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RESUMO Introdução: A doença de Huntington (DH), causada por uma repetição CAG expandida no HTT, não possui tratamento e biomarcadores são necessários para futuros ensaios clínicos. Objetivo: Nosso objetivo foi verificar se os níveis de carnitina livre e aminoácidos de cadeia ramificada se comportam como potenciais biomarcadores na DH. Métodos: Portadores sintomáticos e assintomáticos e controles foram recrutados. Idade, sexo, índice de massa corporal (IMC), idade de início, duração da doença, escores UHDRS e trato CAG expandido foram obtidos; valina, leucina, isoleucina e carnitina livre foram medidas. Foram realizadas análises basal e longitudinal. Resultados: Setenta e quatro portadores sintomáticos, 20 portadores assintomáticos e 22 não portadores foram incluídos. No início do estudo, os níveis de valina estavam reduzidos em portadores de DH sintomáticos e assintomáticos quando comparados aos não portadores. Não foram observadas diferenças nos níveis de carnitina livre ou isoleucina + leucina entre os grupos. O IMC dos indivíduos sintomáticos foi menor que o dos não portadores. Níveis de valina correlacionaram-se com o IMC. Avaliação de acompanhamento foi realizada em 43 indivíduos sintomáticos. A pontuação do escore motor total da UHDRS aumentou 4,8 pontos/ano em média. Não foram observadas reduções significativas no IMC ou na valina, enquanto os níveis de carnitina livre e isoleucina+leucina aumentaram. Conclusões: Embora os níveis de valina tenham sido menores nos portadores de DH e estivessem relacionados às perdas de IMC observadas em indivíduos pré-sintomáticos, nenhum desses metabólitos parece ser biomarcador para a DH.

ABSTRACT Background: Huntington’s disease (HD), caused by an expanded CAG repeat at HTT, has no treatment, and biomarkers are needed for future clinical trials. Objective: The objective of this study was to verify if free carnitine and branched chain amino acids levels behave as potential biomarkers in HD. Methods: Symptomatic and asymptomatic HD carriers and controls were recruited. Age, sex, body mass index (BMI), age of onset, disease duration, UHDRS scores, and expanded CAG tract were obtained; valine, leucine, isoleucine, and free carnitine were measured. Baseline and longitudinal analysis were performed. Results: Seventy-four symptomatic carriers, 20 asymptomatic carriers, and 22 non-carriers were included. At baseline, valine levels were reduced in symptomatic and asymptomatic HD carriers when compared to non-carriers. No difference in free carnitine or isoleucine+leucine levels were observed between groups. BMI of symptomatic individuals was lower than those of non-carriers. Valine levels correlated with BMI. Follow-up evaluation was performed in 43 symptomatic individuals. UHDRS total motor score increased 4.8 points/year on average. No significant reductions in BMI or valine were observed, whereas free carnitine and isoleucine+leucine levels increased. Conclusions: Although valine levels were lower in HD carriers and were related to BMI losses observed in pre-symptomatic individuals, none of these metabolites seem to be biomarkers for HD.

https://doi.org/10.1590/0004-282x20190152 937 downloads

Minimal prevalence of Huntington’s disease in the South of Brazil and instability of the expanded CAG tract during intergenerational transmissions
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Castilhos, Raphael Machado de

; Santos, José Augusto dos

; Augustin, Marina Coutinho

; Pedroso, José Luiz

; Barsottini, Orlando

; Saba, Roberta

; Ferraz, Henrique Ballalai

; Godeiro Junior, Clécio

; Vargas, Fernando Regla

; Salarini, Diego Zanotti

; Furtado, Gabriel Vasata

; Polese-Bonatto, Marcia

; Rodrigues, Luiza Paulsen

; Sena, Lucas Schenatto

; Saraiva-Pereira, Maria Luiza

; Jardim, Laura Bannach

Genetics and Molecular Biology

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jun 2019, Volume 42 N. 2 Pages 329 - 336

Abstract: En | Text: En | PDF: En

Abstract Huntington’s disease (HD) is due to dominant expansions of the CAG repeat of the HTT gene. Meiotic instability of the (CAG)n might impact the disorder frequency. We report on HD minimal prevalence in Rio Grande do Sul (RS) state, Brazil, and on intergenerational instability of the (CAG)n in HD families. Symptomatic and at-risk subjects from 179 HD families were ascertained between 2013 and 2016. Clinical, molecular and family history data were obtained. Expanded (CAG)n length differences between parent and child (delta-expanded-(CAG)n) were calculated. Effect of parental age on the (CAG)n instability upon transmission was inferred by correlating delta-expanded-(CAG)n between siblings to their age differences. HD minimal prevalence in RS state was estimated as 1.85:100,000 inhabitants. Alleles with (CAG)27-35 were found on 21/384 non-disease associated chromosomes (5.5%); among 253 expanded alleles, four (1.6%) were within reduced penetrance range with (CAG)36-39. In 32 direct transmissions, mean instability was larger among paternal than maternal transmissions. In direct transmissions and in 51 sibling pairs, parental age at the time of child birth were not correlated with delta-expanded-(CAG)n. Briefly, HD prevalence in RS state was lower than those reported for European populations. Expanded (CAG)n transmissions were unstable and not associated to parental age.

https://doi.org/10.1590/1678-4685-gmb-2018-0032 1288 downloads

Population medical genetics: translating science to the community
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Giugliani, Roberto

; Bender, Fernanda

; Couto, Rowena

; Bochernitsan, Aline

; Brusius-Facchin, Ana Carolina

; Burin, Maira

; Amorim, Tatiana

; Acosta, Angelina Xavier

; Purificação, Antônio

; Leistner-Segal, Sandra

; Saraiva-Pereira, Maria Luiza

; Jardim, Laura Bannach

; Matte, Ursula

; Riegel, Mariluce

; Cardoso-dos-Santos, Augusto César

; Rodrigues, Graziella

; Oliveira, Marcelo Zagonel de

; Tagliani-Ribeiro, Alice

; Heck, Selia

; Dresch, Vanusa

; Schuler-Faccini, Lavínia

; Kubaski, Francyne

Genetics and Molecular Biology

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2019, Volume 42 N. 1 Pages 312 - 320

Abstract: En | Text: En | PDF: En

Abstract Rare genetic disorders are currently in the spotlight due to the elevated number of different conditions and significant total number of affected patients. The study of these disorders is extremely helpful for the elucidation of physiological processes related with complex disorders. Isolated populations are instrumental for the study of genetic disorders, considering their homogeneity and high proportion of affected patients in a small geographic area. These favorable conditions lead to the creation of a new discipline, known as “population medical genetics”, which integrates medical genetics, population genetics, epidemiological genetics and community genetics. In order to develop practical activities in this new discipline, the National Institute of Population Medical Genetics (INaGeMP) was created in 2008 in Brazil. INaGeMP has developed several tools and funded numerous research activities. In this review, we highlight three successful projects developed in the first 10 years of INaGeMP activities (2008-2018): a newborn screening pilot study for MPS VI in Northeast Brazil, the study of Machado-Joseph disease in Brazilian families with Azorian ancestry, and the high twinning rate in a small town in southern Brazil. The results of these projects in terms of scientific output and contributions to the affected communities highlight the success and importance of INaGeMP.

https://doi.org/10.1590/1678-4685-gmb-2018-0096 971 downloads

State biomarkers for Machado Joseph disease: Validation, feasibility and responsiveness to change
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Furtado, Gabriel Vasata

; Oliveira, Camila Maria de

; Bolzan, Gabriela

; Saute, Jonas Alex Morales

; Saraiva-Pereira, Maria Luiza

; Jardim, Laura Bannach

Genetics and Molecular Biology

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2019, Volume 42 N. 1 Pages 238 - 251

Abstract: En | Text: En | PDF: En

Abstract Machado-Joseph disease (SCA3/MJD) is the most common spinocerebellar ataxia worldwide, and particularly so in Southern Brazil. Due to an expanded polyglutamine at ataxin-3, SCA3/MJD presents a relentless course with no current disease modifying treatment. Clinical scales used to measure SCA3/MJD progression present moderate effect sizes, a major drawback for their use as main outcomes in clinical trials, given the rarity and slow progression of the disease. This limitation might be overcome by finding good surrogate markers. We present here a review of studies on peripheral and neurophysiological markers in SCA3/MJD that can be candidates for state biomarkers. Data on markers already studied were summarized, giving emphasis on validation against clinical scale, and responsiveness to change. While some biological fluid compounds and neurophysiological parameters showed poor responsiveness, others seemed to be good candidates. Some potential candidates that are waiting for responsiveness studies were serum levels of neuron specific enolase, vestibulo-ocular reflex and video-oculography. Candidates evaluated by RNA and microRNA expression levels need further studies to improve their measurements. Data on peripheral levels of Beclin-1 and DNAJB1 are promising but still incipient. We conclude that several potential candidates should follow onto validating studies for surrogate state biomarkers of SCA3/MJD.

https://doi.org/10.1590/1678-4685-gmb-2018-0103 931 downloads

Information and Diagnosis Networks – tools to improve diagnosis and treatment for patients with rare genetic diseases
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Vieira, Taiane Alves

; Trapp, Franciele Barbosa

; Souza, Carolina Fischinger Moura de

; Faccini, Lavínia Schuler

; Jardim, Laura Bannach

; Schwartz, Ida Vanessa Doederlein

; Riegel, Mariluce

; Vargas, Carmen Regla

; Burin, Maira Graeff

; Leistner-Segal, Sandra

; Ashton-Prolla, Patrícia

; Giugliani, Roberto

Genetics and Molecular Biology

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2019, Volume 42 N. 1 Pages 155 - 164

Abstract: En | Text: En | PDF: En

Abstract Brazil is a country of continental dimensions and most genetic services are concentrated in the Southeast and South, including the Medical Genetics Service of the Hospital de Clínicas de Porto Alegre (MGS/HCPA). As many areas on the country do not have adequate medical genetics support, networks were designed to extend the service of the MGS/HCPA reference center. This paper presents the information and diagnosis networks that have their headquarters at MGS/HCPA: SIAT (National Information System on Teratogenic Agents), SIEM (Information Service on Inborn Errors of Metabolism), Alô Genética (Hello Genetics - Medical Genetics Information Service for Primary Health Care Professionals); Rede MPS Brasil (MPS-Mucopolysaccharidosis Brazil Network); Rede EIM Brasil (IEM-Inborn Errors of Metabolism Brazil Network), Rede NPC Brasil (Niemann-Pick C - NPC Brazil Network), Rede DLD Brasil (LSD-Lysosomal Storage Disorders Brazil Network), Rede DXB (MSUD-Maple Syrup Urine Disease Network), RedeBRIM (Brazilian Network of Reference and Information in Microdeletion Syndromes Project), Rede Neurogenética (Neurogenetics Network), and Rede Brasileira de Câncer Hereditário (Brazilian Hereditary Cancer Network). These tools are very useful to provide access to a qualified information and/or diagnostic service for specialized and non-specialized health services, bypassing difficulties that preclude patients to access reference centers.

https://doi.org/10.1590/1678-4685-gmb-2018-0214 1176 downloads

Cross-cultural adaptation and validation of the International Cooperative Ataxia Rating Scale (ICARS) to Brazilian Portuguese
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Maggi, Fernanda Aparecida

; Braga-Neto, Pedro

; Chien, Hsin Fen

; Gama, Maria Thereza Drumond

; Rezende Filho, Flávio Moura

; Saraiva-Pereira, Maria Luiza

; Jardim, Laura Bannach

; Voos, Mariana Callil

; Pedroso, José Luiz

; Barsottini, Orlando Graziani Povoas

Arquivos de Neuro-Psiquiatria

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oct 2018, Volume 76 N. 10 Pages 674 - 684

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

RESUMO Introdução: A avaliação clínica de pacientes atáxicos requer instrumentos confiáveis. Nosso objetivo foi traduzir, adaptar culturalmente e validar a International Cooperative Ataxia Rating Scale (ICARS) para a língua portuguesa do Brasil. Métodos: As etapas foram tradução, síntese das traduções, retrotradução, comitê de especialistas, pré-teste e avaliação final. O pré-teste foi realizado com 30 pacientes. Outros 61 pacientes foram avaliados para validade do constructo, consistência interna, confiabilidade intra e interexaminadores e consistência externa. Resultados: Este estudo mostrou boa validade do constructo e alta consistência interna para o total da escala, exceto para o domínio Oculomotor (alfa de Cronbach = 0.316, CCIintra = 82.4% e CCIinter = 79.2%). Alta correlação com a Scale for the Assessment and Rating of Ataxia foi observada. Nós encontramos boa concordância intraexaminador e relativa discordância interexaminadores, com exceção dos domínios postura e marcha. Conclusão: Esta versão da ICARS está adaptada para a cultura brasileira e pode ser usada em pacientes com ataxia.

ABSTRACT Introduction: The clinical assessment of patients with ataxias requires reliable scales. We aimed to translate, adapt and validate the International Cooperative Ataxia Rating Scale (ICARS) into Brazilian Portuguese. Methods: The steps of this study were forward translation, translation synthesis, backward translation, expert committee meeting, preliminary pilot testing and final assessment. Thirty patients were enrolled in the preliminary pilot testing and 61 patients were evaluated for construct validity, internal consistency, intra- and inter-rater reliability and external consistency. Results: This study showed good validity of the construct and high internal consistency for the full scale, except for the oculomotor domain (Cronbach's alpha = 0.316, intraclass correlation coefficients intra- = 82.4% and inter- = 79.2%). A high correlation with the Scale for the Assessment and Rating of Ataxia was observed. We found good intra-rater agreement and relative inter-rater disagreement, except in the posture and gait domain. Conclusion: The present ICARS version is adapted for the Brazilian culture and can be used to assess our ataxic patients.

https://doi.org/10.1590/0004-282x20180098 2180 downloads

Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a family report from South Brazil
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Burguêz, Daniela

; Oliveira, Camila Maria de

; Rockenbach, Marcio Aloísio Bezerra Cavalcanti

; Fussiger, Helena

; Vedolin, Leonardo Modesti

; Winckler, Pablo Brea

; Maestri, Marcelo Krieger

; Finkelsztejn, Alessandro

; Santorelli, Filippo Maria

; Jardim, Laura Bannach

; Saute, Jonas Alex Morales

Arquivos de Neuro-Psiquiatria

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jun 2017, Volume 75 N. 6 Pages 339 - 344

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

RESUMO A ataxia espástica autossômica recessiva de Charlevoix-Saguenay (ARSACS) é uma doença neurodegenerativa de início precoce causada por mutações no gene SACS que foi inicialmente descrita na região de Quebec, Canadá. A apresentação típica de ARSACS é caracterizada por ataxia, espasticidade, polineuropatia e hipermielinização das fibras nervosas da retina de início infantil. No presente artigo, descrevemos os achados clínicos e neurorradiológicos que levaram à suspeita de ARSACS em duas primas descendentes de alemães naturais do Rio Grande do Sul, Brasil e revisamos os achados de neuroimagem, oftalmológicos e neurofisiológicos de ARSACS. O fenótipo de ataxia-espástica de início infantil precoce apresentado pelas pacientes era similar ao classicamente descrito em Quebec. O sequenciamento do SACS revelou a mutação nova c.5150_5151insA (mudança na matriz de leitura), em homozigose, confirmando o diagnóstico de ARSACS. A ARSACS é uma causa frequente de ataxia/ataxia-espástica de início precoce mundialmente, entretanto sua frequência é desconhecida no Brasil.

ABSTRACT Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset, neurodegenerative disorder caused by mutations in SACS, firstly reported in Quebec, Canada. The disorder is typically characterized by childhood onset ataxia, spasticity, neuropathy and retinal hypermyelination. The clinical picture of patients born outside Quebec, however, is often atypical. In the present article, the authors describe clinical and neuroradiological findings that raised the suspicion of an ARSACS diagnosis in two female cousins with Germanic background from Rio Grande do Sul, Brazil. We present a review on the neuroimaging, ophthalmologic and neurophysiologic clues for ARSACS diagnosis. The early-onset, slowly progressive, spastic-ataxia phenotype of reported patients was similar to ARSACS patients from Quebec. The SACS sequencing revealed the novel homozygous c.5150_5151insA frameshift mutation confirming the ARSACS diagnosis. ARSACS is a frequent cause of early onset ataxia/spastic-ataxia worldwide, with unknown frequency in Brazil.

https://doi.org/10.1590/0004-282x20170044 2562 downloads

Neurological outcomes after hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy, late onset metachromatic leukodystrophy and Hurler syndrome
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Saute, Jonas Alex Morales

; Souza, Carolina Fischinger Moura de

; Poswar, Fabiano de Oliveira

; Donis, Karina Carvalho

; Campos, Lillian Gonçalves

; Deyl, Adriana Vanessa Santini

; Burin, Maira Graeff

; Vargas, Carmen Regla

; Matte, Ursula da Silveira

; Giugliani, Roberto

; Saraiva-Pereira, Maria Luiza

; Vedolin, Leonardo Modesti

; Gregianin, Lauro José

; Jardim, Laura Bannach

Arquivos de Neuro-Psiquiatria

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dec 2016, Volume 74 N. 12 Pages 953 - 966

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

RESUMO O transplante de células tronco hematopoiéticas (TCTH) é o único tratamento disponível para o envolvimento neurológico de doenças como a leucodistrofia metacromática (MLD), a mucopolissacaridose tipo I-Hurler (MPS-IH) e a adrenoleucodistrofia (CALD). Objetivos Descrever a sobrevida e os desfechos neurológicos após o TCTH nessas doenças. Métodos Sete pacientes CALD, 2 MLD e 2 MPS-IH realizaram TCTH entre 2007 e 2014. Avaliações neurológicas, ressonância nuclear magnética e estudos bioquímicos e moleculares foram feitos no baseline e repetidos quando apropriado. Resultados Desfechos favoráveis foram obtidos em 4/5 TCTH de doadores relacionados e em 3/6 não relacionados. Dois pacientes faleceram de complicações do procedimento. Nove transplantados sobreviveram após uma mediana de 3,7 anos: estabilização neurológica foi obtida em 5/6 CALD, ½ MLD e em um caso MPS-IH. As lesões encefálicas de um caso MPS-IH reduziram-se quatro anos após o TCTH. Conclusão Bons desfechos foram obtidos quando o TCTH foi feito antes da vida adulta, cedo no curso clínico e/ou a partir de um doador relacionado.

ABSTRACT Hematopoietic stem cell transplantation (HSCT) is the only available treatment for the neurological involvement of disorders such as late-onset metachromatic leukodystrophy (MLD), mucopolysaccharidosis type I-Hurler (MPS-IH), and X-linked cerebral adrenoleukodystrophy (CALD). Objective To describe survival and neurological outcomes after HSCT for these disorders. Methods Seven CALD, 2 MLD and 2 MPS-IH patients underwent HSCT between 2007 and 2014. Neurological examinations, magnetic resonance imaging, molecular and biochemical studies were obtained at baseline and repeated when appropriated. Results Favorable outcomes were obtained with 4/5 related and 3/6 unrelated donors. Two patients died from procedure-related complications. Nine transplanted patients were alive after a median of 3.7 years: neurological stabilization was obtained in 5/6 CALD, 1/2 MLD, and one MPS-IH patient. Brain lesions of the MPS-IH patient were reduced four years after HSCT. Conclusion Good outcomes were obtained when HSCT was performed before adulthood, early in the clinical course, and/or from a related donor.

https://doi.org/10.1590/0004-282x20160155 4791 downloads

Genetic counseling and presymptomatic testing programs for Machado-Joseph disease: lessons from Brazil and Portugal
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Schuler-Faccini, Lavínia

; Osorio, Claudio Maria

; Romariz, Flavia

; Paneque, Milena

; Sequeiros, Jorge

; Jardim, Laura Bannach

Genetics and Molecular Biology

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2014, Volume 37 N. 1 Pages 263 - 270

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

Machado-Joseph disease (MJD) is an autosomal dominant, late-onset neurological disorder and the most common form of spinocerebellar ataxia (SCA) worldwide. Diagnostic genetic testing is available to detect the disease-causing mutation by direct sizing of the CAG repeat tract in the ataxin 3 gene. Presymptomatic testing (PST) can be used to identify persons at risk of developing the disease. Genetic counseling provides patients with information about the disease, genetic risks, PST, and the decision-making process. In this study, we present the protocol used in PST for MJD and the relevant observations from two centers: Brazil (Porto Alegre) and Portugal (Porto). We provide a case report that illustrates the significant ethical and psychological issues related to PST in late-onset neurological disorders. In both centers, counseling and PST are performed by a multidisciplinary team, and genetic testing is conducted at the same institutions. From 1999 to 2012, 343 individuals sought PST in Porto Alegre; 263 (77%) of these individuals were from families with MJD. In Porto, 1,530 individuals sought PST between 1996 and 2013, but only 66 (4%) individuals were from families with MJD. In Brazil, approximately 50% of the people seeking PST eventually took the test and received their results, whereas 77% took the test in Portugal. In this case report, we highlight several issues that might be raised by the consultand and how the team can extract significant information. Literature about PST testing for MJD and other SCAs is scarce, and we hope this report will encourage similar studies and enable the implementation of PST protocols in other populations, mainly in Latin America.

2997 downloads Cited 2 times in SciELO

10.

Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment
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Giugliani, Roberto

; Federhen, Andressa

; Muñoz Rojas, Maria Verônica

; Vieira, Taiane

; Artigalás, Osvaldo

; Lapagesse Pinto, Louise

; Azevedo, Ana Cecília

; Acosta, Angelina

; Bonfim, Carmen

; Lourenço, Charles Marques

; Chong Ae, Kim

; Horovitz, Dafne

; Bonfim, Denize

; Norato, Denise

; Marinho, Diane

; Palhares, Durval

; Santos, Emerson Santana

; Ribeiro, Erlane

; Valadares, Eugênia

; Guarany, Fábio

; Lucca, Gisele Rosone de

; Pimentel, Helena

; Souza, Isabel Neves de

; Correa Neto, Jordão

; Fraga, José Carlos

; Goes, José Eduardo

; Cabral, José Maria

; Simionato, José

; Llerena Jr., Juan

; Jardim, Laura

; Giuliani, Liane

; Silva, Luiz Carlos Santana da

; Santos, Mara L.

; Moreira, Maria Angela

; Kerstenetzky, Marcelo

; Ribeiro, Márcia

; Ruas, Nicole

; Barrios, Patricia

; Aranda, Paulo

; Honjo, Rachel

; Boy, Raquel

; Costa, Ronaldo

; Souza, Carolina

; Alcantara, Flavio F.

; Avilla, Silvio Gilberto A.

; Fagondes, Simone

; Martins, Ana Maria

Genetics and Molecular Biology

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2010, Volume 33 N. 4 Pages 589 - 604

Abstract: En | Text: En | PDF: En

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.

8605 downloads Cited 6 times in SciELO

11.

Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros
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Giugliani, Roberto

; Federhen, Andressa

; Muñoz Rojas, Maria Verónica

; Vieira, Taiane Alves

; Artigalás, Osvaldo

; Pinto, Louise Lapagesse Carmargo

; Azevedo, Ana Cecília

; Acosta, Angelina Xavier

; Bomfim, Carmem

; Lourenço, Charles Marques

; Kim, Chong Ae

; Horovitz, Dafne

; Souza, Denize Bomfim

; Norato, Denise

; Marinho, Diane

; Palhares, Durval

; Santos, Emerson Santana

; Ribeiro, Erlane

; Valadares, Eugênia Ribeiro

; Guarany, Fábio

; De Lucca, Gisele Rosone

; Pimentel, Helena

; Souza, Isabel Neves de

; Corrêa Neto, Jordão

; Fraga, José Carlos

; Góes, José Eduardo

; Cabral, José Maria

; Simeonato, José

; Llerena Jr, Juan Clinton

; Jardim, Laura Bannach

; Giuliani, Liane de Rosso

; Silva, Luiz Carlos Santana da

; Santos, Mara

; Moreira, Maria Ângela

; Kerstenetzky, Marcelo

; Ribeiro, Márcia

; Ruas, Nicole

; Barrios, Patricia

; Aranda, Paulo

; Honjo, Rachel

; Boy, Raquel

; Costa, Ronaldo

; Souza, Carolina Fishinger Moura de

; Alcântara, Flavio F

; Avilla, Sylvio Gilberto A

; Fagondes, Simone

; Martins, Ana Maria

Revista da Associação Médica Brasileira

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2010, Volume 56 N. 3 Pages 271 - 277

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

As mucopolissacaridoses (MPS) são doenças genéticas raras causadas pela deficiência de enzimas lisossômicas específicas que afetam o catabolismo de glicosaminoglicanos (GAG). O acúmulo de GAG em vários órgãos e tecidos nos pacientes afetados pelas MPS resulta em uma série de sinais e sintomas, integrantes de um quadro clínico multissistêmico que compromete ossos e articulações, vias respiratórias, sistema cardiovascular e muitos outros órgãos e tecidos, incluindo, em alguns casos, as funções cognitivas. Já foram identificados 11 defeitos enzimáticos que causam sete tipos diferentes de MPS. Antes do advento de terapias dirigidas para a restauração da atividade da enzima deficiente, o tratamento das MPS tinha como principal foco a prevenção e o cuidado das complicações, aspecto ainda bastante importante no manejo desses pacientes. Na década de 80 foi proposto o tratamento das MPS com transplante de medula óssea/transplante de células tronco hematopoiéticas (TMO/TCTH) e na década de 90 começou o desenvolvimento da Terapia de Reposição Enzimática (TRE), que se tornou uma realidade aprovada para uso clínico nas MPS I, II e VI na primeira década do século 21. Os autores deste trabalho têm a convicção de que um melhor futuro para os pacientes afetados pelas MPS depende da identificação, compreensão e manejo adequado das manifestações multissistêmicas dessas doenças, incluindo medidas de suporte (que devem fazer parte da assistência multidisciplinar regular destes pacientes) e terapias específicas. Embora a inibição da síntese de GAG e o resgate da atividade enzimática com moléculas pequenas também possam vir a ter um papel no manejo das MPS, o grande avanço disponível no momento é a TRE intravenosa. A TRE permitiu modificar radicalmente o panorama do tratamento das mucopolissacaridoses I, II e VI na última década, sendo que ainda pode estender seus benefícios em breve para a MPS IV A (cuja TRE já está em desenvolvimento clínico), com perspectivas para o tratamento da MPS III A e do déficit cognitivo na MPS II através de administração da enzima diretamente no sistema nervoso central (SNC). Um grande número de centros brasileiros, incluindo serviços de todas as regiões do país, já têm experiência com TRE para MPS I, II e VI. Essa experiência foi adquirida não só com o tratamento de pacientes como também com a participação de alguns grupos em ensaios clínicos envolvendo TRE para essas condições. Somados os três tipos de MPS, mais de 250 pacientes já foram tratados com TRE em nosso país. A experiência dos profissionais brasileiros, somada aos dados disponíveis na literatura internacional, permitiu elaborar este documento, produzido com o objetivo de reunir e harmonizar as informações disponíveis sobre o tratamento destas doenças graves e progressivas, mas que, felizmente, são hoje tratáveis, uma realidade que traz novas perspectivas para os pacientes brasileiros afetados por essas condições.

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primnarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies. Although inhibition of synthesis of GAG and the recovery of enzyme activity with small molecules also may play a role in the management of MPS, the breakthrough is the currently available intravenous ERT. ERT radically changed the setting for treatment of mucopolysaccharidosis I, II and VI in the last decade., Benefits can even be extended soon to MPS IV A (ERT for this condition is already in clinical development), with prediction for treatment of MPS III A and the cognitive deficit in MPS II by administration of the enzyme directly into the central nervous system (CNS). A large number of Brazilian services, from all regions of the country, already have experience with ERT for MPS I, II and VI. This experience was gained not only by treating patients but also with the participation of some groups in clinical trials involving ERT for these conditions. Summing up the three types of MPS, more than 250 patients have already been treated with ERT in Brazil. The experience of professionals coupled to the data available in international literature, allowed us to elaborate this document, produced with the goal of bringing together and harmonize the information available for the treatment of these severe and progressive diseases, which, fortunately, are now treatable, a situation which bring new perspectives for Brazilian patients, affected by these conditions.

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12.

White matter lesions in Fabry disease before and after enzyme replacement therapy: a 2-year follow-up
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Jardim, Laura B.

; Aesse, Flávio

; Vedolin, Leonardo M.

; Pitta-Pinheiro, Cláudio

; Marconato, João

; Burin, Maira G.

; Cecchin, Cláudia

; Netto, Cristina B.O.

; Matte, Ursula S.

; Pereira, Fernanda

; Kalakun, Luciane

; Giugliani, Roberto

Arquivos de Neuro-Psiquiatria

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sep 2006, Volume 64 N. 3b Pages 711 - 717

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

OBJETIVO: Relatar os achados neurológicos e de imagem do sistema nervoso central (SNC), observados durante 24 meses de tratamento de reposição enzimática (ERT) com agalsidase-alfa, em pacientes com a doença de Fabry (FD). MÉTODO: 8 pacientes foram incluídos; 6 completaram 24 meses de ERT. Os dados foram obtidos aos 0, 12 e 24 meses de ERT. Lesões de substância branca (WML) foram avaliadas assim como sua relação com a idade e o exame neurológico (escore SNC). RESULTADOS: Os achados de ressonância nuclear magnética foram estáveis em 3 pacientes. As WML e o escore SNC pioraram em um caso; flutuaram em um outro caso; e melhoraram no sexto paciente. No todo, havia 15 WML antes da ERT e 19 WML depois de 24 meses de ERT. Em dois anos, 4 lesões desapareceram e 8 novas surgiram. CONCLUSÕES: Viu-se um padrão difuso de WML assintomáticas, na FD. Em dois anos, algumas WML surgiram, enquanto outras desapareceram. Resta demonstrar se esses fenômenos fazem parte da história natural da doença.

PURPOSE: To report the clinical and neuroimaging, central nervous system (CNS) findings of patients with Fabry disease (FD) during 24 months of enzyme replacement therapy (ERT) with agalsidase-alpha. METHOD: Eight patients were included. Six completed 24 months of ERT. Clinical and magnetic resonance imaging (MRI) data were obtained at 0, 12 and 24 months of ERT. White matter lesions (WML) were evaluated as well as their relation to age, symptoms and neurological examination (CNS score). RESULTS: MRI was stable in 3 patients. WML and CNS score worsened in one patient, fluctuated in another, and improved in the sixth patient. In the whole series, there were 15 WML at baseline, and 19 at the 24th month. In two years, 4 lesions disappeared, whereas 8 appeared. CONCLUSION: A widespread pattern of silent WML in FD was seen. In two years, some WML appeared, and some disappeared. If these phenomena were related to the natural history, remains to be demonstrated.

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13.

Huntington disease: DNA analysis in brazilian population
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RASKIN, SALMO

; ALLAN, NASSER

; TEIVE, HÉLIO A.G.

; CARDOSO, FRANCISCO

; HADDAD, MÔNICA SANTORO

; LEVI, GILBERTO

; BOY, RAQUEL

; LERENA JR, JUAN

; SOTOMAIOR, VANESSA SANTOS

; JANZEN-DÜCK, MÔNICA

; JARDIM, LAURA BANNACH

; FELLANDER, FLÁVIO R.

; ANDRADE, LUIZ AUGUSTO FRANCO

Arquivos de Neuro-Psiquiatria

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dec 2000, Volume 58 N. 4 Pages 977 - 985

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

A doença de Huntington (DH) está associada a expansões da seqüência repetitiva de trinucleotídeos CAG no gene HD. Através de análise do número de repetições CAG em indivíduos brasileiros, amostras de 92 indivíduos-controle não afetados pela DH, 44 pacientes com DH e 40 indivíduos de 6 famílias com a DH, demonstrou-se a presença de repetições de 7 até 33 trinucleotídeos CAG nos indivíduos-controle e de 39 até 88 nos alelos mutados dos indivíduos afetados. Foi constatada relação inversa entre a idade de manifestação dos primeiros sintomas da doença e o tamanho do fragmento encontrado. Também foi observado que o número de casos em que ocorrem expansões do trinucleotídeo foi maior quando o pai transmite o alelo mutado do que quando a mãe o transmite. Os dados gerados com este estudo têm importância significativa para a compreensão da etiologia, incidência, diagnóstico, prognóstico e tratamento dos pacientes com DH na população brasileira. O conhecimento da base genética desta doença na população brasileira permitirá um aconselhamento genético mais eficiente às famílias em risco.

Huntington disease (HD) is associated with expansions of a CAG trinucleotide repeat in the HD gene. Accurate measurement of a specific CAG repeat sequence in the HD gene in 92 Brazilian controls without HD, 44 Brazilian subjects with clinical findings suggestive of HD and 40 individuals from 6 putative HD families, showed a range from 7 to 33 repeats in normal subjects and 39 to 88 repeats in affected subjects. A trend between early age at onset of first symptoms and increasing number of repeats was seen. Major increase of repeat size through paternal inheritance than through maternal inheritance was observed. Data generated from this study may have significant implications for the etiology, knowledge of the incidence, diagnosis, prognosis, genetic counseling and treatment of HD Brazilian patients.

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14.

Clinical and biochemical findings in 7 patients with X-linked adrenoleukodystrophy treated with Lorenzo's Oil
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Vargas, Carmen R.

; Barschak, Alethéa G.

; Coelho, Daniella M.

; Furlanetto, Vivian

; Souza, Carolina F.M. de

; Karam, Simone M.

; Jardim, Laura

; Wajner, Moacir

; Giugliani, Roberto

Genetics and Molecular Biology

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dec 2000, Volume 23 N. 4 Pages 697 - 701

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

A adrenoleucodistrofia ligada ao X (X-ALD) é uma desordem hereditária do metabolismo peroxissomal, bioquimicamente caracterizada pelo acúmulo de ácidos graxos de cadeia muito longa (`very long chain fatty acids"- VLCFA) em diferentes tecidos e em fluidos biológicos, sendo os principais ácidos acumulados o hexacosanóico (C26:0) e o tetracosanóico (C24:0). O acúmulo destes ácidos graxos está associado com desmielinização cerebral e insuficiência adrenal. A incidência desta condição é estimada em 1 para 25.000 em homens. Pelo menos seis fenótipos podem ser distinguidos, sendo a adrenoleucodistrofia (ALD) cerebral infantil e a adrenomieloneuropatia (AMN) os mais comuns. O tratamento preconizado consiste na utilização da mistura gliceroltrioleato/gliceroltrierucato (GTO/GTE), conhecida como Óleo de Lorenzo, combinada com dieta pobre em VLCFA. Existem ainda, terapias alternativas como transplante de medula óssea e imunossupressão, além da utilização de lovastatina e fenilacetato de sódio. Neste trabalho fez-se uma avaliação do tratamento com Óleo de Lorenzo associado à dieta restrita em VLCFA de 7 pacientes homens com X-ALD analisando a evolução clínica e bioquímica. Os pacientes apresentaram uma redução média de 50% nos valores de C26:0 e de 42,8% na razão C26:0/C22:0 após o início do tratamento. A maioria dos pacientes permaneceu clinicamente bem e aproximadamente 30% dos pacientes apresentaram uma progressão rápida no curso clínico da doença. Parece não haver uma clara correlação bioquímico-clínica do tratamento. Os resultados nos mostram que novas terapias mais eficazes para X-ALD são necessárias para que se possa obter um melhor prognóstico da doença com progressão mais lenta dos sintomas apresentados ou mesmo reversão dos sintomas já presentes nos pacientes.

X-Linked adrenoleukodystrophy (X-ALD) is a hereditary disorder of the peroxisomal metabolism biochemically characterized by the accumulation of very long chain fatty acids (VLCFA) in tissues and biological fluids. The major accumulated acids are hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0). The disorder is characterized clinically by central and peripheral demyelination and adrenal insufficiency closely related to the accumulation of fatty acids. The incidence of X-ALD is estimated to be 1:25,000 males. At least six phenotypes can be distinguished. The most common phenotypes are childhood cerebral ALD and adrenomyeloneuropathy (AMN). The recommended therapy consists of the use of the glyceroltrioleate/glyceroltrierucate (GTO/GTE) mixture, known as Lorenzo's Oil, combined with a VLCFA-poor diet. There are alternative treatments such as bone marrow transplantation and immunosuppression, as well as the use of lovastatin and sodium phenylacetate. In the present study we report the clinical and biochemical course of 7 male patients with X-ALD treated with Lorenzo's Oil and a VLCFA-restricted diet. Treatment produced 50% reduction in C26:0 and 42.8% reduction in the C26:0/C22:0 ratio. Most patients remained clinically well, although approximately 30% of them presented a rapid clinical deterioration. The results showed a poor biochemical-clinical correlation for treatment, indicating that new therapies for X-ALD are needed in order to obtain a better prognosis for patients.

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15.

Neuronal ceroid lipofuscinoses: a clinical and morphological study of 17 patients from Southern Brazil
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PUGA, ANA CRISTINA S

; JARDIM, LAURA B

; CHIMELLI, LEILA

; SOUZA, CAROLINA F M DE

; CLIVATI, MARTA

Arquivos de Neuro-Psiquiatria

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sep 2000, Volume 58 N. 3A Pages 597 - 606

Abstract: Pt En | Text: Pt En | PDF: Pt | PDF: En

As lipofuscinoses ceroides neuronais (LCN) constituem um grupo de desordens neurodegenerativas, progressivas e de origem genética. O início dos sintomas varia desde a infancia até a vida adulta. Três principais formas infantis são estabelecidas com base na idade de início, evolução clínica e morfologia celular, através de microscopia eletrônica: infantil (LCNI), infantil tardia (LCNIT) e juvenil (LCNJ). Vários subtipos têm sido descritos. Investigação genética e bioquímica vem possibilitando melhor entendimento, diagnóstico e classificação destas desordens. Relatamos achados clínicos, neurofisiológicos, neurorradiológicos e morfológicos de 17 pacientes com diferentes formas de LCN (infantil, infantil tardia e juvenil), avaliados no Hospital de Clínicas de Porto Alegre, durante 6 anos (1992-1997). Tivemos 7 diagnósticos de LCNI, 5 de LCNIT, e 5 casos de LCNJ. Proporção entre gêneros foi 11:6 (masculino:feminino). Convulsões (6 pacientes) e retardo psicomotor (1 paciente) foram os sintomas iniciais no grupo LCNI. Todos os casos de LCNIT tiveram achados usuais. Os pacientes com LCNJ apresentaram diferentes sintomas iniciais, embora tendendo a similaridade em casos familiais. Não há dados epidemiológicos sobre LCN no Brasil. Esperamos que esta serie de casos contribua para maior investigação deste grupo de desordens em nossa população.

The neuronal ceroid lipofuscinoses (NCL) are a group of inherited progressive neurodegenerative disorders with presentation from infancy to adulthood. Three main childhood forms can be established on the basis of age of onset, clinical course, and ultrastructural morphology: infantile (INCL), late infantile (LINCL), and juvenile (JNCL). Several variant subtypes have been described. Genetic and biochemical analysis are helping to better understand, diagnose and classify these disorders. We report on clinical, neurophysiological, neuroradiological, and morphological data from 17 patients with different forms (infantile, late infantile, and juvenile ) of neuronal ceroid lipofuscinoses (NCL) evaluated at Hospital de Clínicas de Porto Alegre, Southern Brazil, during 6 years (1992-1997). Seven cases were infantile; 5 were late infantile; and 5 were juvenile NCL. Gender ratio was male:female, 11:6. Age at presentation varied from 2-24 months for INCL; 2,5 to 5 years for LINCL ; and 4-10 years for the JNCL cases. Seizures (6 patients) and psychomotor retardation (1 patient) were the initial symptoms in the INCL group. All the patients in the group of LINCL had the usual findings. JNCL patients manifested different initial symptoms, although tending to follow a similar clinical picture within familial cases. Epidemiological data on the prevalence of NCLs in Brazil are not available, we expect this series of cases to contribute to further research in our population.

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