Innovative mechanisms of pre-marketing authorization access for rare diseases in Brazil: a case study of pabinafusp-alfa for mucopolysaccharidosis type II / Mecanismos inovadores de acesso pré-comercialização a tecnologias para doenças raras no Brasil: um estudo de caso de alfapabinafuspe para mucopolissacaridose tipo II

Patients with rare diseases frequently face unmet medical needs due to the high costs, lengthy development times, and slow approval processes for new treatments. This case study discusses innovative access alternatives for rare diseases in Brazil, focusing on early access to pabinafusp-alfa for mucopolysaccharidosis type II (MPS-II), a rare genetic lysosomal storage disease characterized by a deficiency of the enzyme iduronate-2-sulfatase. From September 2018 to March 2023, 20 Brazilian MPS-II patients received pabinafusp-alfa through a clinical research protocol. This enzyme replacement therapy (ERT) crosses the blood-brain barrier to address central nervous system manifestations unmet by existing treatments. Patients' participation in the clinical study resulted in an estimated BRL 65 million in cost savings for the public healthcare system compared to conventional ERT with idursulfase-alfa and potentially better clinical outcomes. The case study underscores the importance of innovative mechanisms in addressing patients' medical needs. Early access alternatives include: a) clinical study access, with execution/development aligned with healthcare managers and linked to future access strategies; b) regulatory-level risk-sharing, considering effectiveness uncertainties and the possibility of market withdrawal and/or reimbursement in case of negative results; and c) drug pre-delivery, with payment contingent on positive phase III clinical study outcomes. Although public-private partnerships in clinical research are underused, they could benefit all stakeholders by accelerating drug development, facilitating early patient access to innovative medicines, and generating healthcare system savings, particularly for rare diseases.

Pacientes com doenças raras frequentemente enfrentam necessidades médicas não atendidas devido aos altos custos, longos tempos de desenvolvimento e processos de aprovação lentos para novos tratamentos. Este estudo de caso discute alternativas inovadoras de acesso para doenças raras no Brasil, com foco no acesso precoce ao alfapabinafuspe para mucopolissacaridose tipo II (MPS-II), uma doença lisossômica de armazenamento genético rara, caracterizada por uma deficiência da enzima iduronato-2-sulfatase. De setembro de 2018 a março de 2023, 20 pacientes brasileiros com MPS-II receberam alfapabinafuspe por meio de pesquisa clínica. Essa terapia de reposição enzimática (TRE) atravessa a barreira hematoencefálica para tratar manifestações do sistema nervoso central não atendidas pelos tratamentos existentes. A participação dos pacientes no estudo clínico resultou em uma economia estimada de 65 milhões de reais para o sistema público de saúde, em comparação com a TRE convencional com idursulfase alfa, além de potencialmente melhores resultados clínicos. O estudo de caso destaca a importância de mecanismos inovadores no atendimento das necessidades médicas dos pacientes. As alternativas de acesso precoce incluem: a) acesso por meio de estudos clínicos, com execução/desenvolvimento alinhada aos gestores de saúde e vinculada a estratégias futuras de acesso; b) compartilhamento de risco em nível regulatório, considerando as incertezas de eficácia e a possibilidade de retirada do mercado e reembolso em caso de resultados negativos; e c) pré-entrega do medicamento, com pagamento condicionado aos resultados positivos do estudo clínico de fase III. Embora as parcerias público-privadas em pesquisa clínica sejam subutilizadas, elas poderiam beneficiar todas as partes interessadas ao acelerar o desenvolvimento de medicamentos, facilitar o acesso precoce dos pacientes a medicamentos inovadores e gerar economias para o sistema de saúde, especialmente para doenças raras.

Clinical Profile Among Brazilian Mucopolysaccharidosis type II Patients: Subgroup Analysis from the Hunter Outcome Survey

Abstract Mucopolysaccharidosis type II (MPS II) is a rare genetic, multiorgan disease. Little information about the Brazilian context is available to date; thus, this descriptive subgroup analysis was conducted on Brazilian data from the Hunter Outcome Survey (HOS), including clinical characteristics among MPS II patients from Brazil. HOS is a global, multi-center, long-term, observational registry of patients with MPS II (NCT03292887). Variables related to organ system involvement, signs and symptoms, surgical procedures and survival among Brazilian patients were extracted from HOS database. Data from 153 Brazilian patients with MPS II were analyzed. Musculoskeletal (96.6%), abdomen/gastrointestinal (95.2%), neurological (88.7%), pulmonary (86.2%), and ear (81.3%) were the most frequently observed organ/systems involved. Regarding signs and symptoms, the most prevalent symptom was coarse facial features consistent with the disease (94.6%), followed by joint stiffness and limited function (89.3%), hernia (84.2%) and hepatomegaly (82.2%). Median survival time was 22.0 years, and the major cause of death was respiratory failure (31.8%). These data may be helpful to understand disease characteristics and to help improve the quality of MPS II patient care in Brazil.

Manifestaciones bucales de pacientes con mucopolisacaridosis / Oral manifestations in patients with mucopolysaccharidosis

Objetivo: Describir las características bucales prevalentes de pacientes argentinos con mucopolisacaridosis (MPS) atendidos en el Servicio de Odontología del Hospital Nacional "Prof. Alejandro Posadas". Materiales y métodos: Se consideraron las historias clínicas de 19 pacientes con diagnóstico de MPS. Se registraron la edad, el sexo, el lugar de residencia, el tipo de MPS y la presencia de retraso madurativo. La muestra estuvo constituida por 13 niños (6,7±3 años) y 6 adultos (26±9 años): 2 eran mujeres (1 con MPS tipo I; 1 con MPS tipo IV A) y 17 eran hombres (15 con MPS tipo 2; 1 con MPS tipo 1; 1 con MPS tipo III); 13 de los pacientes presentaban discapacidad intelectual. Se evaluaron: tipo de dentición, oclusión, macroglosia, hipoplasias del esmalte, tipo de respiración predominante, clase molar y tratamiento realizado. Resultados: Ambos casos con MPS I presentaban mordida abierta anterior y giroversión dental, y solo uno de estos, diastemas, microdoncia, hipoplasias del esmalte, macroglosia y respiración bucal. De los 15 pacientes con MPS II, 11 presentaban mordida abierta anterior (73%), 3 mordida cruzada posterior (20%), 5 giroversión dental (33%), 11 diastemas (73%), 3 retraso en la erupción (20%), 4 hiperplasia gingival (26%), 13 macroglosia (87%), 7 hipoplasias del esmalte (47%), 2 microdoncia (13%), 9 respiración bucal (60%). Se registraron 5 pacientes con clase molar I (33%), 3 con clase molar II (20%), 3 con clase molar III (20%) y en 3 casos no se pudo evaluar (20%). En el paciente con MPS tipo III se halló mordida abierta anterior, diastemas, retraso en la erupción, macroglosia, respiración bucal y clase molar II; y en el caso de MPS tipo IV A, mordida abierta anterior, diastemas, hiperplasia gingival, macroglosia y clase molar II. El 90% de los pacientes requirió tratamiento odontológico (AU)

Aim: To identify the most prevalent oral manifestations of 19 Argentine patients with mucopolysaccharidos (MPS) attending the Dentistry Service of the National Posadas Hospital. Materials and methods: The medical records of 19 patients diagnosed with MPS were considered. Age, sex, place of residence, type of MPS, and presence of maturational delay were recorded. The sample consisted of 13 children (6.7 ± 3 years) and 6 adults (26 ± 9 years): 2 were women (1 with MPS type I; 1 with MPS type IV A) and 17 were men (15 with MPS type 2; 1 with MPS type 1; 1 with MPS type III); 13 of the patients had intellectual disabilities. The following were evaluated: type of dentition, occlusion, macroglossia, enamel hypoplasia, predominant type of respiration, molar class and treatment performed Results: Both cases with MPS I presented anterior open bite and dental gyroversion, and only one of these, diastemas, microdontia, enamel hypoplasia, macroglossia and mouth respiration. Of the 15 patients with MPS II, 11 presented anterior open bite (73%), 3 posterior crossbite (20%), 5 dental gyroversion (33%), 11 diastemas (73%), 3 delayed eruption (20%), 4 gingival hyperplasia (26%), 13 macroglossia (87%), 7 enamel hypoplasia (47%), 2 microdontia (13%), 9 mouth breathing (60%). 5 patients with molar class I (33%), 3 with molar class II (20%), 3 with molar class III (20%) and in 3 cases it could not be evaluated (20%). In the patient with type III MPS, anterior open bite, diastemas, delayed eruption, macroglossia, mouth breathing and molar class II were found; and in the case of type IV A MPS, anterior open bite, diastemas, gingival hyperplasia, macroglossia and molar class II. 90% of the patients required dental treatment. Conclusion: The most observed oral manifestations were macroglossia (84.2%) and anterior open bite (73%) (AU)

Conhecimento de familiares sobre cuidados domiciliares à criança com síndrome de Hunter / Family members' knowledge about home care for children with hunter syndrome

Objetivo: avaliar o conhecimento dos familiares quanto aos cuidados em domicílio à criança com síndrome de Hunter. Metodologia: estudo descritivo exploratório qualitativo, realizado por meio de entrevistas com familiares de crianças com síndrome de Hunter, entre em março e abril de 2016 em hospital infantil público de ensino em Teresina-PI. Resultados: observou-se um déficit no conhecimento dos pais, ligado diretamente ao grau de instrução dos mesmos, e como consequência nos cuidados prestados as crianças. Notou-se também a dificuldade de definir o diagnóstico correto em consequência da raridade da doença, o desconhecimento dos profissionais sobre a síndrome, a falta de centros de saúde especializados e a dificuldade da família perante o diagnóstico. Conclusão: para que haja uma extensão do cuidado em todas as suas dimensões, em especial no domicilio, necessárias se fazem políticas efetivas que possam diminuir os mais diversos desconfortos ocasionados pela doença crônica, além de investimentos em capacitação profissional para rápido diagnóstico, tratamento e para que ocorra efetivo reconhecimento e cuidado por parte dos familiares em seu domicilio.

Objective: to evaluate the family's knowledge regarding the care provided to the child with Hunter's syndrome. Methodology: this is a descriptive, qualitative, exploratory study, conducted through interviews with family members of children with Hunter syndrome, between March and April 2016 in a public teaching hospital in Teresina, PI. Results: a deficit in parents ' knowledge was observed, directly linked to their education level, and as a consequence in the care provided to children. It was also noted the difficulty of defining the correct diagnosis as a consequence of the rarity of the disease, the lack of knowledge of the professionals about the syndrome, the shortage of specialized health centers and the difficulty of the family before the diagnosis. Conclusion: in order to have an extension of care in all its dimensions, especially at home, effective policies are made that can reduce the most diverse discomforts caused by chronic disease, in other than investments in professional training for rapid diagnosis, treatment and for effective recognition and care by family members in their home.

Birth of a healthy baby after preimplantation genetic diagnosis in a carrier of mucopolysaccharidosis type II: The first case in Korea / 대한생식의학회지

Mucopolysaccharidosis type II (MPS II) is a rare X-linked recessive lysosomal storage disease caused by mutation of the iduronate-2-sulfatase gene. The mutation results in iduronate-2-sulfatase deficiency, which causes the progressive accumulation of heparan sulfate and dermatan sulfate in cellular lysosomes. The phenotype, age of onset, and symptoms of MPS II vary; accordingly, the disease can be classified into either the early-onset type or the late-onset type, depending on the age of onset and the severity of the symptoms. In patients with severe MPS II, symptoms typically first appear between 2 and 5 years of age. Patients with severe MPS II usually die in the second decade of life although some patients with less severe disease have survived into their fifth or sixth decade. Here, we report the establishment of a preimplantation genetic diagnosis (PGD) strategy using multiplex nested polymerase chain reaction, direct sequencing, and linkage analysis. Unaffected embryos were selected via the diagnosis of a single blastomere, and a healthy boy was delivered by a female carrier of MPS II. This is the first successful application of PGD in a patient with MPS II in Korea

Avaliação da capacidade funcional de adolescentes portadores de Mucopolissacaridose do tipo II / Assessment of functional capacity of teens who are Mucopolysaccharidosis type II carriers

[{"text": "Introdução: A Mucopolissacaridose II (MPS II) é uma doença genética, ligada ao cromossomo X e que\r\nafeta quase que exclusivamente o sexo masculino. Apresenta-se de forma multissistêmica, ocasionada pelo acúmulo progressivo de glicosaminoglicanos (GAG) em tecidos e órgãos, o que causa atraso no desenvolvimento neuropsicomotor, ocasionando limitações na realização de atividades de vida diária. Objetivo: O objetivo deste estudo foi a identificação das áreas de desempenho nas quais os portadores de MPS II apresentam maior comprometimento, além da análise do perfil socioeconômico da respectiva família. Método: A pesquisa se deu através de entrevista com a responsável por três irmãos adolescentes, A1-19 anos, A2-16 anos e A3-15anos, portadores de MPS II, no Estado de Alagoas. A coleta foi efetuada por profissional capacitado, utilizando a Medida de Independência Funcional (MIF) como questionário para identificação de perdas funcionais, e ABEP, para análise do perfil socioeconômico. Resultados: Os resultados\r\napontaram que, em termos socioeconômicos, a família está inserida na classe C1. Em relação ao desempenho, verificou-se que, entre os irmãos, A1 apresenta dependência total nas habilidades investigadas; A2 apresenta perdas funcionais mais incapacitantes, necessitando de auxílio moderado, e A3 possui boa parte das habilidades físicas e cognitivas preservada, porém possui dependência modificada. Conclusão: Diante das dificuldades identificadas neste estudo, foi analisada a importância do diagnóstico precoce e das terapias de reabilitação aliadas à terapia enzimática, para que haja um retardo na progressão da doença.", "_i": "pt"}, {"text": "Introduction: Mucopolysaccharidosis II (MPS II) is an X-linked genetic disease which almost exclusively\r\naffects males. The disease presents a multisystem form, caused by the progressive accumulation of glycosaminoglycans (GAGs) in tissues and organs. It causes developmental delays resulting in limitations on the performance of day-to-day activities. Objective: The aim of this study was to identify occupational performance areas in which people with MPS II have greater impairment and analyze their family's socioeconomic profile. Method: The research was done through interviews with an individual responsible for three adolescent brothers, (A1-19 years, A2-16 years and A3-15 years) who are MPS II carriers from Alagoas, Brazil. Data collection was performed by a trained professional using the Functional\r\nIndependence Measure (FIM) as a questionnaire to identify the functional losses and the ABEP for socioeconomic profile analysis. Results: The results showed that the family is included in the C1 socioeconomic class. Among the siblings, A1 presents total dependence on the investigated skills; A2 presents the most disabling functional losses requiring moderate assistance and A3 has much of his physical and cognitive skills preserved, but has modified dependence. Conclusion: Taking into consideration the difficulties identified in this study, we highlighted the importance of early\r\ndiagnosis and rehabilitation therapies combined with enzyme therapy, which can delay disease progression.", "_i": "en"}]

Hunter Syndrome.

he mini review of Hunter syndrome aimed to explore etiology, incidence, clinical manifestations, diagnosis and treatment by reviewing recent literatures. Hunter syndrome (mucopolysaccharidosis II: MPS II) is a genetic lysosomal storage disease which is rare, It's caused by deficiency of the enzyme iduronate-2-sulfatase (I2S). Initial manifestations of Hunter syndrome are not present at birth, but often begin around ages of 2 to 4, which may include macrocephaly, thickened lips, facial features with typical coarseness like a prominent forehead, a nose with a flattened bridge, and an enlarged protruded tongue, cardiomyopathy, bone deformities, Mongolian spots over the buttocks and neurologic deficits. Hunter syndrome is commonly diagnosed by urine test for glycosaminoglycans (GAGs). Management of MPS II involves palliative treatment, or hematopoietic stem cell therapy (HSCT) which is more effective at an early stage than the enzyme replacement therapy (ERT) by Idursulfase. Intrathecal ERT is under clinical trial and fusion protein treatments, and gene therapy is under development.

A Cerebrospinal Fluid Collection Study in Pediatric and Adult Patients With Hunter Syndrome

Abstract Hunter syndrome (mucopolysaccharidosis II [MPS II]) is characterized by lysosomal glycosaminoglycan (GAG) accumulation. Although a majority of patients with MPS II experience neurocognitive involvement, few data are available on cerebrospinal fluid (CSF) GAG levels in these patients. This study measured GAG levels in CSF collected from 9 patients with MPS II, including 4 adults (aged ≥18 years) with normal cognition, and 5 children, 3 of them with cognitive impairment. The CSF total GAG levels were generally higher in the 3 patients with cognitive impairment (range 842.9-2360.9 ng/mL) versus those with normal cognitive status (range 356.8-1181.1 ng/mL). Heparan sulfate levels, as measured by mass spectrometry, generally followed a similar pattern, with patients with the severe phenotype having the highest values. These data, limited by small sample size, suggest CSF GAG levels and heparan sulfate levels may be higher in patients with cognitive impairment versus patients with cognitively intact MPS II.

Impact of Enzyme Replacement Therapy on Linear Growth in Korean Patients with Mucopolysaccharidosis Type II (Hunter Syndrome)

Hunter syndrome (or mucopolysaccharidosis type II [MPS II]) arises because of a deficiency in the lysosomal enzyme iduronate-2-sulfatase. Short stature is a prominent and consistent feature in MPS II. Enzyme replacement therapy (ERT) with idursulfase (Elaprase(R)) or idursulfase beta (Hunterase(R)) have been developed for these patients. The effect of ERT on the growth of Korean patients with Hunter syndrome was evaluated at a single center. This study comprised 32 patients, who had received ERT for at least 2 yr; they were divided into three groups according to their ages at the start of ERT: group 1 (<6 yr, n=14), group 2 (6-10 yr, n=11), and group 3 (10-20 yr, n=7). The patients showed marked growth retardation as they got older. ERT may have less effect on the growth of patients with the severe form of Hunter syndrome. The height z-scores in groups 2 and 3 revealed a significant change (the estimated slopes before and after the treatment were -0.047 and -0.007, respectively: difference in the slope, 0.04; P<0.001). Growth in response to ERT could be an important treatment outcome or an endpoint for future studies.

Interferência da disfagia orofaríngea no consumo alimentar de indivíduos com mucopolissacaridose II / Interference of oropharyngeal dysphagia in food consumption in patients with mucopolysaccharidosis II

OBJETIVO: o presente estudo visou relacionar o grau de disfagia com o consumo alimentar de indivíduos com mucopolissacaridose II (MPS II). MÉTODO: foram incluídos indivíduos com MPS II do departamento de genética da Universidade Estadual de Alagoas e excluídos aqueles com outros tipos de mucopolissacaridoses, bem como que estivessem em uso de via alternativa de alimentação. Realizadas avaliações antropométrica, dietética, fonoaudiológica para disfagia, clínica otorrinolaringológica e a videoendoscopia da deglutição. RESULTADOS: foram estudados 07 indivíduos, do gênero masculino, entre 5 e 14 anos de idade, dos quais mais de 50% faziam uso de anti-hipertensivo e 42,8% manifestavam a forma grave da doença. Seis deles apresentaram déficit de altura/ idade e mais de 70% encontravam-se obesos segundo o Índice de Massa Corporal (IMC). Foi observada disfagia em cinco deles, com média diária de consumo calórico de 920,15 ± 244,09 calorias, contra 1264,94 ± 106,85 calorias para aqueles sem disfagia, com variação intra-individual significativamente maior no grupo de portadores de disfagia (p < 0,05). Além disso, os indivíduos sem disfagia apresentaram consumo alimentar mais elevado de carboidratos, proteínas e lipídios. Já para os micronutrientes, com exceção da média de consumo diária de ferro e vitamina E, todos os outros avaliados apresentaram médias diárias de consumo maiores no grupo sem disfagia (p < 0,05). CONCLUSÃO: foi observada uma elevada frequência de disfagia nos portadores de MPS II estudados, e isso foi associado ao baixo consumo alimentar calórico e desequilíbrio na proporção e quantidade de macronutrientes e de parte dos micronutrientes.

PURPOSE: this study aimed to relate the degree of dysphagia and food consumption of individuals with mucopolysaccharidosis II (MPS II). METHOD: it was included individuals with MPS II of the genetics department at the State University of Alagoas and excluded those with other types of mucopolysaccharidosis and in use of alternative way of supply. There were performed anthropometric, dietetic, speech therapy for dysphagia,clinical evaluation and otorrinolarigologic videoendoscopy swallowing. RESULTS: there were studied 07 individuals, male, between 5 and 14 years old: from them, more than 50% were taking anti-hypertensive and 42.8% had the severe form of disease. Six had serious deficit height / age and over 70% were obese according to Body Mass Index (BMI). Dysphagia was observed in five subjects, with daily average caloric intake 920.15 ± 244.09 calories, against 1264.94 ± 106.85 calories for those without such changes, with significantly greater intraindividual variation in the group of patients with dysphagia (p <0.05). In addition, individuals without dysphagia had higher food intake of carbohydrates, proteins and lipids. As for micronutrients, except average daily intake of iron and vitamin E, all other assessed had higher average daily consumption in the group without dysphagia (p < 0.05). CONCLUSION: it was observed a high frequency of dysphagia in the studied patients with MPS II, and this was associated with low caloric food consumption and imbalance in the proportion and amount of macronutrients and part of micronutrients.

A study of the relationship between clinical phenotypes and plasma iduronate-2-sulfatase enzyme activities in Hunter syndrome patients / 소아과

PURPOSE: Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare lysosomal storage disorder caused by iduronate-2-sulfatase (IDS) deficiency. MPS II causes a wide phenotypic spectrum of symptoms ranging from mild to severe. IDS activity, which is measured in leukocyte pellets or fibroblasts, was reported to be related to clinical phenotype by Sukegawa-Hayasaka et al. Measurement of residual plasma IDS activity using a fluorometric assay is simpler than conventional measurements using skin fibroblasts or peripheral blood mononuclear cells. This is the first study to describe the relationship between plasma IDS activity and clinical phenotype of MPS II. METHODS: We hypothesized that residual plasma IDS activity is related to clinical phenotype. We classified 43 Hunter syndrome patients as having attenuated or severe disease types based on clinical characteristics, especially intellectual and cognitive status. There were 27 patients with the severe type and 16 with the attenuated type. Plasma IDS activity was measured by a fluorometric enzyme assay using 4-methylumbelliferyl-alpha-iduronate 2-sulphate. RESULTS: Plasma IDS activity in patients with the severe type was significantly lower than that in patients with the attenuated type (P=0.006). The optimal cut-off value of plasma IDS activity for distinguishing the severe type from the attenuated type was 0.63 nmol.4 hr-1.mL-1. This value had 88.2% sensitivity, 65.4% specificity, and an area under receiver-operator characteristics (ROC) curve of 0.768 (ROC curve analysis; P=0.003). CONCLUSION: These results show that the mild phenotype may be related to residual lysosomal enzyme activity.

A study of the relationship between clinical phenotypes and plasma iduronate-2-sulfatase enzyme activities in Hunter syndrome patients / 소아과

PURPOSE: Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare lysosomal storage disorder caused by iduronate-2-sulfatase (IDS) deficiency. MPS II causes a wide phenotypic spectrum of symptoms ranging from mild to severe. IDS activity, which is measured in leukocyte pellets or fibroblasts, was reported to be related to clinical phenotype by Sukegawa-Hayasaka et al. Measurement of residual plasma IDS activity using a fluorometric assay is simpler than conventional measurements using skin fibroblasts or peripheral blood mononuclear cells. This is the first study to describe the relationship between plasma IDS activity and clinical phenotype of MPS II. METHODS: We hypothesized that residual plasma IDS activity is related to clinical phenotype. We classified 43 Hunter syndrome patients as having attenuated or severe disease types based on clinical characteristics, especially intellectual and cognitive status. There were 27 patients with the severe type and 16 with the attenuated type. Plasma IDS activity was measured by a fluorometric enzyme assay using 4-methylumbelliferyl-alpha-iduronate 2-sulphate. RESULTS: Plasma IDS activity in patients with the severe type was significantly lower than that in patients with the attenuated type (P=0.006). The optimal cut-off value of plasma IDS activity for distinguishing the severe type from the attenuated type was 0.63 nmol.4 hr-1.mL-1. This value had 88.2% sensitivity, 65.4% specificity, and an area under receiver-operator characteristics (ROC) curve of 0.768 (ROC curve analysis; P=0.003). CONCLUSION: These results show that the mild phenotype may be related to residual lysosomal enzyme activity.

Estudo prospectivo da deglutição na Mucopolissacaridose II (síndrome de Hunter) antes e após tratamento enzimático / Prospective studies of swallowing in Mucopolysaccharidosis II (Hunter syndrome) before and after enzyme treatment

Estudo de caso para avaliar a deglutição pré e pós-tratamento enzimático de um indivíduo com Mucopolissacaridose e analisar se o tratamento ocasionou melhora na deglutição. Foi realizado o estudo descritivo de um indivíduo com 9 anos e 6 meses do gênero masculino, com a forma grave da doença, com observação em três momentos: uma avaliação pré-tratamento e duas pós-tratamento. Foram realizadas as seguintes avaliações: fonoaudiológica para disfagia; quadro respiratório por um pneumologista; clínica otorrinolaringológica e a videoendoscopia da deglutição. Posteriormente, os resultados foram interpretados segundo a escala Functional Oral Intake Scale (FOIS) e os dados analisados por meio de análise descritiva. Os resultados demonstraram nas avaliações pré e primeira pós-tratamento, presença de disfagia com repercussão na dinâmica alimentar. A segunda avaliação pós-tratamento evidenciou ausência de disfagia, com possibilidade para todas as consistências, porém com restrição da consistência sólida devido à dificuldade na mastigação consequente à alteração oclusal significativa. Além disso, verificou-se normalidade da videoendoscopia da deglutição e gradativa melhora na dinâmica da deglutição no decorrer do tratamento. O estudo mostrou presença de disfagia com repercussão negativa na dinâmica alimentar, e ainda que o tratamento enzimático por mais de um ano trouxe melhoras para a deglutição, com repercussão positiva na dinâmica alimentar.

Case study with the aim to evaluate swallowing pre- and post-enzyme treatment of an individual with Mucopolysaccharidosis, and to analyze whether this treatment caused swallowing improvement. It was carried out a descriptive study of a male subject with 9 years and 6 months with the severe type of the disease. The subject was observed in three distinct moments: one pre-treatment and two post-treatment assessments. It was carried out a speech-language pathology assessment of dysphagia, a pneumologist's respiratory assessment, a clinical otorhinolaryngology assessment, and a fiberoptic endoscopic examination of swallowing. After that, results were interpreted according to the Functional Oral Intake Scale (FOIS), and data were descriptively analyzed. Results showed presence of dysphagia with impact on oral feeding in the pre-treatment and the first post-treatment assessments. The second post-treatment assessment did not show any signs of dysphagia, with possibilities for all consistencies, however with restriction to solid consistency due to a significant occlusal alteration. Moreover, the fiberoptic endoscopic examination of swallowing was normal in this assessment, and there was a gradual improvement on the swallowing dynamics along the treatment. The study showed that dysphagia was present and had a negative impact on food dynamics for the subject studied, and also that the enzyme treatment for over a year improved swallowing, with positive impact on food dynamics.

Changes in Glycogen and Glycosaminoglycan Levels in Hepatocytes of Iduronate-2-Sulfatase Knockout Mice before and after Recombinant Iduronate-2-Sulfatase Supplementation

PURPOSE: Mucopolysaccharidosis II (MPS II) is a lysosomal storage disorder caused by a deficiency of iduronate-2 sulfatase (IdS), which is involved in the degradation of glycosaminoglycan (GAG). In this study, the frequency of fasting hypoglycemia in patients with MPS II was investigated and changes in accumulation of glycogen and GAG in the hepatocytes of IdS-knockout (KO) mice were evaluated before and after recombinant IdS enzyme replacement therapy (ERT). MATERIALS AND METHODS: Plasma glucose levels were evaluated after an 8-hour fast in 50 patients with MPS II. The IdS-KO mice were divided into three groups (group 2; saline, group 3; 0.15 mg/kg of IdS, and group 4; 0.5 mg/kg of IdS); wild-type mice were included as controls (group 1). ERT was initiated intravenously at four weeks of age, and continued every week until 20 weeks of age. RESULTS: The mean glucose level after an 8-hour fast was 94.1 +/- 23.7 mg/dL in the patients with MPS II. Two (4%) out of 50 patients had fasting hypoglycemia. For the mice, GAG in the lysosomes nearly disappeared and glycogen particles in the cytoplasm were restored to the normal range in group 4. CONCLUSION: Glucose metabolism in patients with MPS II appeared to function well despite hepatocytic GAG accumulation and hypothetical glycogen depletion. A higher dose of IdS infusion in MPS II mice led to disappearance of lysosomal GAG and restoration of glycogen to the cytoplasm of hepatocytes.

Síndrome de Hunter Mucopolisacaridosis (II): reporte de un caso / Hunter Syndrome Mucopolysaccharides (II): a Case Report

El síndrome de Hunter, es una alteración genética que afecta principalmente a los varones, debido a la deficiencia o ausencia de la enzima iduronato-2-sulfatasa, que interfiere con la capacidad del cuerpo de descomponer y reciclar los mucopolisacáridos. La incidencia es de 1: 10.000 a 1:25.000 de recién nacidos vivos. Las manifestaciones físicas, incluyen rasgos faciales distintivos, cabeza grande, abdomen aumentado, engrosamiento de válvulas cardíacas, enfermedad respiratoria obstructiva, retraso del desarrollo mental y aumento de tamaño del hígado y del bazo. Presentamos el caso clínico de un paciente de sexo masculino de 7 años de edad, con diagnostico de síndrome de Hunter hace seis años, con antecedentes de crisis convulsivas en dos oportunidades y cuadros de bronconeumonía. Al examen físico presenta fascie tosca, contractura en musculo bíceps braquial, se logra la extensión de las manos, camina con la punta de los pies y presenta hepato y esplenomegalia. Al cual se le trató la sintomatología respiratoria con el uso de antibióticos.

Hunter Syndrome, is a genetic disorder that primarily affects males, due to the deficiency or absence of the enzyme iduronate-2-sulfatase, which interferes with the ability of the body break down and recyele mucopolysaccharides. The incidence is 1: 10.000 to 1:25.000 babies alive. The physical manifestations includes distinctive facial features, large head, abdomen increased thickening of heart valves, obstructive respiratory illness, delayed mental development and enlarged liver and spleen. We present the clinical case of a 7-year-old male patient with diagnosis of Hunter Syndrome six years ago, with a history of seizures in two occasions and schedules of bronchopneumonia. A physical examination presents rough fascie, brachial bicep muscle contracture, is achieved by the extension of the hands, walks with the tip of toes and presents hepato and splenomegaly. Which we treated respiratory symptoms with the use of antibiotics.

Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros / Enzyme replacement therapy for mucopolysaccharidoses I, II and VI: recommendations from a group of Brazilian F experts

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...

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...

A Case of Hunter Syndrome with Characteristic Skin Lesions / 대한피부과학회지

We report a typical case of Hunters syndrr me in a 9 year old boy, who presented with firm skin colored nodules that coalesce to form a reticular pattern on a symmetrical rea between the angles of the scapulas, which is regarded as the pathognornonic cutaneous rnarker, for Hunters syndrome. He also showed growth retardation, clear corneas, hepatomegaly, attertich deficit and mild mental deterioration. The skin biopsy specimen taken frorn a typical nodule shows loosely arranged collagen fibers with massive mucinous material which stains positively with aliar blue at both pH 2.5 and 0.5, metachromatic granules within fibroblast stained with toluidine blue.