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1.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31824646

RESUMO

Exocrine pancreatic insufficiency (EPI) is characterized by inadequate pancreatic enzyme delivery to the small intestine Exocrine pancreatic insufficiency (EPI) is characterized by inadequate pancreatic enzyme delivery to the small intestine, resulting in malabsorption. Clinical manifestations of EPI are often nonspecific and can lead to lack of timely recognition and diagnosis. Central to this clinical dilemma is the lack of highly accurate or specific testing which leads to misdiagnosis and suboptimal treatment. Identification of high-risk patients is key in the diagnosis of EPI and this includes patients with pancreatic parenchyma disorders such as chronic pancreatitis, pancreatic malignancy, cystic fibrosis, and those undergoing pancreatic resection for benign and malignant disease. Less recognized are the number of additional conditions which may also have EPI as a consequence. Owing to an increase in morbidity and impaired quality of life associated with this condition, goals of treatment have been aimed at repleting exocrine enzyme deficiency by oral pancreatic enzyme replacement therapy (PERT). The basis of PERT is to provide activated digestive enzymes to the small bowel during the prandial period, mainly, leading to sufficient absorption of fat and fat-soluble vitamins. The benefits of PERT have been shown to go beyond the improvement in signs and symptoms associated with EPI and include decreasing prevalence of osteopathy and improving survival outcomes in subsets of patients with this condition. However, despite the overall benefits in treatment, the diagnosis and management of EPI are suboptimal. Current literature suggests patients at high risk of developing EPI are not tested and those who are diagnosed are not treated with adequate dosages. In this review, we highlight patients who are at high risk for the development of EPI, analyze consequences and treatment of this disorder, review rationale for enzyme replacement therapy, and examine current evidence for treatment optimization.


Assuntos
Insuficiência Pancreática Exócrina , Pancreatite Crônica , Terapia de Reposição de Enzimas , Humanos , Pâncreas , Qualidade de Vida
2.
Buenos Aires; CONETEC; nov. 2019.
Não convencional em Espanhol | BRISA/RedTESA | ID: biblio-1048252

RESUMO

INTRODUCCIÓN: La hipofosfatasia (HPP) es una enfermedad hereditaria "ultra rara" sumamente heterogénea, del metabolismo fosfo-cálcico generada por un déficit enzimático. Se presenta con múltiples formas clínicas, que van desde alteraciones dentales hasta falta de mineralización ósea generalizada, que lleva a una alta tasa de mortalidad. El pronóstico empeora cuanto más precoz es el inicio de los síntomas (formas perinatales e infantil). No se encuentran disponibles datos de prevalencia locales; se estima una incidencia de aproximadamente 2 casos nuevos de las formas severas cada año en Argentina. DESCRIPCIÓN DE LA TECNOLOGÍA: Asfotase alfa es una enzima de reemplazo diseñada para suplementar la actividad de la TN-SALP, la misma es obtenida por técnicas de ADN recombinante utilizando células de ovario de hámster chino. Se administra de forma subcutánea, la dosis recomendada por el fabricante es de 2 mg/kg tres veces por semana o 1 mg/kg seis veces por semana, aunque se ha utilizado en dosis superiores en los estudios encontrados. METODOLOGÍA: Se realizó una búsqueda en Medline, Lilacs, Cochrane, Tripdatabase, ClínicalTrials.gov, Orphanet y buscadores genéricos de internet. Se utilizaron las palabras clave "asfotase", "hypophosphatasia AND enzyme replacement", "asfotase AND hypophosphatasia", "strensiq". Se consideraron criterios de inclusión a ensayos clínicos controlados aleatorizados (ECCAs), ensayos clínicos no controlados, cohortes prospectivas, casos y controles y estudios de fase 2 o más avanzado, realizados en humanos; en idioma inglés, español, francés o portugués. RESULTADOS: Para la forma clínica perinatal severa e infantil, evidencia de muy baja calidad basada en estudios de fase 2 mostró un beneficio considerable para los desenlaces sobrevida, soporte ventilatorio y cambios radiológicos. Los costos directos anuales de la tecnología para el tratamiento de esta forma clínica se estimaron entre US$ 178.308 y US$ 217.620. En el caso de la forma clínica infanto-juvenil se incluyó un estudio de fase 2 donde se valoró un beneficio considerable para el desenlace cambios radiológicos. Sin embargo, el efecto del tratamiento fue incierto para los desenlaces sobrevida y calidad de vida. La calidad de la evidencia hallada en este caso también fue muy baja. Finalmente, para la forma clínica adulta, en el estudio de fase 2 incluido, no observó beneficio para los desenlaces mineralización ósea y dolor; y un efecto incierto del tratamiento para los desenlaces sobrevida y calidad de vida. La calidad de la evidencia hallada fue baja. CONCLUSIÓN: La información de este reporte contiene las opiniones y perspectivas de una cuidadora de un paciente pediátrico sobre la evolución de la enfermedad hasta llegar al tratamiento, y sobre la vida cotidiana. En el caso de este paciente de 6 años, con diagnostico a los 8 meses de vida, que recibe asfotase alfa hace 3 años, el tratamiento presentó buenos resultados en cuanto al dolor y al desarrollo de la marcha.


Assuntos
Humanos , DNA Recombinante/uso terapêutico , Terapia de Reposição de Enzimas , Hipofosfatasia/tratamento farmacológico , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício/economia
3.
J Biol Regul Homeost Agents ; 33(5 Suppl. 1): 59-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31630715

RESUMO

Anderson-Fabry Disease (AFD) is a rare, X-linked inborn error of glycosphingolipid catabolism caused by a deficient or absent activity of the lysosomal enzyme, α-galactosidase A, resulting in the progressive multisystem lysosomal accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Among the wide spectrum of clinical signs and symptoms and the life-threatening complications of Fabry disease, renal failure causes significant morbidity and mortality. Various evidence shows that the accumulation of Gb3 in different renal cells is present since the first years of life, many years and usually decades before manifest symptoms and signs of renal involvement. Early renal damage can be demonstrated by clinical signs as microalbuminuria and proteinuria, developing as early as in the second decade of life. A decline in GFR is uncommon at paediatric ages but may be seen as early as adolescence. Renal biopsy is rarely used in paediatric patients with Fabry disease although evidence shows that it may be considered a valid tool for the diagnosis of early and potentially reversible nephropathy, as well as for the evaluation of the effectiveness of enzyme replacement therapy (ERT). Although there is consensus in considering the early initiation of ERT as the only tool able to prevent the progression of nephropathy, the issue on the correct timing for the onset of ERT in pediatric age remains open in the management of this chronic and progressive disease.


Assuntos
Doença de Fabry/fisiopatologia , Rim/fisiopatologia , Criança , Progressão da Doença , Terapia de Reposição de Enzimas , Humanos , Triexosilceramidas , alfa-Galactosidase
5.
Medicine (Baltimore) ; 98(41): e17566, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593141

RESUMO

RATIONALE: Coexistence of Fabry disease and IgM nephropathy is rare. The varying severity and unapparent clinical manifestation of Fabry disease makes it difficult to recognize when coexisting with another more prevalent cause of nephropathy requiring electron microscopy and genetic testing to confirm their coexistence. PATIENT CONCERNS: A 54-year-old female presented with proteinuria without any clinical signs or family history of Fabry disease. DIAGNOSES: Immunostaining of the renal biopsy identified mesangial IgM deposition diagnosing it as IgM nephropathy. The light microscopy indicated prominent vacuolization of podocytes. Further examination of toluidine blue stained semi-thin sections and electron microscopy revealed blue bodies and myelin bodies in the cytoplasm of podocytes, respectively. Mutation analysis detected missense mutation establishing the diagnosis of coexisting Fabry disease. INTERVENTIONS: The patient was treated with angiotensin-converting enzyme inhibitors. Enzyme replacement therapy was not administered due to financial constraints. OUTCOMES: After 2 months of treatment the patient demonstrated urine protein to creatinine ratio of 0.21 g/g. LESSONS: Identifying coexistence of Fabry disease with other nephropathy requires meticulous pathologic investigations including electron microscopy especially when Fabry disease presents with atypical phenotype.


Assuntos
Doença de Fabry/complicações , Glomerulonefrite/diagnóstico , Imunoglobulina M/imunologia , Podócitos/ultraestrutura , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Terapia de Reposição de Enzimas/economia , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Doença de Fabry/patologia , Feminino , Glomerulonefrite/complicações , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , Humanos , Microscopia Eletrônica/métodos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Podócitos/patologia , Proteinúria/diagnóstico , Proteinúria/etiologia , Resultado do Tratamento
6.
Brasília; CONITEC; out. 2019. graf, ilus, tab.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1024750

RESUMO

INTRODUÇÃO: a DP, ou glicogenose tipo II, pode ser classificada em DP precoce (idade de início dos sintomas ≤ 12 meses) e DP tardia (idade de início dos sintomas ≥ 12 meses). A DP é uma doença rara, grave, associada à alta morbimortalidade, e que não está incluída no Programa Nacional de Triagem Neonatal. Seu acometimento neuromuscular progressivo - frequentemente fatal nas formas mais graves ­ decorre de mutações patogênicas bialélicas no gene GAA, localizado no cromossomo 17q25.2-q25.3. A DP é uma glicogenose muscular, não associada à ocorrência de hipoglicemia, causada pela atividade deficiente da alfa glicosidase ácida (sinônimo: maltase ácida), enzima lisossômica que libera glicose a partir do glicogênio, conforme a demanda de energia celular. A atividade deficiente desta enzima leva ao acúmulo de glicogênio dentro dos lisossomos e do citoplasma das células da musculatura lisa, esquelética e cardíaca. Este acúmulo acaba danificando o funcionamento celular e destruindo as células, por hipertrofia e ruptura dos lisossomos. A prevenção das manifestações clínicas e o tratamento das manifestações já estabelecidas da DP pode ser realizada, quando indicado, com a terapia de reposição enzimática (TRE) com maltase ácida recombinante humana (alfaalglicosidase), produzida em células de ovário de hamster chinês. TECNOLOGIA: alfa-alglicosidase (myozyme®). PERGUNTA: O uso da alfa-alglicosidase é eficaz e seguro em pacientes com DP? EVIDÊNCIAS CIENTÍFICAS: Dada a existência de menos de 5 ensaios clínicos randomizados (ECR) incluindo uma, outra ou ambas as formas da doença, foram avaliados também ensaios clínicos abertos prospectivos que avaliaram os desfechos de interesse e cujo tamanho amostral era igual ou superior a 5. Assim, trinta e seis estudos foram incluídos, sendo que 13/36 avaliaram DP precoce (entre eles, uma revisão sistemática e um ECR) e 23/36 que avaliaram DP tardia (entre eles, duas revisões sistemáticas e um ECR). DP Precoce: Foi encontrada evidência de benefício da TRE para cardiomiopatia, tempo para início de ventilação mecânica, sobrevida, e segurança. Ressalta-se, contudo, que a maioria dos estudos incluiu pacientes que iniciaram TRE até um ano de idade e que não estavam em ventilação mecânica invasiva, sendo esta a população para a qual este tratamento deve ser indicado. DP Tardio: Foi encontrada evidência de benefício da TRE para capacidade vital forçada (CVF), teste de caminhada em 6 minutos, sobrevida/mortalidade, tempo de ventilação e segurança. AVALIAÇÃO ECONÔMICA: As análises de custo-efetividade resultaram em uma razão de custo efetividade incremental (RCEI) de R$ 1.521.942,46 por ano de vida livre de ventilação para o tratamento da DP precoce com alfa-alglicosidase mais cuidados de suporte em comparação a somente cuidados de suporte; e uma RCEI de R$ 5.306.919,17 por ano de vida ganho (AVG) no tratamento da DP tardia com alfa-alglicosidase mais cuidados de suporte em comparação a somente cuidados de suporte. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A estimativa dos gastos com a incorporação da alfaalglicosidase na perspectiva do SUS, dentro dos cenários propostos para o tratamento dos pacientes com DP precoce, variou de R$ 2,87 milhões a R$ 10,98 milhões no primeiro ano e entre R$ 15,7 milhões e R$ 78,9 milhões após transcorridos cinco anos. Para o tratamento dos pacientes com DP tardia, o impacto orçamentário variou de R$ 102,4 milhões a R$ 156,87 milhões no primeiro ano e entre R$ 613,78 milhões e R$ 1,02 bilhões após transcorridos cinco anos. Finalmente, para o tratamento de todos os pacientes com DP (precoce e tardia), o impacto orçamentário estimado variou de R$ 110,66 milhões a R$ 167,86 milhões no primeiro ano e entre R$ 663,34 milhões e R$ 1,1 bilhões após transcorridos cinco anos de incorporação no SUS. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Reveglucosidase alfa: há 3 ensaios clínicos concluídos, de fase 2, fase 3 e sua extensão, cuja intervenção é intitulada como BMN 701, GAA humana recombinante GILT-tagged, avaliada apenas para DP tardio, sem resultados disponíveis. RECOMENDAÇÃO INICIAL: A Conitec, em sua 76ª reunião ordinária, no dia 3 de abril de 2019, considerando o alto custo da terapia e o elevado impacto orçamentário, o Plenário da Conitec recomendou de forma preliminar a incorporação da alfa-aglicosidade para a forma precoce da doença devido aos ganhos nos desfechos de tempo para início de ventilação mecânica e sobrevida. CONSULTA PÚBLICA: A Consulta Pública nº 33 foi realizada entre os dias 05/06 e 24/06/2019. Foram recebidas 389 contribuições, 61 pelo formulário técnico-científico e 328 pelo formulário de experiência ou opinião sendo 52% concordando totalmente com a recomendação preliminar da Conitec. Foram levantadas questões sobre a utilização da TRE em pacientes com DP tardia, porém os estudos incluídos na CP não trouxeram novas evidências de benefício no tratamento da DP tardia e a proposta de risco compartilhado submetida pela empresa, nas condições apresentadas, não apresentava elementos suficientes para justifica-la. Assim, o plenário da Conitec entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da Conitec presentes na 81ª reunião ordinária, no dia 5 de setembro de 2019, deliberaram, por unanimidade, por recomendar a incorporação no SUS da alfa-alglicosidase para o tratamento da forma precoce da doença de Pompe, conforme Protocolo Clínico do Ministério da Saúde. Foi assinado o Registro de Deliberação nº 470/2019. DECISÃO: Incorporar a alfa-alglicosidase para a forma precoce da doença de Pompe, conforme Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde, no âmbito do Sistema Único de Saúde ­ SUS. Dada pela Portaria nº 48, seção 1, página 65, em 17 de outubro de 2019.


Assuntos
Humanos , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Terapia de Reposição de Enzimas , Glicosídeo Hidrolases/uso terapêutico , Avaliação da Tecnologia Biomédica , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economia
7.
BMC Med Genet ; 20(1): 156, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31510962

RESUMO

BACKGROUND: Pompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase (EC. 3.2.1.20) due to mutations in human GAA gene. The objective of the present study was to examine clinical and molecular characteristics of infantile-onset Pompe disease (IOPD) in Thailand. METHODS: Twelve patients with infantile-onset Pompe disease (IOPD) including 10 Thai and two other Asian ethnicities were enrolled. To examine the molecular characteristics of Pompe patients, GAA gene was analyzed by PCR amplification and direct Sanger-sequencing of 20 exons coding region. The novel mutations were transiently transfected in COS-7 cells for functional verification. The severity of the mutation was rated by study of the GAA enzyme activity detected in transfected cells and culture media, as well as the quantity and quality of the proper sized GAA protein demonstrated by western blot analysis. The GAA three dimensional structures were visualized by PyMol software tool. RESULTS: All patients had hypertrophic cardiomyopathy, generalized muscle weakness, and undetectable or < 1% of GAA normal activity. Three patients received enzyme replacement therapy with variable outcome depending on the age of the start of enzyme replacement therapy (ERT). Seventeen pathogenic mutations including four novel variants: c.876C > G (p.Tyr292X), c.1226insG (p.Asp409GlyfsX95), c.1538G > A (p.Asp513Gly), c.1895 T > G (p.Leu632Arg), and a previously reported rare allele of unknown significance: c.781G > A (p.Ala261Thr) were identified. The rating system ranked p.Tyr292X, p. Asp513Gly and p. Leu632Arg as class "B" and p. Ala261Thr as class "D" or "E". These novel mutations were located in the N-terminal beta-sheet domain and the catalytic domain. CONCLUSIONS: The present study provides useful information on the mutations of GAA gene in the underrepresented population of Asia which are more diverse than previously described and showing the hotspots in exons 14 and 5, accounting for 62% of mutant alleles. Almost all mutations identified are in class A/B. These data can benefit rapid molecular diagnosis of IOPD and severity rating of the mutations can serve as a partial substitute for cross reactive immunological material (CRIM) study.


Assuntos
Predisposição Genética para Doença/genética , Doença de Depósito de Glicogênio Tipo II/genética , Mutação , alfa-Glucosidases/genética , Alelos , Animais , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Células COS , Cardiomiopatia Hipertrófica/genética , Terapia de Reposição de Enzimas , Feminino , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Humanos , Lactente , Masculino , Modelos Moleculares , Patologia Molecular , Análise de Sequência de Proteína , Tailândia , alfa-Glucosidases/química
8.
Adv Exp Med Biol ; 1148: 201-232, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482501

RESUMO

Hypophosphatasia (HPP) is a rare genetic disease, characterized by the defective production of tissue-non-specific alkaline phosphatase (TNSALP). Six subtypes of the disease - affecting neonates (beginning in utero), infants, children, or adults - are recognized: perinatal lethal, prenatal benign, infantile, childhood, adult, and odontohypophosphatasia. The clinical presentation of these subtypes is very different and the severity ranges from mild to lethal. This chapter, after an overview of the genetics, epidemiology, classification, and clinical presentation of the different forms of HPP, will review the current experience with enzyme replacement therapy (ERT).


Assuntos
Fosfatase Alcalina , Terapia de Reposição de Enzimas , Hipofosfatasia/terapia , Humanos
9.
Adv Exp Med Biol ; 1148: 279-322, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482504

RESUMO

Hypophosphatasia (HPP) is an inherited disorder that affects bone and tooth mineralization characterized by low serum alkaline phosphatase. HPP is caused by loss-of-function mutations in the ALPL gene encoding the protein, tissue-nonspecific alkaline phosphatase (TNSALP). TNSALP is expressed by mineralizing cells of the skeleton and dentition and is associated with the mineralization process. Generalized reduction of activity of the TNSALP leads to accumulation of its substrates, including inorganic pyrophosphate (PPi) that inhibits physiological mineralization. This leads to defective skeletal mineralization, with manifestations including rickets, osteomalacia, fractures, and bone pain, all of which can result in multi-systemic complications with significant morbidity, as well as mortality in severe cases. Dental manifestations are nearly universal among affected individuals and feature most prominently premature loss of deciduous teeth. Management of HPP has been limited to supportive care until the introduction of a TNSALP enzyme replacement therapy (ERT), asfotase alfa (AA). AA ERT has proven to be transformative, improving survival in severely affected infants and increasing overall quality of life in children and adults with HPP. This chapter provides an overview of TNSALP expression and functions, summarizes HPP clinical types and pathologies, discusses early attempts at therapies for HPP, summarizes development of HPP mouse models, reviews design and validation of AA ERT, and provides up-to-date accounts of AA ERT efficacy in clinical trials and case reports, including therapeutic response, adverse effects, limitations, and potential future directions in therapy.


Assuntos
Fosfatase Alcalina , Terapia de Reposição de Enzimas , Hipofosfatasia/terapia , Animais , Humanos , Camundongos , Qualidade de Vida
10.
Ital J Pediatr ; 45(1): 93, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370860

RESUMO

BACKGROUND: The treatment with recombinant human growth hormone in patients affected by Mucopolysaccharidoses (MPS) is considered whenever a concurrent diagnosis of growth hormone deficiency is demonstrated. The short- and long-term effects of recombinant human growth hormone in this selected cohort is still debated, given the natural progression of disease-related skeletal malformations and the paucity of treated patients reported in literature. The presented case series provides detailed information about the response to recombinant growth hormone in MPS patients diagnosed with growth hormone deficiency. CASES PRESENTATION: The growth patterns of 4 MPS female patients (current age: 11.7-14.3 years) treated with recombinant human growth hormone due to growth hormone deficiency have been retrospectively analyzed. Two patients, diagnosed with MPS IH, had undergone haematopoietic stem cell transplantation at an early age; the remaining two patients were affected by MPS IV and VI and were treated with enzyme replacement therapy. 4/4 patients presented with a progressive growth deceleration before the diagnosis of growth hormone deficiency was confirmed. This trend was initially reverted by a remarkable increase in height velocity after the start of recombinant growth hormone. We recorded an average increase in height velocity z-score of + 4.23 ± 2.9 and + 4.55 ± 0.96 respectively after 6 and 12 months of treatment. After the first 12-24 months, growth showed a deceleration in all the patients. While in a girl with MPS IH recombinant human growth hormone was discontinued due to a lack in clinical efficacy, 3/4 patients grew at a stable pace, tracking the height centile achieved after the cited initial increase in height velocity. Furthermore, mineral bone density assessed via bone densitometry, showed a remarkable increase in the two patients who were tested before and after starting treatment. CONCLUSIONS: Recombinant human growth hormone appears to have effectively reverted the growth deceleration experienced by MPS patients diagnosed with growth hormone deficiency, at least during the first 12-24 months of treatment.


Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Mucopolissacaridoses/tratamento farmacológico , Adolescente , Densidade Óssea/efeitos dos fármacos , Criança , Terapia de Reposição de Enzimas , Feminino , Transplante de Células-Tronco Hematopoéticas , Hormônio do Crescimento Humano/deficiência , Humanos , Estudos Retrospectivos
11.
Int J Mol Sci ; 20(17)2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31450640

RESUMO

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-ß-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0-7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA.


Assuntos
Terapia de Reposição de Enzimas , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/terapia , Animais , Biomarcadores , Modelos Animais de Doenças , Estabilidade Enzimática , Glicosaminoglicanos/metabolismo , Glicosídeo Hidrolases/administração & dosagem , Glicosídeo Hidrolases/química , Glicosídeo Hidrolases/isolamento & purificação , Masculino , Camundongos , Camundongos Knockout , Mucopolissacaridose IV/etiologia , Mucopolissacaridose IV/metabolismo , Proteínas Recombinantes , Especificidade por Substrato , Temperatura Ambiente , Resultado do Tratamento
12.
G Ital Nefrol ; 36(4)2019 Jul 24.
Artigo em Italiano | MEDLINE | ID: mdl-31373466

RESUMO

Fabry disease is a rare inborn error of the enzyme α-galactosidase (Α-Gal) and results in lysosomal substrate accumulation in tissues with a wide range of clinical presentations. The disease has attracted a lot of interest over the last years and several issues has been discovered up to now leading to increasing knowledge and awareness of the disease. However, several aspects are still unclear and under investigation. Thus, the new challenges that physicians encounter are the discovering of the pathogenic mechanisms, the neutralising antibodies to ERT, the long-term efficacy of therapies. In this article, we summarise and review the latest developments in the science community regarding diagnosis, management and monitoring of Fabry disease concerning in particular its physiopathology, novel biomarkers, antibodies development and novel treatment options.


Assuntos
Doença de Fabry/complicações , Nefropatias/etiologia , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapêutico , Progressão da Doença , Terapia de Reposição de Enzimas , Doença de Fabry/diagnóstico , Doença de Fabry/tratamento farmacológico , Doença de Fabry/genética , Feminino , Glomerulosclerose Segmentar e Focal/etiologia , Glicolipídeos/metabolismo , Heterozigoto , Humanos , Isoenzimas/imunologia , Isoenzimas/uso terapêutico , Nefropatias/diagnóstico , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Masculino , Estresse Oxidativo , Podócitos/metabolismo , Podócitos/patologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Fatores Sexuais , Esfingolipídeos/metabolismo , Triexosilceramidas/metabolismo , alfa-Galactosidase/imunologia , alfa-Galactosidase/uso terapêutico
13.
Saudi Med J ; 40(7): 669-674, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31287126

RESUMO

OBJECTIVES: To report the genotype-phenotype characteristics, demographic features and clinical outcome of Omani patients with congenital hyperinsulinism (CHI). Methods: We retrospectively analyzed the clinical, biochemical, genotypical, phenotypical characteristics and outcomes of  children with CHI who were presented to the pediatric endocrine team in the Royal Hospital, Muscat, Oman between January 2007 and December 2016. Results: Analysis of 25 patients with CHI genetically revealed homozygous mutation in ABCC8 in 23 (92%) patients and 2 patients (8%) with compound heterozygous mutation in ABCC8. Fifteen (60%) patients underwent subtotal pancreatectomy as medical therapy failed and 2 (8%) patients showed response to medical therapy. Three patients expired during the neonatal period, 2 had cardiomyopathy and sepsis, and one had sepsis and severe metabolic acidosis. Out of the 15 patients who underwent pancreatectomy, 6 developed diabetes mellitus, 6 continued to have hypoglycemia and required medical therapy and one had pancreatic exocrine dysfunction post-pancreatectomy, following up with gastroenterology clinic and was placed on pancreatic enzyme supplements, while 2 patients continued to have hypoglycemia and both had abdominal MRI and 18-F-fluoro-L-DOPA positron emission tomography scan (PET-scan), that showed  persistent of the disease and started on medical therapy. Conclusion:  Mutation in ABCC8 is the most common cause of CHI and reflects the early age of presentation. There is a need for early diagnosis and appropriate therapeutic strategy.


Assuntos
Hiperinsulinismo Congênito/metabolismo , Hipoglicemia/metabolismo , Apneia/etiologia , Apneia/fisiopatologia , Pré-Escolar , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/fisiopatologia , Hiperinsulinismo Congênito/terapia , Diabetes Mellitus/tratamento farmacológico , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/tratamento farmacológico , Feminino , Fármacos Gastrointestinais/uso terapêutico , Heterozigoto , Homozigoto , Humanos , Hipoglicemia/complicações , Hipoglicemia/fisiopatologia , Lactente , Recém-Nascido , Letargia/etiologia , Letargia/fisiopatologia , Masculino , Mutação , Octreotida/uso terapêutico , Omã , Pancreatectomia , Peptídeos Cíclicos/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Estudos Retrospectivos , Convulsões/etiologia , Convulsões/fisiopatologia , Sirolimo/uso terapêutico , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Receptores Sulfonilureia/genética , Resultado do Tratamento
15.
Med. clín (Ed. impr.) ; 153(2): 47-55, jul. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-183363

RESUMO

Introduction and objective: Fabry disease (FD) is an X-linked lysosomal storage disorder due to a deficiency of the alpha-galactosidase A enzyme. Although women were historically considered only carriers, many studies have contradicted this fact. The main aim of this work was to set the first Spanish study out of the on-going registries on health status and management of women diagnosed with FD who were not receiving enzyme replacement therapy (ERT). Material and methods: An epidemiological, cross-sectional, descriptive and multicentre study was assessed in women diagnosed for FD who were not receiving ERT. Assessments on symptomatology and severity were collected using several clinical questionnaires. Additionally, clinical information and lab tests were obtained from clinical records. Results: Thirty-three women with a mean age of 45.6±16.2 years were studied. Symptom onset was at a median age of 35.5 years old (range: 30.0-51.5), being diagnosed a median of 2 years later (range: 1.0-1.5). Missense mutations were the most prevalent mutation (n=22, 68.8%). Although 69% considered themselves as asymptomatic, 22 (66.7%) showed at least one FD-related clinical symptom. Using Mainz Severity Score index and Fabry International Prognosis Index neurological symptomatology obtained higher scores both for severity and prognostic. The EQ-5D questionnaire showed 42.2% patients referring to some anxiety or depression, and 30.3% thought that their life was somehow altered by the pain. 62.5% were not receiving any treatment and ERT was offered only to one patient (3.6%) who refused it. Conclusions: Although most of the heterozygous women for FD had not received ERT or either symptomatic treatment, they present symptoms of disease. Careful follow-up of female patients or some adjuvant treatment may be considered to delay progressive organ damage and improve patient quality of life


Introducción y objetivo: La enfermedad de Fabry (EF) es un trastorno de almacenamiento lisosómico hereditario, ligado al cromosoma X y derivado de una deficiencia de la enzima alpha-galactosidasa A. Aunque históricamente solo se ha considerado portadoras a las mujeres, esto ha sido contradicho por muchos estudios. El objetivo principal de este trabajo ha sido establecer un primer estudio español independiente de los registros actuales sobre la situación y seguimiento clínico de las mujeres diagnosticadas con EF que no recibían terapia de sustitución enzimática (TRE). Material y métodos: Se llevó a cabo un estudio epidemiológico, transversal, descriptivo y multicéntrico en mujeres diagnosticadas con EF que no recibían TRE. Las evaluaciones sobre la sintomatología y la gravedad fueron recopiladas mediante varios cuestionarios clínicos. Adicionalmente se obtuvo información clínica y resultados de pruebas de laboratorio de las historias clínicas. Resultados: Se estudiaron 33 mujeres con una edad media de 45,6±16,2 años. El inicio de los síntomas se produjo a una mediana de edad de 35,5 años (rango: 30,0-51,5), siendo diagnosticado en una mediana de 2 años después (rango: 1,0-1,5). Las mutaciones de sentido erróneo fueron las más frecuentes (n=22; 68,8%). Aunque el 69% se consideraron a sí mismas asintomáticas, 22 (66,7%) mostraron al menos un síntoma clínico relacionado con la EF. Utilizando el índice de severidad de Mainz y el índice pronóstico internacional de Fabry, la sintomatología neurológica obtuvo puntuaciones más altas tanto para la gravedad como para el pronóstico. El cuestionario de calidad de vida EQ-5D mostró que el 42,2% de las pacientes referían cierta ansiedad o depresión, y el 30,3% pensó que su vida estaba interferida de alguna manera por el dolor. El 62,5% no recibía ningún tratamiento y solo se ofreció TRE a una paciente (3,6%), que lo rechazó. Conclusiones: Aunque la mayoría de las mujeres heterocigotas para la EF no habían recibido TRE, ni tampoco ningún tratamiento sintomático, sí presentan síntomas de la enfermedad. Un seguimiento cuidadoso de las pacientes junto con alguna terapia adyuvante podría ser de interés para retrasar el daño progresivo de los órganos y mejorar la calidad de vida de las pacientes


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Doença de Fabry/diagnóstico , Seguimentos , Índice de Gravidade de Doença , Estudos Transversais , Métodos Epidemiológicos , Qualidade de Vida , Inquéritos e Questionários/estatística & dados numéricos , Terapia de Reposição de Enzimas , Ficha Clínica , Análise Estatística
16.
World J Gastroenterol ; 25(20): 2430-2441, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31171887

RESUMO

The objective of this study was to analyze the current evidence for the use of pancreatic enzyme replacement therapy (PERT) in affecting survival and quality of life in patients with pancreatic exocrine insufficiency (PEI). Systematic searches of the literature were performed using the PubMed database. Articles were selected for inclusion if they reported findings from trials assessing the effects of PERT on quality of life, survival, malabsorption, growth parameters (such as height, body weight and body mass index), or gastrointestinal symptoms (such as abdominal pain, stool consistency and flatulence). PERT improved PEI-related malabsorption and weight maintenance in patients with cystic fibrosis, chronic pancreatitis, pancreatic cancer, and post-surgical states. In patients with chronic pancreatitis, PERT improved PEI-related symptoms and quality of life measures. Several small retrospective studies have also suggested that PERT may have a positive impact on survival, but long-term studies assessing this effect were not identified. PERT is effective for treating malnutrition and supporting weight maintenance, and it is associated with improved quality of life and possibly with enhanced survival in patients with PEI. However, there is evidence that not all patients with PEI receive adequate PERT. Future work should aim to assess the long-term effects of PERT on the survival of patients with PEI.


Assuntos
Terapia de Reposição de Enzimas/métodos , Medicina Baseada em Evidências/métodos , Insuficiência Pancreática Exócrina/terapia , Desnutrição/tratamento farmacológico , Qualidade de Vida , Insuficiência Pancreática Exócrina/complicações , Insuficiência Pancreática Exócrina/mortalidade , Humanos , Desnutrição/etiologia , Desnutrição/mortalidade , Pâncreas/patologia , Fatores de Tempo , Resultado do Tratamento
17.
Ann Pharm Fr ; 77(5): 349-362, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31253354

RESUMO

Organophosphorus compounds (OP) are toxic molecules developed as insecticides and chemical warfare nerve agents (CWNAs). Most OP are neurotoxic and act as nervous system disruptors by blocking cholinergic transmission. They are therefore responsible for many poisonings worldwide. OP toxicity may result either from acute or chronic exposure, and their poisoning effect were evaluated using several animal models. These latter were also used for evaluating the efficacy of antidotes. Strategies based on enzymes that can trap (stoichiometric bioscavengers) or degrade (catalytic bioscavengers) OP, were particularly studied since they allow effective decontamination, without toxicity or environmental impact. This review summarizes the results obtained in vivo with enzymes through three levels: prophylaxis, treatment and external decontamination. The efficiency of enzymatic treatments in different animal models is presented and the relevance of these models is also discussed for a better extrapolation to humans.


Assuntos
Substâncias para a Guerra Química , Reativadores da Colinesterase/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Inseticidas/envenenamento , Intoxicação por Organofosfatos/terapia , Animais , Antídotos/uso terapêutico , Humanos , Intoxicação por Organofosfatos/enzimologia
18.
Dig Dis Sci ; 64(7): 1985-2005, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31161524

RESUMO

BACKGROUND/OBJECTIVES: The epidemiology of exocrine pancreatic insufficiency (EPI) after acute pancreatitis (AP) is uncertain. We sought to determine the prevalence, progression, etiology and pancreatic enzyme replacement therapy (PERT) requirements for EPI during follow-up of AP by systematic review and meta-analysis. METHODS: Scopus, Medline and Embase were searched for prospective observational studies or randomized clinical trials (RCTs) of PERT reporting EPI during the first admission (between the start of oral refeeding and before discharge) or follow-up (≥ 1 month of discharge) for AP in adults. EPI was diagnosed by direct and/or indirect laboratory exocrine pancreatic function tests. RESULTS: Quantitative data were analyzed from 370 patients studied during admission (10 studies) and 1795 patients during follow-up (39 studies). The pooled prevalence of EPI during admission was 62% (95% confidence interval: 39-82%), decreasing significantly during follow-up to 35% (27-43%; risk difference: - 0.34, - 0.53 to - 0.14). There was a two-fold increase in the prevalence of EPI with severe compared with mild AP, and it was higher in patients with pancreatic necrosis and those with an alcohol etiology. The prevalence decreased during recovery, but persisted in a third of patients. There was no statistically significant difference between EPI and new-onset pre-diabetes/diabetes (risk difference: 0.8, 0.7-1.1, P = 0.33) in studies reporting both. Sensitivity analysis showed fecal elastase-1 assay detected significantly fewer patients with EPI than other tests. CONCLUSIONS: The prevalence of EPI during admission and follow-up is substantial in patients with a first attack of AP. Unanswered questions remain about the way this is managed, and further RCTs are indicated.


Assuntos
Insuficiência Pancreática Exócrina/epidemiologia , Pancreatite/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/tratamento farmacológico , Insuficiência Pancreática Exócrina/enzimologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Pancreatite/diagnóstico , Prevalência , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Resultado do Tratamento
19.
Int J Mol Sci ; 20(12)2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234327

RESUMO

The role of glucosylsphingosine (lyso-Gb1), a downstream metabolic product of glucosylceramide, for monitoring treated and untreated children with Gaucher disease (GD) has not yet been studied. We reviewed the clinical charts of 81 children (<18 years), 35 with mild type 1 GD (GD1), 34 with severe GD1 and 12 with type 3 GD (GD3), followed at Shaare Zedek Medical Center between 2014-2018. Disease severity for GD1 was based on genotypes. Forty children (87%) with severe GD1 and GD3 received enzyme replacement therapy (ERT) compared to two children (6%) with mild GD1. Lyso-Gb1 measurements were conducted on dried blood spot samples taken at each clinic visit. Lyso-Gb1 levels were significantly lower in children with mild compared to severe GD1 (p = 0.009). In untreated children, lyso-Gb1 levels were inversely correlated with platelet counts. During follow-up, lyso-Gb1 increased in almost 50% of untreated children, more commonly in younger children. In treated children, lyso-Gb1 levels were inversely correlated with hemoglobin levels. The increase of lyso-Gb1 while receiving ERT, seen in eight children, was partly associated with compliance and weight gain. Lyso-Gb1 seems to be a useful biomarker for monitoring children with GD and should be included in the routine follow-up. Progressive increase in lyso-Gb1 levels in untreated children suggests ERT initiation.


Assuntos
Doença de Gaucher/sangue , Psicosina/análogos & derivados , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Doença de Gaucher/diagnóstico , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Humanos , Lactente , Masculino , Psicosina/sangue
20.
Drugs ; 79(10): 1103-1134, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31209777

RESUMO

Mucopolysaccharidoses (MPS) are inborn errors of metabolism produced by a deficiency of one of the enzymes involved in the degradation of glycosaminoglycans (GAGs). Although taken separately, each type is rare. As a group, MPS are relatively frequent, with an overall estimated incidence of around 1 in 20,000-25,000 births. Development of therapeutic options for MPS, including hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), has modified the natural history of many MPS types. In spite of the improvement in some tissues and organs, significant challenges remain unsolved, including blood-brain barrier (BBB) penetration and treatment of lesions in avascular cartilage, heart valves, and corneas. Newer approaches, such as intrathecal ERT, ERT with fusion proteins to cross the BBB, gene therapy, substrate reduction therapy (SRT), chaperone therapy, and some combination of these strategies may provide better outcomes for MPS patients in the near future. As early diagnosis and early treatment are imperative to improve therapeutic efficacy, the inclusion of MPS in newborn screening programs should enhance the potential impact of treatment in reducing the morbidity associated with MPS diseases. In this review, we evaluate available treatments, including ERT and HSCT, and future treatments, such as gene therapy, SRT, and chaperone therapy, and describe the advantages and disadvantages. We also assess the current clinical endpoints and biomarkers used in clinical trials.


Assuntos
Mucopolissacaridoses/tratamento farmacológico , Adolescente , Barreira Hematoencefálica/metabolismo , Criança , Pré-Escolar , Terapia Combinada/métodos , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Terapia de Reposição de Enzimas/métodos , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Proteínas de Fusão de Membrana/química , Proteínas de Fusão de Membrana/metabolismo , Permeabilidade , Resultado do Tratamento , Adulto Jovem
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