equity

Luteoma Recorrente da Gravidez com Virilização Materna e Fetal Recurrent Luteoma of Pregnancy with Maternal and Fetal Virilization

Os luteomas da gravidez são pseudotumores ovarianos diagnosticados pelo exame ultra-sonográfico ou durante realização de cesariana e laqueadura pós-parto. Determinam, na segunda metade da prenhez, sinais de virilização materna em um quarto dos casos, o mesmo ocorrendo com a metade dos fetos femininos destas gestantes virilizadas nos quais se observa hipertrofia clitoridiana ou fusão labial. As dosagens séricas maternas dos hormônios androgênicos durante a prenhez e do sangue umbilical por ocasião do parto revelam taxas significativamente aumentadas. No exame ultra-sonográfico apresentam-se como estruturas sólidas ou cístico-sólidas, que após o parto tendem a regredir com o ovário readquirindo as dimensões normais em poucas semanas. Os autores apresentam uma paciente que em duas gestações sucessivas apresentou virilização materna e fetal. Ao exame ultra-sonográfico foram evidenciadas imagem ovariana nodular e dosagens elevadas dos androgênios plasmáticos.<br>Luteomas of pregnancy are ovarian pseudotumors diagnosed by ultrasound, during cesarean section or at postdelivery tubal ligation. Twenty-five per cent of the cases appear around the second half of pregnancy. Usually there are signs of maternal virilization and 50% are detected because female newborns show clitorimegaly and/or labial fusion. The concentrations of androgenic steroids in the maternal blood during pregnancy and in the cord blood at child-birth show significantly increased rates. The ultrasound shows solid or cystic-solid structures and few weeks after the delivery they decrease and the ovary size returns to normal. The authors report a case of a patient who exhibited virilization signs in two consecutive pregnancies as well as in the two female fetuses. At adnexal sonographic examination a solid tumoral image was found in both pregnancies. Serum androgen levels were increased

Dandy-Walker Malformation and Down Syndrome Association: Good Developmental Outcome and Successful Endoscopic Treatment of Hydrocephalus

The association of Down syndrome (DS) with Dandy Walker malformation (DWM) is extremely rare, with only 3 cases reported to date. All cases reported have shown a bad life expectancy and a bad developmental outcome. The present case reveals the possibility of a good prognosis. A 19-month-old male patient had successful endoscopic hydrocephalus treatment and a good developmental outcome. He probably had a better outcome because of good DS and DWM prognostic parameters. Our patient suffered from a DWM with vermis identification of 2 fissures and 3 lobes and a DS with a well-preserved tonus, which was not associated with other congenital systemic defects. We may conclude that the prognosis of DS-DWM association may separately depend on the degree of clinical and neurological involvement of each malformation