RESUMO
Mutations in the acidic alpha-glucosidase (GAA) coding gene cause Pompe disease. Late-onset Pompe disease (LOPD) is characterized by progressive proximal and axial muscle weakness and atrophy, causing respiratory failure. Enzyme replacement therapy (ERT), based on recombinant human GAA infusions, is the only available treatment; however, the efficacy of ERT is variable. Here we address the question whether proteins at variance in LOPD muscle of patients before and after 1 year of ERT, compared withhealthy age-matched subjects (CTR), reveal a specific signature. Proteins extracted from skeletal muscle of LOPD patients and CTR were analyzed by combining gel based (two-dimensional difference gel electrophoresis) and label-free (liquid chromatography-mass spectrometry) proteomic approaches, and ingenuity pathway analysis. Upstream regulators targeting autophagy and lysosomal tethering were assessed by immunoblotting. 178 proteins were changed in abundance in LOPD patients, 47 of them recovered normal level after ERT. Defects in oxidative metabolism, muscle contractile protein regulation, cytoskeletal rearrangement, and membrane reorganization persisted. Metabolic changes, ER stress and UPR (unfolded protein response) contribute to muscle proteostasis dysregulation with active membrane remodeling (high levels of LC3BII/LC3BI) and accumulation of p62, suggesting imbalance in the autophagic process. Active lysosome biogenesis characterizes both LOPD PRE and POST, unparalleled by molecules involved in lysosome tethering (VAMP8, SNAP29, STX17, and GORASP2) and BNIP3. In conclusion this study reveals a specific signature that suggests ERT prolongation and molecular targets to ameliorate patient's outcome.
Assuntos
Terapia de Reposição de Enzimas/métodos , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/terapia , Músculo Esquelético/metabolismo , Proteômica/métodos , Adulto , Autofagia , Cromatografia Líquida/métodos , Eletroforese em Gel Bidimensional/métodos , Feminino , Glucana 1,4-alfa-Glucosidase/genética , Humanos , Lisossomos/metabolismo , Masculino , Microscopia Eletrônica de Transmissão , Proteínas Musculares/metabolismo , Músculo Esquelético/ultraestrutura , Proteoma/metabolismo , Proteínas Recombinantes/uso terapêutico , Espectrometria de Massas em Tandem/métodosRESUMO
OBJECTIVE: To characterize the extent of CNS involvement in children with Pompe disease using brain MRI and developmental assessments. METHODS: The study included 14 children (ages 6-18 years) with infantile Pompe disease (IPD) (n = 12) or late-onset Pompe disease (LOPD) (n = 2) receiving enzyme replacement therapy. White matter (WM) hyperintense foci seen in the brain MRIs were systematically quantified using the Fazekas scale (FS) grading system with a novel approach: the individual FS scores from 10 anatomical areas were summed to yield a total FS score (range absent [0] to severe [30]) for each child. The FS scores were compared to developmental assessments of cognition and language obtained during the same time period. RESULTS: Mild to severe WM hyperintense foci were seen in 10/12 children with IPD (median age 10.6 years) with total FS scores ranging from 2 to 23. Periventricular, subcortical, and deep WM were involved. WM hyperintense foci were seen throughout the path of the corticospinal tracts in the brain in children with IPD. Two children with IPD had no WM hyperintense foci. Children with IPD had relative weaknesses in processing speed, fluid reasoning, visual perception, and receptive vocabulary. The 2 children with LOPD had no WM hyperintense foci, and high scores on most developmental assessments. CONCLUSION: This study systematically characterized WM hyperintense foci in children with IPD, which could serve as a benchmark for longitudinal follow-up of WM abnormalities in patients with Pompe disease and other known neurodegenerative disorders or leukodystrophies in children.
Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Deficiências do Desenvolvimento/diagnóstico por imagem , Doença de Depósito de Glicogênio Tipo II/diagnóstico por imagem , Imageamento por Ressonância Magnética , Neuroimagem , Adolescente , Idade de Início , Encéfalo/patologia , Encefalopatias Metabólicas Congênitas/etiologia , Criança , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Estudos Transversais , Deficiências do Desenvolvimento/etiologia , Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/psicologia , Humanos , Transtornos da Linguagem/diagnóstico por imagem , Transtornos da Linguagem/etiologia , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Substância Branca/diagnóstico por imagemRESUMO
Plaque accumulation and white spot lesions are common adverse effects of fixed orthodontic appliance use. This study compared the effects between enzyme-containing and conventional dentifrices on orthodontic patients. This double-blind randomized controlled trial included 42 orthodontic patients (25 women and 17 men: 22.7 ± 4.2 years) from Taipei Medical University Hospital between 2017 and 2018. The patients were randomly divided into three groups and assigned to dentifrice use during the first 3 months of the orthodontic treatment: group 1 used dentifrices containing enzymes including amyloglucosidase and glucose oxidase, group 2 used dentifrices containing 1450 ppm fluoride, and group 3 used natural dentifrices containing no chemical agent. White spot lesion index (WSL), gingival bleeding index (GBI), and visible plaque index (VPI) were recorded and analyzed. WSL, GBI, and VPI values exhibited no significant difference among the three groups. WSL increased significantly in group 3, GBI decreased significantly in all groups, and VPI decreased significantly in groups 1 and 2. No significant difference was observed between the use of enzyme-containing and conventional dentifrices after fixed orthodontic appliance placement.
Assuntos
Dentifrícios/uso terapêutico , Fluoretos/uso terapêutico , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Glucose Oxidase/uso terapêutico , Adolescente , Adulto , Índice de Placa Dentária , Método Duplo-Cego , Feminino , Gengivite , Humanos , Masculino , Saúde Bucal , Aparelhos Ortodônticos , Índice Periodontal , Adulto JovemAssuntos
Cardiomegalia , Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/diagnóstico por imagem , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , Lactente , MasculinoRESUMO
Late-onset Pompe disease (LOPD) is an adult type of classical Pompe disease and presents without cardiomyopathy. Neuroimaging in LOPD is typically limited to posterior circulation and involves dilative arteriopathy, especially dolichoectasia and intracranial aneurysms. We report an interesting case of an established diagnosis of asymptomatic LOPD in a young man with a restrictive-variant pattern in posterior vasculature. We discuss the clinical presentation, neuroimaging, existing literature, and prognosis in vascular variants of LOPD.
Assuntos
Doença de Depósito de Glicogênio Tipo II/complicações , Acidente Vascular Cerebral/etiologia , Insuficiência Vertebrobasilar/etiologia , Idade de Início , Angiografia Cerebral/métodos , Angiografia por Tomografia Computadorizada , Imagem de Difusão por Ressonância Magnética , Progressão da Doença , Terapia de Reposição de Enzimas , Evolução Fatal , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , Masculino , Inibidores da Agregação Plaquetária/uso terapêutico , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Resultado do Tratamento , Insuficiência Vertebrobasilar/diagnóstico por imagem , Insuficiência Vertebrobasilar/tratamento farmacológicoRESUMO
BACKGROUND AND OBJECTIVE: Although named because of its sucrose hydrolytic activity, this mucosal enzyme plays a leading role in starch digestion because of its maltase and glucoamylase activities. Sucrase-deficient mutant shrews, Suncus murinus, were used as a model to investigate starch digestion in patients with congenital sucrase-isomaltase deficiency.Starch digestion is much more complex than sucrose digestion. Six enzyme activities, 2 α-amylases (Amy), and 4 mucosal α-glucosidases (maltases), including maltase-glucoamylase (Mgam) and sucrase-isomaltase (Si) subunit activities, are needed to digest starch to absorbable free glucose. Amy breaks down insoluble starch to soluble dextrins; mucosal Mgam and Si can either directly digest starch to glucose or convert the post-α-amylolytic dextrins to glucose. Starch digestion is reduced because of sucrase deficiency and oral glucoamylase enzyme supplement can correct the starch maldigestion. The aim of the present study was to measure glucogenesis in suc/suc shrews after feeding of starch and improvement of glucogenesis by oral glucoamylase supplements. METHODS: Sucrase mutant (suc/suc) and heterozygous (+/suc) shrews were fed with C-enriched starch diets. Glucogenesis derived from starch was measured as blood C-glucose enrichment and oral recombinant C-terminal Mgam glucoamylase (M20) was supplemented to improve starch digestion. RESULTS: After feedings, suc/suc and +/suc shrews had different starch digestions as shown by blood glucose enrichment and the suc/suc had lower total glucose concentrations. Oral supplements of glucoamylase increased suc/suc total blood glucose and quantitative starch digestion to glucose. CONCLUSIONS: Sucrase deficiency, in this model of congenital sucrase-isomaltase deficiency, reduces blood glucose response to starch feeding. Supplementing the diet with oral recombinant glucoamylase significantly improved starch digestion in the sucrase-deficient shrew.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/tratamento farmacológico , Suplementos Nutricionais , Digestão/fisiologia , Fármacos Gastrointestinais/uso terapêutico , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Amido/metabolismo , Complexo Sacarase-Isomaltase/deficiência , Sacarase/deficiência , Administração Oral , Animais , Animais Geneticamente Modificados , Biomarcadores/metabolismo , Glicemia/metabolismo , Erros Inatos do Metabolismo dos Carboidratos/metabolismo , Masculino , Distribuição Aleatória , Musaranhos , Complexo Sacarase-Isomaltase/metabolismo , Resultado do TratamentoRESUMO
Pompe disease is an autosomal recessive disease resulting from deficiency of the acid alpha-glucosidase (GAA). The late-onset Pompe Disease (LOPD) patients develop muscular and respiratory complications later in life. We describe a retrospective observational cohort study including 22 patients with LOPD. The cohort was assessed at baseline before Enzyme Replacement Therapy (ERT) with alglucosidase alpha (20mg/kg biweekly) was commenced and subsequently relevant information was collected at 2, 4 and 5years later. The median age of the patients at study entry was 44years (16-64years), with median disease duration of 11.5years (4-31years). At baseline, 10 patients (45%) could walk without support, 12 (55%) could walk with unilateral or bilateral support including 3/12 were wheelchair bound. Mean predicted FVC % was 55.7 (95% CI 45-66) of predicted normal at baseline and showed no significant change after 5years (54.6 (95% CI 43-66)), (all p=0.9815). Mean FVC % supine was 41.8 (95% CI 33.8-49) of predicted normal at baseline and remained significantly unchanged at 5years (48.4 (95% CI 37-59.6)), (all p=0.8680). The overnight non-invasive ventilator dependence increased by 18.2% as compared with baseline and requirement of mobility aids increased during this period by 5.2% as compared with the baseline. Mean walking distance at 6min walk test was 411.5 (95% CI 338-485) at baseline, 266.5 (95% CI 187-346) m at 2years, 238.6 (95% CI 162-315) m at 4years and 286.8 (95% CI 203-370) m at 5years (p=0.1981; ANOVA was completed only for 14 patients). A gradual decline in FVC% predicted was noted only in four cases and a decline in FVC% supine in two other. Only one patient showed a decline in both pulmonary function tests. In all remaining cases (17/22) respiratory function remains stable. In conclusion overall pulmonary function tests and mobility remained stable for 5years in majority of patients on ERT. However, in some patients they continued to decline in spite of ERT resulting in increased number of patients requiring ventilation and increase wheel chair dependence at the end of 5years.
Assuntos
Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/terapia , Adolescente , Adulto , Idade de Início , Feminino , Glucana 1,4-alfa-Glucosidase/administração & dosagem , Glucana 1,4-alfa-Glucosidase/efeitos adversos , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Atividade Motora , Testes de Função Respiratória , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: To evaluate whether very early treatment in our patients would result in better clinical outcomes and to compare these data with other infantile-onset Pompe disease (IOPD) cohort studies. METHODS: In this nationwide program, 669,797 newborns were screened for Pompe disease. We diagnosed IOPD in 14 of these newborns, and all were treated and followed in our hospital. RESULTS: After 2010, the mean age at first enzyme-replacement therapy (ERT) was 11.92 days. Our patients had better biological, physical, and developmental outcomes and lower anti-rh acid α-glucosidase antibodies after 2 years of treatment, even compared with one group that began ERT just 10 days later than our cohort. No patient had a hearing disorder or abnormal vision. The mean age for independent walking was 11.6 ± 1.3 months, the same age as normal children. CONCLUSIONS: ERT for patients with IOPD should be initiated as early as possible before irreversible damage occurs. Our results indicate that early identification of patients with IOPD allows for the very early initiation of ERT. Starting ERT even a few days earlier may lead to better patient outcomes.
Assuntos
Intervenção Médica Precoce , Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fatores de Tempo , Resultado do TratamentoRESUMO
A doença de Fabry é uma enfermidade genética ligada ao cromossomoX e de caráter progressivo, causada pela deficiênciaparcial ou total da enzima alfa galactosidase A (?-Gal A). Habitualmenteo diagnóstico é tardio em função das complicaçõespatológicas provocadas pela deficiência da enzima. OBJETIVO:Neste estudo, descrevemos os aspectos clínicos de um caso familiaratravés do acompanhamento ao longo de 3 anos, duranteo tratamentopela reposição enzimática. MÉTODOS: O métodoadotado foi indutivo, relacionado ao estudo de caso familiarde pacientes com doença de Fabry. Quanto à natureza das informações,a pesquisafoi qualitativa, utilizando-se, quanto aoseu objetivo, à pesquisa exploratória. Com relação as fonte deinformação e procedimento de coleta, a pesquisa caracteriza-secomo sendo bibliográfica e documental. A amostra foi compostapor três pacientesque realizamacompanhamento quinzenalpara aplicação de terapia de reposição enzimática. O critério deinclusão para a pesquisa partiu do pressuposto de se considerarque a doença de Fabry é uma afecção rara e que a família estudadacontempla com riqueza manifestações clínicas, capazesde caracterizar a doença de Fabry. RESULTADOS: Os principaissintomas clínicos relatados pelos pacientes foram: crisede dor generalizada, fadiga, acroparestesia, febre, mialgia, dorabdominal, hipohidrose, intolerância ao frio, calor e ao exercíciofísico. Esses sintomas segundo os pacientes surgiram nainfância e foram amenizados após o uso da terapia de reposiçãoenzimática, propiciando uma melhor qualidade de vida para osmesmos. Também, se observou sinais específicos desta patologianos pacientes, como córnea verticillata e angioqueratoma. Atravésda genotipagem se verificou a semelhança da mutação entre os pacientes do estudo, demonstrando padrão típico de herançarecessiva ligada ao cromossomo X. CONCLUSÃO: Os pacientesdeste estudo apresentaram quadro clínico semelhante,sendoque a sintomatologia iniciou na infância. Córnea verticillata eangioqueratoma umbilical foram sinais encontrados nos pacientes do sexo masculino e são considerados manifestações clínicas frequentes desta patologia. A herança encontrada nesta amostra tem um padrão típico de herança recessiva ligada ao cromossomo X. Desta forma, apesar de ser uma afecção rara na população em geral, o diagnóstico precoce e a terapia de reposição enzimática permitem a evolução clínica favorável e a melhoria da qualidade de vida do paciente.(AU)
Fabry disease is a genetic disorder linked to the X chromosomeand progressive, caused by partial or total deficiency of alphagalactosidase A (?-Gal A). Usually the diagnosis is delayed dueto the pathological complications caused by deficiency of theenzyme. OBJECTIVE: In this study, we describe the clinicalaspects of a family case by monitoring for over three years,during the treatment by enzyme replacement. METHODS:The method adopted was inductive, related to the study of afamily case with patients with Fabry disease. About the nature ofthe information, the research was qualitative, using, as its goal,the exploratory research. Regarding the source of informationand collection procedure, the research is characterized asbibliographical and documentary. The sample was composed ofthree patients submitted to biweekly monitoring for applicationof enzyme replacement therapy. The inclusion criterion forthe research assumed to consider that Fabry disease is a raredisease and that the studied family contemplates with wealththe clinical manifestations, able to characterize the Fabrydisease. RESULTS: The main clinical symptoms related bypatients were: generalized pain crisis, fatigue, acroparesthesia,fever, myalgia, abdominal pain, hypohidrosis, intolerance tocold, heat and exercise. These symptoms according to patientsemerged in childhood and were alleviated after the use ofenzyme replacement therapy, providing a better quality of lifefor them. Also, we found specific signs of this disease in patients,as verticillata cornea and angiokeratoma. By genotyping, it wasfound the similarity of the mutation among patients in thestudy, showing typical pattern of recessive inheritance linkedto chromosome X. CONCLUSION: The patients in this study showed similar clinical condition, and the symptoms began inchildhood. Verticillata cornea and umbilical angiokeratomasigns were found in male patients and are considered commonclinical manifestations of this pathology. The heritage found inthis sample has a typical pattern of recessive inheritance linkedto chromosome X. Thus, despite being a rare disease in generalpopulation, early diagnosis and enzyme replacement therapyallow favorable clinical evolution and improved patient qualityof life.(AU)
Assuntos
Humanos , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Fabry/diagnóstico , Terapia de Reposição de Enzimas , Angioceratoma , Ensaios Enzimáticos Clínicos/instrumentação , Técnicas de Genotipagem/instrumentaçãoRESUMO
INTRODUCTION: Pompe disease is a generalized progressive disease caused by a deficiency of the lysosome enzyme acid alpha-glucosidase (GAA). We present three cases with different clinical symptomatology and treated with enzyme replacement therapy (ERT) with positive evolution. CASE REPORTS: Case 1: three-month old male, with weakness and rejecting meals; mild hepatomegaly, discrete macroglossia and muscular hypotony; and increased muscular enzymes. Case 2: five-month old male, with delayed motor development, severe neurosensory deafness, and respiratory disorder of difficult evolution; muscular hypotony; and mild increase in creatine kinase. Case 3: 22-year old male, with progressive dyspnea, with history of increased creatine kinase and transaminases, and hypercholesterolemia. He suffered from severe respiratory failure requiring endotraqueal intubation Muscular biopsy showed glycogen storage suggestive of Pompe disease. In the three cases, the EMG showed a characteristic pattern with pseudomyotonic discharges and the deficiency in GAA was confirmed in lymphocytes. One single mutation was observed in one case and two in the other two cases. Every patient received ERT showing a favorable evolution; with disappearance of cardiac disorders in case 1, improvement in motor development in both infants and no longer need for mechanical ventilation in case 3. CONCLUSION: Pompe disease has a wide variability in clinical expression. ERT achieves a good response, especially in infant forms of the disease. The survival of treated patients with these Pompe disease forms will allow knowing further the course of the disease.
TITLE: Variabilidad en la presentacion clinica en la enfermedad de Pompe: evolucion tras terapia de reemplazo enzimatico.Introduccion. La enfermedad de Pompe es un trastorno generalizado progresivo producido por el deficit de la enzima alfa-glucosidasa acida (AGA) de los lisosomas. Se presentan tres casos manifestados de forma muy diferente y tratados con terapia enzimatica sustitutiva (TES), con evolucion favorable. Casos clinicos. Caso 1: varon de 3 meses, con debilidad y rechazo de la alimentacion, hepatomegalia leve, ligera macroglosia e hipotonia, y aumento de las enzimas musculares. Caso 2: varon de 5 meses, con retraso del desarrollo motor, sordera neurosensorial grave, trastornos respiratorios de repeticion de evolucion torpida, hipotonia y leve elevacion de la creatincinasa. Caso 3: varon de 22 años con disnea progresiva, con antecedentes de elevacion de la creatincinasa y las transaminasas, e hipercolesterolemia. Sufrio insuficiencia respiratoria grave que preciso intubacion endotraqueal. La biopsia muscular presento depositos de glucogeno sugestivos de la enfermedad. En los tres casos, el estudio electromiografico dio un patron caracteristico, con descargas pseudomiotonicas, y se confirmo el deficit de AGA en los linfocitos. Se encontro una mutacion en un caso y dos mutaciones en los otros dos. Todos recibieron TES con evolucion favorable: desaparicion de las alteraciones cardiacas en el caso 1, mejoria en los hitos motores en los dos casos infantiles y retirada del respirador en el caso 3. Conclusion. La enfermedad de Pompe tiene una amplia variabilidad en la expresion clinica. La TES consigue una buena respuesta, especialmente en las formas infantiles. La supervivencia a largo plazo de las formas infantiles tratadas permitira conocer mas aspectos del curso de la enfermedad.
Assuntos
Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Idade de Início , Cardiomiopatia Hipertrófica/etiologia , Doenças em Gêmeos , Heterogeneidade Genética , Glucana 1,4-alfa-Glucosidase/deficiência , Glucana 1,4-alfa-Glucosidase/genética , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Hepatomegalia/etiologia , Humanos , Hiperlipoproteinemia Tipo II/complicações , Lactente , Deficiência Intelectual/etiologia , Masculino , Hipotonia Muscular/etiologia , Fenótipo , Transtornos Respiratórios/etiologia , Gêmeos Dizigóticos , Adulto JovemRESUMO
These guidelines provide a short summary of recommendations on Pompe disease, how to diagnose this disease, management of adult patients with this disease, follow-up of the patients and recommendations on therapy and genetic testing. Early diagnosis and management of patients with Pompe disease requires a multidisciplinary approach of several different experts. These guidelines were produced by the Division of Metabolic Diseases, Department of Internal Medicine, University Hospital Center Zagreb which is a Referral expert center for rare and metabolic diseases of the Ministry of Health of the Republic of Croatia. They were endorsed by the Croatian Society for Rare Diseases, Croatian Medical Association.These are the first guidelines published in Croatia on diagnosis, treatment and follow-up of Pompe disease.
Assuntos
Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/terapia , Adulto , Croácia , Terapia de Reposição de Enzimas , Testes Genéticos , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/genética , HumanosRESUMO
Substitution of the defective lysosomal enzyme in lysosomal storage disorders (LSDs) often elicits antibody formation towards the infused protein. Aside from Gaucher disease, antibodies often lead to infusion associated reactions and a reduced biochemical response. In Pompe disease, antibody titer is predictive of clinical outcome, but this is less apparent in other LSDs and warrants further study. Few laboratories are capable of enzyme-antibody determination: often physicians need to rely on the enzyme manufacturer for analysis. Currently, laboratories employ different antibody assays which hamper comparisons between cohorts or treatment regimens. Assay standardisation, including measurement of antibody-related enzyme inhibition, is therefore urgently needed. Successful immunomodulation has been reported in Pompe and in Gaucher disease, with variable success. Immunomodulation regimens that contain temporary depletion of B-cells (anti-CD20) are most used. Bone marrow transplantation in MPS-I results in disappearance of antibodies. No other clinical studies have been conducted in humans with immunomodulation in other LSDs.
Assuntos
Terapia de Reposição de Enzimas , Terapia Enzimática , Isoanticorpos/imunologia , Doenças por Armazenamento dos Lisossomos/tratamento farmacológico , Anticorpos/imunologia , Enzimas/imunologia , Doença de Fabry/tratamento farmacológico , Doença de Fabry/imunologia , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/imunologia , Glucana 1,4-alfa-Glucosidase/imunologia , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Glucosilceramidase/imunologia , Glucosilceramidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/imunologia , Humanos , Doenças por Armazenamento dos Lisossomos/imunologia , alfa-Galactosidase/imunologia , alfa-Galactosidase/uso terapêuticoRESUMO
Antibodies formed against the therapeutic protein are a life-threatening complication that arises during enzyme replacement therapy for Pompe disease (acid α-glucosidase deficiency; GAA). To provide an effective alternative to current practices, we investigated the capacity of anti-B-cell activating factor (BAFF) as a novel drug candidate to prevent antibody formation in a Pompe disease mouse model. A BAFF-neutralizing antibody was administered prophylactically and with maintenance doses in association with enzyme replacement therapy using recombinant human GAA in Gaa(-/-) mice. BAFF blockade delayed antibody production and increased GAA activity within tissues with protection from anaphylaxis. Anti-BAFF also resolved antibody formation during an immune response and precluded the maturation of antibody secreting cells from entering the bone marrow compartment. This treatment modality may therefore be a viable alternative for the clinical management of antibody formation for Pompe disease and has potential use against antibody formation in other protein replacement therapies.
Assuntos
Anticorpos/imunologia , Fator Ativador de Células B/antagonistas & inibidores , Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/imunologia , Animais , Modelos Animais de Doenças , Feminino , Deleção de Genes , Regulação Enzimológica da Expressão Gênica , Terapia Genética/métodos , Glucana 1,4-alfa-Glucosidase/genética , Glucana 1,4-alfa-Glucosidase/imunologia , Glucana 1,4-alfa-Glucosidase/metabolismo , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Masculino , Camundongos , Camundongos Knockout , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
Aunque el tratamiento con alglucosidasa alfa ha contribuido a mejorar el pronóstico de los pacientes con enfermedad de Pompe de inicio tardío, es necesario hacer un seguimiento periódico de la evolución de la enfermedad y de la eficacia del tratamiento. Por este motivo, un comité de expertos españoles ha elaborado una guía para el seguimiento de estos pacientes. El comité propone un modelo de pruebas de seguimiento para la enfermedad de Pompe de inicio tardío. En primer lugar, ha de valorarse el estado nutricional y la función deglutoria. En segundo lugar, y debido a la variabilidad del cuadro clínico, el comité recomienda el uso simultáneo de varias escalas que midan distintas funciones y pará- metros. De este modo, la fuerza muscular se evalúa con la escala del Medical Research Council; la función motora, con la prueba de la marcha en seis minutos y pruebas cronometradas; la discapacidad, con la escala de actividad específica de la enfermedad de Pompe construida según el análisis de Rasch; la función respiratoria, con la medida de la capacidad vital forzada y la saturación de oxígeno; y la fatiga, con la escala de intensidad de la fatiga. Por último, la seguridad y la tolerabilidad del tratamiento enzimático sustitutivo se controlan con el registro y tratamiento de los potenciales efectos adversos y la medición de los anticuerpos antialglucosidasa alfa. Se incluyen también diversas recomendaciones generales (AU)
Although treatment with alglucosidase alfa has helped improve the prognosis of patients with late-onset Pompe disease, both the development of the disease and the effectiveness of the treatment need to be monitored on a regular basis. This is the reason that has led a committee of Spanish experts to draw up a series of guidelines on how to follow up these patients. The committee proposes a model of follow-up tests for late-onset Pompe disease. First of all, the nutritional status and swallowing function must be evaluated. Second, and due to the variability of the clinical features, the committee recommends the simultaneous use of several scales to measure different functions and parameters. Thus, muscular force is assessed with the Medical Research Council scale; motor functioning, with the six-minute walk test and timed tests; disability, with the Rasch-built Pompe-specific Activity scale; respiratory functioning, with measurement of the forced vital capacity and oxygen saturation; and fatigue, with the fatigue intensity scale. Lastly, the safety and tolerability of enzyme replacement therapy are controlled by registering and treating the potential side effects and measurement of the anti-alglucosidase alfa antibodies. A number of different general recommendations are also included (AU)
Assuntos
Humanos , Adolescente , Criança , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Força Muscular , Idade de Início , Doença de Depósito de Glicogênio Tipo II/epidemiologia , Biomarcadores , Capacidade Vital , Índice de Gravidade de Doença , Doenças do Sistema Digestório/etiologia , Proteínas Recombinantes/uso terapêutico , Monitoramento de MedicamentosRESUMO
Although treatment with alglucosidase alfa has helped improve the prognosis of patients with late-onset Pompe disease, both the development of the disease and the effectiveness of the treatment need to be monitored on a regular basis. This is the reason that has led a committee of Spanish experts to draw up a series of guidelines on how to follow up these patients. The committee proposes a model of follow-up tests for late-onset Pompe disease. First of all, the nutritional status and swallowing function must be evaluated. Second, and due to the variability of the clinical features, the committee recommends the simultaneous use of several scales to measure different functions and parameters. Thus, muscular force is assessed with the Medical Research Council scale; motor functioning, with the six-minute walk test and timed tests; disability, with the Rasch-built Pompe-specific Activity scale; respiratory functioning, with measurement of the forced vital capacity and oxygen saturation; and fatigue, with the fatigue intensity scale. Lastly, the safety and tolerability of enzyme replacement therapy are controlled by registering and treating the potential side effects and measurement of the anti-alglucosidase alfa antibodies. A number of different general recommendations are also included.
TITLE: Guia para el seguimiento de la enfermedad de Pompe de inicio tardio.Aunque el tratamiento con alglucosidasa alfa ha contribuido a mejorar el pronostico de los pacientes con enfermedad de Pompe de inicio tardio, es necesario hacer un seguimiento periodico de la evolucion de la enfermedad y de la eficacia del tratamiento. Por este motivo, un comite de expertos españoles ha elaborado una guia para el seguimiento de estos pacientes. El comite propone un modelo de pruebas de seguimiento para la enfermedad de Pompe de inicio tardio. En primer lugar, ha de valorarse el estado nutricional y la funcion deglutoria. En segundo lugar, y debido a la variabilidad del cuadro clinico, el comite recomienda el uso simultaneo de varias escalas que midan distintas funciones y parametros. De este modo, la fuerza muscular se evalua con la escala del Medical Research Council; la funcion motora, con la prueba de la marcha en seis minutos y pruebas cronometradas; la discapacidad, con la escala de actividad especifica de la enfermedad de Pompe construida segun el analisis de Rasch; la funcion respiratoria, con la medida de la capacidad vital forzada y la saturacion de oxigeno; y la fatiga, con la escala de intensidad de la fatiga. Por ultimo, la seguridad y la tolerabilidad del tratamiento enzimatico sustitutivo se controlan con el registro y tratamiento de los potenciales efectos adversos y la medicion de los anticuerpos antialglucosidasa alfa. Se incluyen tambien diversas recomendaciones generales.
Assuntos
Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Adolescente , Idade de Início , Biomarcadores , Criança , Doenças do Sistema Digestório/etiologia , Avaliação da Deficiência , Gerenciamento Clínico , Monitoramento de Medicamentos , Glucana 1,4-alfa-Glucosidase/deficiência , Doença de Depósito de Glicogênio Tipo II/classificação , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/epidemiologia , Humanos , Imageamento por Ressonância Magnética , Força Muscular , Estado Nutricional , Proteínas Recombinantes/uso terapêutico , Índice de Gravidade de Doença , Capacidade VitalRESUMO
Infantile Pompe disease is a rare, metabolic disorder due to deficiency of the enzyme acid α-glucosidase that degrades lysosomal glycogen. The deficiency leads to multisystem dysfunction. Neuromuscular weakness due to metabolic myopathy is present, which predisposes children to sleep-disordered breathing. With the advent of enzyme replacement therapy (ERT), children are living longer, and there is a new natural history that is emerging. In a prior paper on our cohort of infantile Pompe disease patients, we reported a high incidence of both hypoventilation and obstructive sleep apnea (OSA). In this retrospective study, we analyzed longitudinal nocturnal polysomnography results from 10 patients with infantile-onset Pompe disease, all of which were on enzyme replacement therapy for a mean of 34.9 months at the time of follow-up study. Patients demonstrated relative stability in sleep disordered breathing, with a trend towards improvement in both OSA and central sleep apnea. ERT may help in the treatment of sleep apnea in this cohort.
Assuntos
Doença de Depósito de Glicogênio Tipo II/fisiopatologia , Terapia de Reposição de Enzimas , Feminino , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Humanos , Lactente , Masculino , Polissonografia , Estudos Retrospectivos , Síndromes da Apneia do Sono/tratamento farmacológico , Resultado do TratamentoRESUMO
Late-onset Pompe disease (LOPD) is an autosomal recessive disorder caused by deficiency of the enzyme acid glucosidase alfa (GAA). Recently, enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA) became clinically available, and is expected to modify the clinical course in LOPD of various stages. In this study, we evaluated the efficacy and adverse events of ERT for 48 weeks in Korean LOPD patients. Five Korean LOPD patients were included in the study. At baseline, clinical and laboratory features, including muscular and pulmonary function, were assessed, and rhGAA was infused every 2 weeks. Then, patients were examined at every 12-week interval for evaluation of changes in motor and pulmonary function for 48 weeks along with adverse reactions to ERT. The muscular and pulmonary function of the patients varied depending on the baseline condition of the patient after 48 weeks of ERT. However, the overall function of the patients showed stabilization of the disease rather than the improvement seen in infantile-onset Pompe disease. This is the first clinical study on ERT of Korean LOPD patients. Results of our study showed stabilization of muscular and pulmonary function in LOPD patients for 48 weeks with a favorable prognosis for patients who received early diagnosis and ambulatory patients. One of our patients developed a serious anaphylactic reaction, which necessitated the cessation of further ERT. Therefore, our study shows that early diagnosis and ERT are important in preventing further deterioration of the disease.
Assuntos
Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/terapia , Adulto , Glicemia , Criança , Creatina Quinase/sangue , Feminino , Seguimentos , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Projetos Piloto , Estudos RetrospectivosRESUMO
INTRODUCTION: Pompe disease/glycogen storage disease type II is a congenital metabolic disorder. It is an autosomal recessive disease where there is a deficiency of acid alpha-glucosidase (GAA), an enzyme required for lysosomal glycogen degradation. We describe two infantile onset cases with heterogeneous presentations. CASE REPORTS: The first case is a newborn with maintained bradycardia, a cardiologic study revealed severe biventricular hypertrophy. The second case is a 14 months old patient with motor delay and arreflexic hypotonia. Creatine kinase, lactate dehydrogenase, glutamic-oxaloacetic transaminase and glutamic-pyruvic trans aminase were high. The electromyogram showed myopathic alteration and the muscle biopsy vacuolar myopathy with glycogen accumulation. In both of them, GAA activity was decreased and the genetic exam of the GAA gene revealed heterozygous mutations already described in Pompe disease. They started enzyme replacement therapy at 1 month old and 18 months old respectively, improving the cardiomyopathy hypertrophy, motor wise however less advance was seen. At the present time, the patients are 9 months and 5 years old respectively, the last one has a Gross Motor Function Measure (GMFM) III level. CONCLUSION: GAA is the only authorized option for Pompe disease treatment; the effects observed are similar to the ones described in the literature, with excellent outcome in the hypertrophic cardiomyopathy but less effective in the skeletal muscle.
TITLE: Variabilidad en la presentacion clinica de la enfermedad de Pompe infantil: presentacion de dos casos y respuesta al tratamiento con enzima recombinante humana.Introduccion. La enfermedad de Pompe o glucogenosis tipo II es un error innato del metabolismo, de herencia autosomica recesiva, causado por un deficit de la enzima lisosomal alfa-glucosidasa acida (GAA), que ocasiona un acumulo multisistemico de glucogeno. Describimos dos casos de inicio temprano (infantil) con diferentes formas de presentacion. Casos clinicos. El primer caso se trata de un neonato que presento una bradicardia mantenida desde el nacimiento, lo que motivo el estudio cardiologico, en el que se evidencio una hipertrofia biventricular grave. El segundo caso se trata de un niño de 14 meses con retraso motor e hipotonia con arreflexia. En la analitica destacaban una creatincinasa, lactato deshidrogenasa, transaminasa glutamico oxalacetica y transaminasa glutamico piruvica elevadas. El electromiograma mostro signos de afectacion miopatica, y la biopsia muscular, una miopatia vacuolar con deposito de glucogeno. En ambos, la actividad de la GAA estaba disminuida y el analisis genetico del gen GAA evidencio que eran portadores heterocigotos de mutaciones descritas en la enfermedad de Pompe. Iniciaron tratamiento con enzima recombinante humana al mes y a los 18 meses de vida, respectivamente, con mejoria evidente de la miocardiopatia hipertrofica, aunque mas limitada a nivel motor. En la actualidad tienen, respectivamente, 9 meses y 5 años, y este ultimo presenta un nivel III de la escala GMFM (Gross Motor Function Measure). Conclusion. La GAA recombinante humana es la unica opcion terapeutica autorizada para estos pacientes. Los efectos que hemos observado son similares a los descritos en otros casos, con una excelente evolucion de la miocardiopatia hipertrofica y un efecto variable sobre la musculatura esqueletica.
Assuntos
Terapia de Reposição de Enzimas , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Bradicardia/etiologia , Deficiências do Desenvolvimento/etiologia , Progressão da Doença , Duplicação Gênica , Genótipo , Glucana 1,4-alfa-Glucosidase/genética , Doença de Depósito de Glicogênio Tipo II/sangue , Doença de Depósito de Glicogênio Tipo II/complicações , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Direita/etiologia , Lactente , Recém-Nascido , Hipotonia Muscular/etiologia , Fenótipo , Mutação Puntual , Proteínas Recombinantes/uso terapêutico , Transtornos Respiratórios/etiologia , Resultado do TratamentoRESUMO
Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.
Assuntos
Terapia de Reposição de Enzimas/economia , Glucana 1,4-alfa-Glucosidase/economia , Doença de Depósito de Glicogênio Tipo II/economia , Seguro de Serviços Farmacêuticos/economia , Doenças Raras/economia , Idade de Início , Idoso , Efeitos Psicossociais da Doença , Feminino , Glucana 1,4-alfa-Glucosidase/uso terapêutico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Guias como Assunto , Humanos , Honorários por Prescrição de Medicamentos , Doenças Raras/tratamento farmacológico , SuíçaRESUMO
Respiratory impairment is the most important prognostic factor in patients with adult-onset Pompe disease. The effect of long-term enzyme replacement therapy (ERT) on pulmonary function remains unclear.Respiratory parameters (vital capacity (VCmax); forced expiratory volume (FEV1); peak expiratory flow (PEF); and blood gas analysis) were monitored every 6 months during a treatment period of 48-77 months of ERT in six patients with genetically and biochemically confirmed adult-onset Pompe disease. Postural drop of VCmax from sitting to supine position, maximal inspiratory muscle pressure (PImax), mouth occlusion pressure after 100 ms (P0.1), and peak cough flow (PCF) were measured over a period of 12 months. Mean change to baseline were +8.8 % points for ΔVCmax, +6.2 % points for ΔFEV1, and +6.6 % points for ΔPEF after 48 months of ERT. In one patient, a decrease of respiratory parameters with later stabilization was observed under ERT until month 42, but noninvasive ventilation (NIV) had to be initiated due to nocturnal desaturation. In the final 12 months period, progressive diaphragm weakness was detected in 3/6 patients (median change in VC% drop +8 %).ERT seems to stabilize pulmonary function and may delay the requirement for ventilation in patients with late-onset Pompe disease.