Calidad de vida en pacientes con enfermedad de Pompe: estudio observacional / Quality of Life in Patients with Pompe Disease: Cross-Sectional Study

Introducción: La enfermedad de Pompe es una enfermedad genética multisistémica y rápidamente progresiva, que causa compromiso muscular (esquelético, cardíaco y liso), severa hipotonía y dificultad en la deglución. Debido a la naturaleza de la enfermedad, la calidad de vida de las personas que la padecen puede verse más afectada con respecto a la población general. Método: Se llevó a cabo un estudio descriptivo de corte transversal. Se diseñó un instrumento tipo encuesta con preguntas de caracterización sociodemográfica y referentes a la enfermedad. Para medir la calidad de vida se aplicó el Medical Outcomes Study 36-Item Short Form (SF-36) Questionnaire. Se hizo una comparación entre grupos, con nivel de significancia de 0,05. Resultados: Se obtuvieron encuestas de 27 pacientes de seis países. La edad media fue de 40,52 años, el 59 % fueron mujeres, el 51 % casados, el 63 % activos laboralmente, con edad media de diagnóstico de 30,3 años (SD = 15,557). La dimensión con menor media fue el rol físico (10,2; IC 95 % = 1,5-21,9), mientras que la de mayor media fue la salud mental (65,5; IC 95 % = 56,9-74,0). El 29,7 % (IC 95 % = 11,2-48,0) de los encuestados consideró sentirse en peores condiciones de salud que el año anterior. Discusión: Se evidencia una baja calidad de vida en pacientes con EP, en comparación con la población general, si se tienen en cuenta otros estudios que utilizan el mismo cuestionario. Conclusiones: Se evidencia una baja calidad de vida en los pacientes con enfermedad de Pompe participantes; las dimensiones asociadas con parámetros físicos fueron las de menores puntuaciones.

Introduction: Pompe disease is a rapidly progressive, multisystemic genetic disease that causes muscle involvement (skeletal, cardiac and smooth), severe hypotonia and difficulty in swallowing. Due to the nature of the disease, the quality of life may be more affected compared to the general population. Method: A descriptive cross-sectional study was carried out. A survey-type instrument was designed with questions of sociodemographic characterization and those referring to the disease. To measure Quality of Life, the Medical Outcomes Study 36-Item Short Form (SF-36) questionnaire was applied. A comparison was made between groups with a significance level of 0,05. Results: 27 surveys of patients from six countries were obtained. The mean age 40.52 years, women 59 %, married 51 %, 63 % active in employment, with a mean age of diagnosis of 30.3 years (SD = 15,557). The dimension with the lowest mean was the Physical Role (10.2; 95 % CI = 1.5 - 21.9), while the one with the highest mean was the Mental Health dimension (65.5; 95 % CI = 56.9 - 74.0). 29.7 % (95 % CI = 11.2 - 48.0) of those surveyed considered they felt in worse health conditions than the previous year. Discussion: Low quality of life is evidenced in patients with PD in comparison to the general population described in other studies using the same questionnaire. Conclusions: A low quality of life is evidenced in the study individuals where the dimensions related to the physical area were lower.

Tratamiento de la enfermedad de Pompe

Introducción: La enfermedad de Pompe es un trastorno de origen genético causado por la deficiencia de la enzima alfa-glucosidasa ácida, que se caracteriza por el acumulo anormal de glucógeno en los músculos y otros tejidos, generando una debilidad muscular progresiva, la cual debe ser diagnosticada y tratada de forma oportuna, ya que de esto dependerá el pronóstico, la sobrevida y la funcionalidad de los pacientes con esta condición. Contenidos: El abordaje multidisciplinario incluye tanto una adecuada valoración y soporte nutricional como el inicio del tratamiento modificador de enfermedad a través de la terapia de reemplazo enzimático, que a su vez dependerá de la forma de presentación, la variante genética, el perfil inicial del paciente, las condiciones especiales que puedan existir y las metas propias para cada paciente. Para garantizar un manejo adecuado, se deben realizar estudios de seguimiento con parámetros objetivos, evaluar posibles eventos secundarios e instaurar su manejo en caso de presentarlos. Conclusiones: El pronóstico de esta enfermedad dependerá del inicio oportuno del tratamiento, la implementación de pautas nutricionales adecuadas y el establecimiento del seguimiento de los parámetros clínicos y paraclínicos para cada uno de los pacientes.

Introduction: Pompe disease is a disorder of genetic origin caused by the deficiency of the acid alpha-glucosidase enzyme, which is characterized by the abnormal accumulation of glycogen in the muscles and other tissues, generating progressive muscle weakness, which must be diagnosed and treated in a timely manner, since the prognosis, survival, and functionality of patients with this condition will depend on this. Contents: The multidisciplinary approach includes both an adequate evaluation and nutritional support as well as the initiation of disease-modifying treatment through enzyme replacement therapy, which in turn will depend on the form of presentation, the genetic variant, the initial profile of the patient, the special conditions that may exist and the specific goals for each patient. To guarantee adequate management, follow-up studies must be carried out with objective parameters, evaluate possible secondary events and establish their management in case of presenting them. Conclusions: The prognosis of this disease will depend on the timely initiation of treatment, the implementation of adequate nutritional guidelines and the establishment of monitoring of clinical and paraclinical parameters for each of the patients.

Rehabilitación en la enfermedad de Pompe

Introducción: Gracias a la nueva herramienta de tratamiento con la terapia de reemplazo enzimático en la enfermedad de Pompe, se ha reducido la mortalidad a corto plazo. Contenidos: Esta herramienta permite a los pacientes mantener la independencia funcional y la adaptación de las habilidades motrices para su participación en varios aspectos de la vida diaria. Conclusiones: El abordaje de estos pacientes debe ser multidisciplinario, para dar un manejo integral a la condición clínica de cada individuo, y procurar el tratamiento de los sistemas físicos y emocionales que se pueden ver alterados con el curso de la enfermedad: osteomuscular, cardiovascular y respiratorio, deglución, lenguaje, nutrición y psicológico, incluidos los cuidados paliativos y el manejo del dolor.

Introduction: Enzyme replacement therapy in Pompe disease reduces short-term mortality. Contents: This therapy allows patients to maintain functional independence and adaptation of motor skills for patient participation in various aspects of daily life. Conclusions: The approach with this patients should be multidisciplinary to provide comprehensive management of the clinical condition of each individual seeking treatment of the physical and emotional aspects that may be altered in the disease progression: musculoskeletal, cardiovascular, respiratory, swallowing, language, nutritional and psychological; also including palliative care and pain management.

Reacciones de hipersensibilidad a alglucosidasa alfa en enfermedad de Pompe: dos casos de desensibilización exitosa / Hypersensitivity reactions to alglucosidase alfa in Pompe disease: two cases of successful desensitization

La enfermedad de Pompe es un desorden neuromuscular autosómico recesivo de baja prevalencia, causado por la deficiencia total o parcial de la enzima alfa glucosidasa ácida (GAA), cuya única terapia de reemplazo enzimático disponible es la alglucosidasa alfa recombinante. Las reacciones adversas asociadas a la infusión se presentan con frecuencia. Se reportan dos casos de desensibilización exitosa con alglucosidasa alfa utilizando protocolos con dosis meta de 20 mg/kg, administrados quincenalmente; el primero de ellos, en una niña con historia de reacción adversa grave a los 15 meses de edad, en quien se utilizó un esquema con una dilución inicial de 1/10.000.000 de 28 pasos y una duración total de 13,1 horas. En el segundo caso, la paciente tuvo una reacción adversa grave a los 4 años de edad, se utilizó el protocolo de 22 pasos, concentración inicial de 1/1.000.000 y duración total de 7,2 horas. Se concluye que en pacientes con enfermedad de Pompe que presentan reacciones adversas durante la terapia de reemplazo enzimático, es posible realizar la desensibilización cada dos semanas con la dosis estándar de 20 mg/kg de forma exitosa, y progresivamente lograr la administración usual de la infusión

Pompe disease is a low prevalence autosomal recessive neuromuscular disorder, caused by total or partial deficiency of the acid alpha-glucosidase (GAA) enzyme, and its only available enzyme replacement therapy is the recombinant alglucosidase alfa. Infusion-associated adverse reactions occur frequently. Two cases of successful desensitization with alglucosidase alfa using protocols with a target dose of 20 mg/kg administered biweekly are reported; the first was a girl who had a history of serious adverse reaction at the age of 15 months, and undergone to a scheme with an initial dilution of 1/10,000,000 with 28 steps and a total duration of 13.1 hours. In the second case, the patient had a severe adverse reaction at the age of 4 years, a 22-step protocol was used with an initial concentration of 1/1,000,000 and a total duration of 7.2 hours. In conclusion, in patients with Pompe disease who presented adverse reactions during enzyme replacement therapy with alglucosidase alfa, it is possible to perform desensitization every two weeks with the standard dose of 20 mg/kg, and progressively achieve the usual administration of the infusion

Equipe de enfermagem no cuidado à criança com doença de Pompe em terapia intensiva / Nursing team in care for children with Pompe disease in intensive care / Equipo de enfermería en la atención de niños con enfermedad de Pompe en cuidados intensivos

Objetivo: investigar o conhecimento e práticas da equipe de enfermagem em relação ao cuidado à criança com Doença de Pompe em terapia intensiva. Método: trata-se de um estudo descritivo com abordagem qualitativa. A coleta de dados foi realizada com entrevista semiestruturada com enfermeiras e técnicas em enfermagem que atuavam na Unidade de Terapia Intensiva Neonatal de um hospital do Rio Grande do Sul, após aprovação pelo Comitê de Ética em Pesquisa. Os dados foram analisados pela análise de conteúdo. Resultados: as profissionais enfatizaram experiências que superam procedimentos técnicos, na busca de fornecer um cuidado integral qualificado e seguro, para proporcionar vivências mais próximas de um lar para a criança e familiares. Conclusão: a equipe de enfermagem possui conhecimentos para o cuidado e atua de forma multiprofissional. Conclui-se que estudos relacionados às doenças raras oferecem subsídios para qualificar o cuidado de enfermagem.

Objective: to investigate nursing team knowledge and practices regarding care for children with Pompe disease in intensive care. Method: in this qualitative, descriptive study, data were collected by semi-structured interviews of nurses and nursing technicians working in the neonatal intensive care unit of a hospital in Rio Grande do Sul, after ethics committee approval. Data were subjected to content analysis. Result: the nurses emphasized experiences that go beyond technical procedures, in the endeavor to provide safe and qualified comprehensive care in order to provide experiences closer to a home for the children and their families. Conclusion: the nursing team was knowledgeable about care and worked in multidisciplinary manner. It was concluded that studies relating to rare disease offer input to inform nursing care.

Objetivo: investigar el conocimiento y las prácticas del equipo de enfermería sobre el cuidado de niños con enfermedad de Pompe en cuidados intensivos. Método: en este estudio cualitativo descriptivo, los datos fueron recolectados mediante entrevistas semiestructuradas a enfermeras y técnicos de enfermería que laboran en la unidad de cuidados intensivos neonatales de un hospital de Rio Grande do Sul, previa aprobación del comité de ética. Los datos se sometieron a análisis de contenido. Resultado: las enfermeras destacaron experiencias que van más allá de los procedimientos técnicos, en el afán de brindar una atención integral segura y calificada con el fin de brindar experiencias más cercanas a un hogar para los niños y sus familias. Conclusión: el equipo de enfermería tenía conocimiento del cuidado y trabajaba de manera multidisciplinar. Se concluyó que los estudios relacionados con las enfermedades raras ofrecen información para informar la atención de enfermería.

Functional assessment using short tests in a patient with pompe disease receiving enzyme replacement therapy: case report

ABSTRACT Introduction: Pompe disease is characterized by the deficiency of the acid alfa glucosidase enzyme, which leads to a glycogen accumulation mainly in cardiac and skeletal muscles. Its onset may be early or late; the late form is more difficult to handle given the variety of presentations. Enzyme replacement therapy has shown to improve gross motor function and lung function in patients. Case description: Female patient who presented chronic quadriparesis. She was diagnosed with Pompe disease, which required enzyme replacement therapy that helped improve the symptoms, which was evident with the performance of rapid functional evaluation tests. Discussion: Enzyme replacement therapy in Pompe disease modifies the natural history of the disease. A brief review of the literature about the functional tests that can be used to assess a patient with this disorder is presented. Conclusion: The 10-meter walk test, one-leg stance test, cervical flexion in supine position, five times sit to stand test, and coin rotation task are useful for clinical evaluation in patients with Pompe disease receiving enzyme replacement therapy.

RESUMEN Introducción. La enfermedad de Pompe se caracteriza por una alteración de la enzima alfa glucosidasa ácida lisosomal que produce acumulación de glicógeno, principalmente en el músculo esquelético y cardiaco. Se presentan formas de inicio temprano y tardío, esta última de más difícil manejo dada la múltiple variedad de presentaciones. La terapia de reemplazo enzimático ha demostrado mejorar la función motora gruesa y pulmonar de los pacientes con esta patología. Presentación del caso. Paciente femenino quien presentó cuadro crónico de cuadriparesia y a quien se le documentó enfermedad de Pompe, por lo que requirió terapia de reemplazo enzimático con mejoría franca de sintomatología, objetivizada con la realización de pruebas rápidas de evaluación funcional. Discusión. La terapia de reemplazo enzimático en la enfermedad de Pompe modifica la historia natural de la enfermedad. Se realiza una breve revisión de la literatura acerca de las pruebas funcionales que pueden ser utilizadas dentro de la evaluación del paciente con este trastorno. Conclusiones. La prueba de caminata de 10m, de equilibrio monopodal, de flexión cervical en supino, de levantarse-sentarse cinco veces y de la moneda resultan útiles para la evaluación clínica de los pacientes con enfermedad de Pompe en terapia de remplazo enzimático.

Pseudodeficiency alleles affect the newborn screening of glycogen storage disease typeⅡ / 中华检验医学杂志

Objective@#To investigate the effect of pseudodeficiency alleles on the newborn screening of glycogen storage disease type Ⅱ(GSDⅡ) by using afluorometric enzymatic assay to determine acid α-glucosidase (GAA) activity in dried blood spot (DBS).@*Methods@#A total of 30 507 newborns′ DBSs, obtained from Newborn Screening Center of Xinhua Hospital Shanghai Jiao Tong University School of Medicine from May to December 2017, were screened for GSD Ⅱ by fluorometric enzymatic assay of GAA activity. The suspected positive DBSs after the first and second screening were directly analyzed by Sanger sequencing of GAA to confirm the diagnosis. Retrospective analysis of 3 172 controls without GSDⅡand 36 GSD Ⅱ patients were conducted to investigate the carrier status of pseudodeficiency alleles. Statistical analysis of frequency of pseudodeficiency alleles were carried out by Chi-square test or Fisher exact probability test.@*Results@#GAA activity of 30 507 newborns showed a positively skewed distribution.Twenty-nine cases of newborns, suspected to be GSDⅡwere confirmed to be normal with genetic analysis of the original DBSs. Among the 29 suspected positive cases, 24 cases were homozygous for pseudodeficiency alleles c.[1726A/A; 2065A/A], and the other 5 cases were c.[1726G/A; 2065G/A] heterozygote. The frequency of c.1726G>Ahomozygote in 3 172 non-GSD Ⅱcontrols was 2.08% (66/3 172), and c.1726G>A homozygote occurred in allelic conjunction with c.2065G>Ahomozygote. Frequency of c.[1726A; 2065A] haplotype in 3 172 controls was 3.2%(206/6 344). Frequency of c.[1726A/A; 2065A/A] homozygote in 36 GSDⅡpatients (16.67%, 6/36) was significantly higher than that in non-GSD Ⅱcontrols(2.08%, 66/3 172) (χ2=34.517, P<0.001).@*Conclusions@#Pseudodeficiency alleles show a high frequency in Chinese, which leads to a high false positive rate in the newborns screening of GSDⅡ.The afterword genetic analysis of the original DBS after the GAA activity screening could reduce the effect of pseudodeficiency alleles on the newborns screening of GSDⅡ.

Pseudodeficiency alleles affect the newborn screening of glycogen storage disease typeⅡ / 中华检验医学杂志

Objective To investigate the effect of pseudodeficiency alleles on the newborn screening of glycogen storage disease typeⅡ(GSDⅡ) by using afluorometric enzymatic assay to determine acidα-glucosidase (GAA) activity in dried blood spot (DBS). Methods A total of 30507 newborns' DBSs, obtained from Newborn Screening Center of Xinhua Hospital Shanghai Jiao Tong University School of Medicine from May to December 2017, were screened for GSDⅡby fluorometric enzymatic assay of GAA activity. The suspected positive DBSs after the first and second screening were directly analyzed by Sanger sequencing of GAA to confirm the diagnosis. Retrospective analysis of 3172 controls without GSDⅡand 36 GSDⅡpatients were conducted to investigate the carrier status of pseudodeficiency alleles. Statistical analysis of frequency of pseudodeficiency alleles were carried out by Chi-square test or Fisher exact probability test. Results GAA activity of 30507 newborns showed a positively skewed distribution. Twenty-nine cases of newborns, suspected to be GSDⅡwere confirmed to be normal with genetic analysis of the original DBSs. Among the 29 suspected positive cases, 24 cases were homozygous for pseudodeficiency alleles c. [1726A/A; 2065A/A], and the other 5 cases were c. [1726G/A; 2065G/A] heterozygote. The frequency of c. 1726G>Ahomozygote in 3172 non-GSDⅡcontrols was 2.08％(66/3172), and c. 1726G>A homozygote occurred in allelic conjunction with c. 2065G>Ahomozygote. Frequency of c. [1726A; 2065A] haplotype in 3172 controls was 3.2％(206/6344). Frequency of c. [1726A/A;2065A/A] homozygote in 36 GSDⅡpatients (16.67％, 6/36) was significantly higher than that in non-GSDⅡcontrols(2.08％, 66/3172) (χ2=34.517, P<0.001). Conclusions Pseudodeficiency alleles show a high frequency in Chinese, which leads to a high false positive rate in the newborns screening of GSDⅡ.The afterword genetic analysis of the original DBS after the GAA activity screening could reduce the effect of pseudodeficiency alleles on the newborns screening of GSDⅡ.

Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation? / Doença de Pompe de início tardio: qual é a prevalência na apresentação de fraqueza muscular de cinturas?

ABSTRACT Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with "unexplained" limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an "unexplained" limb-girdle weakness even without vacuolar myopathy in muscle biopsy.

RESUMO A doença de Pompe é uma doença hereditária causada pela deficiência da enzima alfa-glicosidase ácida (GAA). Estudo observacional foi realizado, em um único centro, para determinar a prevalência da doença de Pompe de início tardio (LOPD) em uma população brasileira de alto risco, usando teste em gota seca (DBS) como ferramenta principal de triagem para detectar a deficiência da GAA. DBS foi coletado para avaliar a atividade da GAA em 24 pacientes com fraqueza muscular de cinturas "não explicada" sem miopatia vacuolar na biópsia muscular. As amostras com atividade enzimática reduzida foram também submetidas a análise de mutações no gene GAA. Dos 24 pacientes com DBS, baixa atividade da enzima GAA (NaG/AaGIA: 40.42; %INH: 87.22%) foi encontrada em um paciente (4.2%). Nessa paciente, a análise genética confirmou duas mutações em heterozigose composta no gene GAA (c.-32-13T > G/p.Arg854Ter). Nossos resultados confirmam que LOPD deve ser investigada quando a manifestação clínica é uma fraqueza muscular de cinturas "não explicada", mesmo na ausência de miopatia vacuolar na biópsia muscular.

Assistência de enfermagem à criança com doença de Pompe: estudo de caso / Nursing care for children with Pompe disease: a case study / Cuidados de enfermería del niño con enfermedad de Pompe: estudio de caso

OBJETIVO: identificar diagnósticos, intervenções e resultados esperados de enfermagem à criança com doença de Pompe, utilizando a Classificação Internacional para a Prática de Enfermagem® 2017. MÉTODO: estudo de caso realizado em dezembro de 2017, com uma mãe de criança com doença de Pompe. RESULTADOS: elencaram-se dezessete diagnósticos de enfermagem, distribuídos entre as demandas de cuidados medicamentosos, tecnológicos, habituais modificados, de desenvolvimento e familiares. DISCUSSÃO: os diagnósticos de enfermagem relacionaram-se ao tratamento e às complicações apresentadas pela criança em decorrência da doença de Pompe, acrescidas pelas necessidades familiares para desenvolver os cuidados no domicílio. CONCLUSÃO: verificou-se que a classificação das práticas de enfermagem permitiu criar possibilidades mais especializadas para elaborar e executar um plano de cuidados com base nas reais necessidades desta criança, podendo existir generalização para os portadores da mesma enfermidade.

AIM: to identify diagnoses, interventions and expected nursing outcomes for the child with Pompe disease using the International Classification for Nursing Practice® 2017. METHOD: case study conducted in December 2017, with a mother of child with Pompe disease. RESULTS: seventeen nursing diagnoses were presented, distributed among the demands of medicated, technological, habitual, modified, developmental, and family care. DISCUSSION: the nursing diagnoses were related to the treatment and complications presented by the child as a result of Pompe disease, increased by the family needs to develop the care at home. CONCLUSION: it was verified that the classification of the nursing practices allowed creating more specialized possibilities to elaborate and execute a care plan based on the real needs of this child, allowing the possibility of generalization for the patients with the same disease

OBJETIVO: identificar diagnósticos, intervenciones y resultados esperados de enfermería en el niño con enfermedad de Pompe, utilizando la Clasificación Internacional para la Práctica de Enfermería® 2017. MÉTODO: estudio de caso realizado en diciembre de 2017, con una madre de un niño con enfermedad de Pompe. RESULTADOS: se relacionaron diecisiete diagnósticos de enfermería, distribuidos entre las demandas de cuidados medicamentosos, tecnológicos, habituales modificados, de desarrollo y familiares. DISCUSIÓN: los diagnósticos de enfermería se relacionaron al tratamiento y a las complicaciones presentadas por el niño derivados de la enfermedad de Pompe, acrecidas por las necesidades familiares para desarrollar los cuidados en el domicilio. CONCLUSIÓN: se verificó que la Clasificación de las prácticas de enfermería permitió crear posibilidades más especializadas para elaborar y ejecutar un plan de cuidados con base en las reales necesidades del niño, pudiendo generalizarse para los portadores de la misma enfermedad

Identification of Seven Novel Mutations in the Acid Alpha-glucosidase Gene in Five Chinese Patients with Late-onset Pompe Disease / 中华医学杂志(英文版)

<p><b>Background</b>Pompe disease is a rare lysosomal glycogen storage disorder linked to the acid alpha-glucosidase gene (GAA). A wide clinical and genetic variability exists between patients from different ethnic populations, and the genotype-phenotype correlations are still not well understood. The aim of this study was to report the clinicopathological and genetic characteristics of five Chinese patients with late-onset Pompe disease (LOPD) who carried novel GAA gene mutations.</p><p><b>Methods</b>Clinical and pathological data of patients diagnosed with glycogen storage disease at our institution from April 1986 to August 2017 were collected, and next-generation sequencing of frozen muscle specimens was conducted.</p><p><b>Results</b>Of the five patients included in the study, the median disease onset age was 13 years, with a median 5 years delay in diagnosis. The patients mainly manifested as progressive weakness in the proximal and axial muscles, while one patient developed respiratory insufficiency that required artificial ventilation. In muscle biopsies, vacuoles with variable sizes and shapes appeared inside muscle fibers, and they stained positive for both periodic acid-Schiff and acid phosphatase staining. Ten GAA gene mutations, including seven novel ones (c.796C>A, c.1057C>T, c.1201C>A, c.1780C>T, c.1799G>C, c.2051C>A, c.2235dupG), were identified by genetic tests.</p><p><b>Conclusions</b>The seven novel GAA gene mutations revealed in this study broaden the genetic spectrum of LOPD and highlight the genetic heterogeneity in Chinese LOPD patients.</p>

Respiratory manifestations in late-onset Pompe disease: a case series conducted in Brazil / Manifestações respiratórias na doença de Pompe de início tardio: uma série de casos no Brasil

ABSTRACT Objective: To describe respiratory function in a series of patients with late-onset Pompe disease after the definitive diagnosis and before enzyme replacement therapy. Methods: This was a cross-sectional study involving patients with a definitive molecular diagnosis of late-onset Pompe disease. The data analyzed included age at symptom onset; age at definitive diagnosis; type of initial symptoms; time from symptom onset to diagnosis; FVC in the sitting and supine positions; six-minute walk distance; and locomotor ability. Analyses were carried out using frequencies, medians, minimum values, and maximum values. Results: Six patients were included in the study. The median age at symptom onset was 15 years (range, 13-50 years), and the median age at diagnosis was 39.5 years (range, 10-64 years). The median time from symptom onset to diagnosis was 8 years (range, 0-45 years). In all cases, the initial manifestation of the disease had been motor weakness. The median FVC in percentage of the predicted value (FVC%) in the sitting and supine positions was 71.0% (range, 22.9-104.6%) and 58.0% (range, 10.9-106.9%), respectively. The median ΔFVC% was 24.5% (range, −4.59 to 52.40%).The median six-minute walk distance was 391.7 m (range, 97-702 m) . Conclusions: In this case series, the time from symptom onset to diagnosis was long. Although respiratory signs or symptoms were not the initial manifestations of the disease, 66.7% of the patients showed reduced FVC% in the sitting and supine positions at diagnosis.

RESUMO Objetivo: Descrever a função respiratória em uma série de pacientes com doença de Pompe de início tardio após o diagnóstico definitivo e antes do início do tratamento através de terapia de reposição enzimática. Métodos: Estudo transversal em pacientes com diagnóstico molecular de doença de Pompe de início tardio. As informações analisadas incluíram idade ao início dos sintomas e ao diagnóstico, tipo de sintoma inicial, tempo entre início dos sintomas e diagnóstico, CVF em posição sentada e supina, distância percorrida no teste de caminhada de seis minutos e capacidade de locomoção. Análises por frequência, mediana, valor mínimo e valor máximo foram realizadas. Resultados: Foram incluídos seis pacientes no estudo. A mediana de idade ao início dos sintomas foi de 15 anos (variação, 13-50 anos) e a de idade ao diagnóstico foi de 39,5 anos (variação, 10-63 anos). A mediana de tempo entre o início dos sintomas e a confirmação diagnóstica foi de 8 anos (variação, 0-45 anos). A manifestação inicial da doença foi de sintomas motores de fraqueza muscular em todos os casos. As medianas da CVF em porcentagem do previsto (CVF%) em posição sentada, em supino e ΔCVF% foram de, respectivamente, 71,0% (variação, 22,9-104,6%), 58,0% (variação, 10,9-106,9%) e 24,5% (−4,59 a 52,40%). A mediana da distância percorrida no teste de caminhada de seis minutos foi de 391,7 m (variação, 97-702 m) . Conclusões: Nesta série, o tempo entre o início dos sintomas e o diagnóstico foi longo. A manifestação inicial da doença não foi de sinais ou sintomas respiratórios, embora 66,7% dos pacientes apresentassem redução da CVF% em posição sentada e em supino no momento do diagnóstico.

Guidelines for the diagnosis, treatment and clinical monitoring of patients with juvenile and adult Pompe disease / Diretriz para o diagnóstico, tratamento e acompanhamento clínico de pacientes com doença de Pompe juvenil e do adulto

ABSTRACT Pompe disease (PD) is a potentially lethal illness involving irreversible muscle damage resulting from glycogen storage in muscle fiber and activation of autophagic pathways. A promising therapeutic perspective for PD is enzyme replacement therapy (ERT) with the human recombinant enzyme acid alpha-glucosidase (Myozyme®). The need to organize a diagnostic flowchart, systematize clinical follow-up, and establish new therapeutic recommendations has become vital, as ERT ensures greater patient longevity. A task force of experienced clinicians outlined a protocol for diagnosis, monitoring, treatment, genetic counseling, and rehabilitation for PD patients. The study was conducted under the coordination of REBREPOM, the Brazilian Network for Studies of PD. The meeting of these experts took place in October 2013, at L’Hotel Port Bay in São Paulo, Brazil. In August 2014, the text was reassessed and updated. Given the rarity of PD and limited high-impact publications, experts submitted their views.

RESUMO A doença de Pompe (DP) é uma doença grave, potencialmente letal, devida ao depósito de glicogênio na fibra muscular e ativação de vias autofágicas. Tratamento promissor para a DP é a reposição enzimática com a enzima recombinante humana alfa-glicosidase ácida (rhAGA -Myozyme®). A necessidade de organizar uma propedêutica diagnóstica, sistematizar o seguimento clínico e sedimentar as novas recomendações terapêuticas tornaram-se vitais à medida que o tratamento permite uma maior longevidade aos pacientes. Uma força-tarefa de clínicos experientes no manejo da DP foi constituída para elaborar um protocolo para o diagnóstico, acompanhamento clínico, tratamento, aconselhamento genético, entre outras considerações voltadas ao paciente adulto. O estudo foi realizado sob a coordenação da Rede Brasileira de Estudos da Doença de Pompe (REBREPOM). Diante da raridade da DP e escassez de trabalhos de alto impacto de evidência científica, os especialistas emitiram suas opiniões.

Muscle biopsy in Pompe disease / Biópsia muscular na doença de Pompe

Pompe disease (PD) can be diagnosed by measuring alpha-glucosidase levels or by identifying mutations in the gene enzyme. Muscle biopsies can aid diagnosis in doubtful cases. Methods: A review of muscle biopsy from 19 cases of PD (infantile, 6 cases; childhood, 4 cases; and juvenile/adult, 9 cases). Results: Vacuoles with or without glycogen storage were found in 18 cases. All cases had increased acid phosphatase activity. The vacuole frequency varied (almost all fibers in the infantile form to only a few in the juvenile/adult form). Atrophy of type 1 and 2 fibers was frequent in all forms. Atrophic angular fibers in the NADH-tetrazolium reductase and nonspecific esterase activity were observed in 4/9 of the juvenile/adult cases. Conclusion: Increased acid phosphatase activity and vacuoles were the primary findings. Most vacuoles were filled with glycogen, and the adult form of the disease had fewer fibers with vacuoles than the infantile or childhood forms. .

O diagnóstico da doença de Pompe (PD) pode ser feito pela dosagem da enzima alfa-glicosidase ou pela mutação do seu gene codificador. A biópsia muscular pode ajudar em casos duvidosos. Métodos: Revisão das biópsias musculares de 19 casos de PD (forma infantil, 6 casos; infantil tardia, 4; e juvenil/adulto, 9). Resultados: Encontrados vacúolos em 18 casos, com ou sem depósito de glicogênio. Todos mostraram aumento da fosfatase ácida. Os vacúolos estavam presentes na maioria das fibras nas formas infantis, menos frequentes nas formas juvenil e mais raros nas formas do adulto. A atrofia de fibras dos tipos 1 e 2 ocorreram em todas as formas. Fibras atróficas na NADH-tetrazolium redutase e esterase não específica foram observadas em 4/9 das formas infantil tardia/adulta. Conclusões: Os dados mais frequentes foram vacúolos, preenchidos por glicogênio com atividade aumentada da fosfatase ácida. A forma adulta apresenta menor número de vacúolos que as formas infantil e infantil tardia. .

Revisão sistemática das escalas utilizadas para avaliação funcional na doença de Pompe / Systematic review of functional assessment scales in Pompe disease / Revisión sistemática de las escalas utilizadas para evaluación funcional en la enfermedad de Pompe

Identificar as escalas utilizadas para avaliação funcional na doença de Pompe (DP) e descrever seu nível de evidência e recomendação. FONTES DE DADOS: Revisão sistemática sobre as escalas de avaliação funcional na DP. Pesquisa realizada nos bancos de dados Medline, Lilacs, Registro Cochrane de Ensaios Controlados Central (CCTR) e SciELO com artigos (exceto artigos de revisão) publicados entre 2000 e 2010. As palavras-chave utilizadas nos idiomas português e inglês foram: doença de depósito de glicogênio tipo II, atividades cotidianas, avaliação. Os artigos foram classificados em nível de evidência e recomendação. SÍNTESE DOS DADOS: Foram incluídos 14 estudos que avaliaram desde recém-nascidos a adultos (amostra total=449). Foram encontradas as seguintes escalas na literatura: Pediatric Evaluation of Disability Inventory (PEDI) e sua forma adaptada para DP (Pompe-PEDI), Alberta Infant Motor Scale (AIMS), Rotterdam Handiscap Scale (RHS), Functional Independence Measure (FIM), Gross Motor Function Measure (GMFM) e Peabody Developmental Motor Scales (PDMS-II). A maioria dos estudos apresentou nível de evidência III, por serem não randomizados. Grau de recomendação das escalas: C para AIMS e Pompe-PEDI; D para GMFM e PDMS-II; E para RHS e FIM. CONCLUSÕES: A maioria das escalas utilizadas para avaliação funcional na DP apresenta baixo nível de evidência e recomendação. As que apresentam melhor grau de recomendação (C) são as escalas AIMS e Pompe-PEDI aplicadas em Pediatria.

To identify functional assessment scales used in Pompe disease (PD) and to describe their levels of evidence and grades of recommendation. DATA SOURCE: Systematic review of the functional assessment scales used in PD. Review conducted in the databases Medline, Lilacs, Cochrane Central Register of Controlled Trials (CCTR), and SciELO including articles (except review articles) published between 2000 and 2010. The key-words used in Portuguese and English were: glycogen storage disease type II, activities of daily living, assessment. The articles were classified according to their level of evidence and grade of recommendations. DATA SYNTHESIS: 14 studies assessing patients ranging from newborns to adults were included in the present review (total sample=449). The scales found in the literature were: Pediatric Evaluation of Disability Inventory (PEDI) and its adapted version for PD (Pompe-PEDI), Alberta Infant Motor Scale (AIMS), Rotterdam Handicap Scale (RHS), Functional Independence Measure (FIM), Gross Motor Function Measure (GMFM), and Peabody Developmental Motor Scales (PDMS-II). Most studies had level of evidence III because they were non-randomized studies. The grades of recommendation of the scales were C for AIMS and Pompe-PEDI, D for GMFM and PDMS-II; and E for RHS and FIM. CONCLUSIONS: Most functional assessment scales used in PD show low level of evidence and grade of recommendation. The scales showing the highest grade of recommendation (C) were the AIMS and Pompe-PEDI used in Pediatrics.

Identificar las escalas utilizadas para evaluación funcional en la enfermedad de Pompe (EP) y describir su nivel de evidencia y recomendación. FUENTES DE DATOS: Revisión sistemática sobre las escalas de evaluación funcional en la EP. Investigaciones realizadas en las bases de datos Medline, Lilacs, Registro Cochrane de Ensayos Controlados Central (CCTR) y SciELO con artículos (excepto artículos de revisión) publicados entre 2000 y 2010. Las palabras clave utilizadas en los idiomas portugués e inglés fueron: enfermedad de depósito de glucógeno tipo II, actividades cotidianas, evaluación. Los artículos fueron clasificados en nivel de evidencia y recomendación según Cook et al. SÍNTESIS DE LOS DATOS: Se incluyeron 14 estudios que evaluaron desde recién-nacidos a adultos (muestra total=449). Se encontraron las siguientes escalas en la literatura: Pediatric Evaluation of Disability Inventory (PEDI) y su forma adaptada para 1DP (Pompe-PEDI), Alberta Infant Motor Scale (AIMS), Rotterdam Handiscap Scale (RHS), Functional Independence Measure (FIM), Gross Motor Function Measure (GMFM) y Peabody Developmental Motor Scales (PDMS-II). La mayoría de los estudios presentó nivel de evidencia III, por tratarse de estudios no randomizados. Grado de recomendación de las escalas: C para AIMS y Pompe-PEDI; D para GMFM y PDMS-II; E para RHS y FIM. CONCLUSIONES: La mayoría de las escalas utilizadas para evaluación funcional en la EP presenta bajo nivel de evidencia y recomendación. Las que presentan mejor grado de recomendación (C) son las escalas AIMS y Pompe-PEDI aplicadas en Pediatría.

The cost-effectiveness of enzyme replacement therapy (ERT) for the infantile form of Pompe disease: comparing a high-income country's approach (England) to that of a middle-income one (Colombia) / Costo-Efectividad de la terapia del reemplazo enzimático (TRE) para la forma infantil de la enfermedad Pompe: perspectiva económica comparativa de un país ingresos altos (Inglaterra) vs uno de ingresos medios (Colombia)

Objectives Determining the cost-effectiveness of enzyme replacement therapy (ERT) for the classical infantile form of Pompe disease (complete acid a-glucosidase deficiency-related) in two different settings: England and Colombia. Pompe disease is very rare (1:40,000 births incidence). Methods A literature review was made and historic databases searched for National Health Service (NHS) reimbursed costs in England and by health insurers in Colombia; expert opinion was elicited. Two Markov models were constructed for comparing both countries; alive with symptoms and dead were the transition states used. Patients aged < 6 months receiving ERT were assumed to have 75 % survival rate and better health-related quality of life (HR-QoL) compared to those without treatment (0.700 HR- QoL using the EQ-5D scale). Results The incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained was £234,307.7 for England and £109,991 for Colombia. Uncertainty about Anal HR-QoL with ERT, disease progression and cost from palliative care had the biggest impact on the ICER in both models. If ERT costs were reduced to 10,000 times per dose and HR-QoL was 0.750-0.820 ICER, then £165,000 could be attainable for England and £65,000 for Colombia. Transaction costs per case in Colombia were high. Conclusions ERT was more effective than no ERT in treating infantile Pompe disease, but high levels of uncertainty still remain about survival and progression rates and QoL in the long-run. ICERs were high compared to CE thresholds. Manufacturers' ERT costs and monopoly had a major impact on Anal CEA results.

Objetivo Determinar la costo-efectividad de la TRE como indicación para la forma clásica de la enfermedad de Pompe (relacionada con deficiencia completa de a-glucosidasa ácida) desde dos perspectivas, Inglaterra y Colombia. La enfermedad de Pompe es muy rara (incidencia 1:40000 nacimientos). Métodos Revisiónbibliográfica y bases de datos para calcular costosasociados al tratamiento en NHS en Inglaterra, aseguradores de salud en Colombia y opinión de expertos. Dos procesos de Markov fueron construidos para comparar entre países; los estados de transición fueron: vivo sintomático y fallecido. En pacientes de < 6 meses de edad con TRE, se asume un incremento de 75 % de sobrevida y mejor calidad de vida comparada con los que no reciben TRE (HR-QoL 0.700 usando EQ-5D). Resultados Inglaterra alcanzo ICER por QALY ganado £234307, 7 y Colombia £109991. Incertidumbre sobre HR-QoL con TRE, progresión de enfermedad y costo de cuidado paliativo tuvieron el mayor impacto en losICERs;sí el costo de TREfuera 10.000 menor y la HR-QoLalcanzara 0.750-0.820 ICERs de £165000y £65000 podrían obtenerse para Inglaterra y Colombia respectivamente. Los costos transaccionales en Colombia son representativos. Conclusiones La TRE es más efectiva que no dar tratamiento, pero incertidumbre sobre tasas desobrevida, progresión y HR-QoLpermanecen en el largo plazo. Los ICERsson altos comparados a los umbrales establecidos de CE. Los costos de TRE y el podermonopolístico del fabricante tienen un impacto importante en los resultados Anales de CEA. Investigación adicional debe realizarsea futuro.

Homozygotic intronic GAA mutation in three siblings with late-onset Pompe's disease / Mutação homozigótica intrônica no gene GAA em três irmãos com doença de Pompe de início tardio

Pompe's disease (PD) is a metabolic myopathy caused by the accumulation of lysosomal glycogen, secondary to acid α-glucosidase (GAA) enzyme deficiency. Childhood and late-onset forms are described, differing by the age of onset and symptoms. In this study were analyzed affected siblings with Pompe's disease (PD) and their distinct clinical and pathological presentations. METHOD: Diagnosis was performed by the clinical presentation of limb-girdle dystrophies and respiratory compromise. Confirmatory diagnoses were conducted by muscle biopsy, GAA activity measurement and by GAA gene genotyping. RESULTS: The findings suggested muscular involvement due to GAA deficiency. GAA genotyping showed they are homozygous for the c.-32-3C>A mutation. CONCLUSION: Herein we reported a family where three out of five siblings were diagnosed with late-onset PD, although it is a rare metabolic disease inherited in an autossomal recessive manner. We emphasize the importance of including this presentation within the differential diagnoses of the limb-girdle dystrophies once enzyme replacement therapy is available.

A doença de Pompe (DP) é uma miopatia originada do acúmulo lisossomal de glicogênio, devido à deficiência da enzima α-glicosidase ácida (GAA), sendo descritas formas de inicio precoce e tardio. Neste estudo analisamos retrospectivamente o perfil clinico e patológico de 3 irmãos portadores de doença de Pompe de inicio tardio. MÉTODO: O diagnóstico foi realizado mediante apresentação clinica de distrofia de cinturas associado a comprometimento respiratório, sendo confirmado por biópsia muscular e análise da atividade e genotipagem da GAA. RESULTADOS: Os exames clínicos e laboratoriais demonstram envolvimento muscular devido à deficiência da GAA, com uma mutação c.-32-3C>A em homozigose. CONCLUSÃO: Relatamos os aspectos clínicos e laboratoriais de 3 irmãos afetados por doença de Pompe de início tardio. Enfatizamos a importância de incluir esta patologia no diagnóstico diferencial das distrofias de cinturas, uma vez que para esta patologia específica existe a possibilidade terapêutica através de reposição enzimática.

Relato do primeiro paciente brasileiro com a forma infantil da doença de Pompe tratado com alfa-glicosidase recombinante humana / Report of the first Brazilian infantile Pompe disease patient to be treated with recombinant human acid alpha-glucosidase

Objetivo: Relatar o primeiro caso de forma infantil da doença de Pompe tratado no Brasil. Descrição: Trata-se de doença de depósito lisossomal que se caracteriza por defeitos da enzima alfa-glicosidase ácida, com acúmulo intracelular de glicogênio, principalmente nos músculos. São descritas a forma infantil e tardia. Desde 2006, está disponível tratamento com enzima recombinante humana. Descreve-se o primeiro caso de forma infantil da doença tratado no Brasil. Trata-se de menina com 2,5 meses de idade e progressão rápida da doença, com perda dos movimentos dos membros, miocardiopatia hipertrófica e insuficiência respiratória aos 7 meses de idade. Após 10 meses de tratamento, apresentou boa resposta clínica, com remissão da insuficiência respiratória, recuperação parcial dos movimentos dos membros e melhora importante do quadro cardiológico. Comentários: Apesar de pouco freqüente, a forma infantil da doença de Pompe é letal. A disponibilidade de tratamento eficaz aumenta a necessidade de conhecimento e diagnóstico precoce da doença.

Objective: To describe the first case of infantile Pompe disease to be treated in Brazil. Description: Pompe disease is a glycogen storage disease related to defects in the acid alpha-glucosidase enzyme, leading to an intracellular accumulation of glycogen, mainly in muscles. Two forms are described: infantile and juvenile. Since 2006, treatment with recombinant human acid alpha-glucosidase has been available. This article describes the first case of infantile Pompe disease treated in Brazil. A girl presented at 2.5 months of age with rapid disease progression, exhibiting severe hypotonia, loss of movements in both upper and lower limbs and hypertrophic cardiomyopathy, progressing to respiratory failure by the age of 7 months. After 10 months of treatment, she exhibited a good clinical response, with remission of the respiratory failure, partial recovery of arm and leg movements and improvement of cardiologic condition. Comments: Despite its low incidence, infantile Pompe disease is lethal. The availability of an effective treatment has created an urgent need to improve knowledge and early diagnosis of this disease.

Glycogen Storage Disease Type II: A Case Report

Glycogen Storage Disease Type II is caused by the deficiency of acid maltase resulting in lysosomal accumulation of glycogen. There are two major clinical syndromes, a severe generalized and invariable fatal disease of infancy, and a myopathy starting in juvenile or adult life. The clinical and laboratory findings of a patient with Glycogen Storage Disease Type II are presented. The patient, a 17-year-old male, experienced slowly progressive weakness of muscle of the pelvis shoulder girdles and trunk. Muscle biopsy showed vacuolar myopathy and electromyograph showed features of myopathy with fibrillation potentials, positive sharp waves, myotonic discharges, without clinical myotonia at rest, and polyphasic potentials on volition. Clinical features, histopathologic and electrophysiologic findings of this disease and differential diagnosis were reviewed.