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Introducción: La enfermedad de Gaucher es una entidad de acúmulo lisosomal, con un patrón de herencia autosómico recesivo, debido a la deficiencia de le enzima betaglucocerebrosidasa ácida. El gen está mapeado en el cromosoma 1q21 y se han descrito más de 500 mutaciones. Se caracteriza por presentar anemia, trombocitopenia, hepatoesplenomegalia, manifestaciones esqueléticas y, en ocasiones, compromiso neurológico. Entre los tratamientos se utiliza el reemplazo enzimático con imiglucerasa. Objetivo: Evaluar los resultados de la aplicación de imiglucerasa (Cerezyme®) en pacientes con enfermedad de Gaucher. Métodos: Se realiza un estudio longitudinal, descriptivo para evaluar el comportamiento de las variables clínicas, hematológicas y ultrasonográficas de ocho pacientes cubanos con enfermedad de Gaucher tras recibir el tratamiento sustitutivo enzimático. Se evaluaron al año, cinco y de diez a quince años de tratamiento. Resultados: Al inicio, todos los pacientes presentaron anemia y la mayoría tuvieron trombocitopenia y hepatoesplenomegalia al diagnóstico de la enfermedad. Los pacientes con manifestaciones neurológicas y la mutación L444P en estado homocigótico se clasificaron en EG tipo 3, el resto en tipo1. En todos los pacientes se constató aumento de las cifras de hemoglobina, la elevación del número de plaquetas y reducción de la hepatoesplenomegalia posterior al año de tratamiento. Los pacientes con tipo 3 mantuvieron la afectación neurológica. No se reportaron reacciones adversas al medicamento. Conclusiones: La terapia de reemplazo enzimática con imiglucerasa (Cerezyme®) es un pilar fundamental en el tratamiento de los pacientes con esta enfermedad, lo cual influye de forma positiva en la calidad de vida, obteniéndose mejores resultados con su comienzo en edad pediátrica.
Introduction: Gaucher disease is an entity of lysosomal accumulation, with an autosomal recessive inheritance pattern, due to the deficiency of the acid betaglucocerebrosidase enzyme. The gene is mapped on chromosome 1q21 and more than 500 mutations have been described. It is characterized by anemia, thrombocytopenia, hepatosplenomegaly, skeletal manifestations and sometimes neurological involvement. Among the treatments, enzyme replacement with imiglucerase is used. Objective: To evaluate the results of the application of imiglucerase in patients with Gaucher disease. Methods: A longitudinal, descriptive study to evaluate the behavior of the clinical, hematological and ultrasonographic variables of eight Cuban patients with Gaucher disease after receiving enzyme replacement treatment was carried out. They were evaluated after one, five and ten to fifteen years of treatment. Results: At debut, all patients presented anemia, and the majority showed thrombocytopenia and hepatosplenomegaly at diagnosis of the disease. Patients with neurological manifestations and the L444P mutation in a homozygous state were classified as type 3 GD, the rest as type 1. In all patients, an increase in hemoglobin levels, an increase in the number of platelets and a reduction in hepatosplenomegaly was observed after one year of treatment. Patients with type 3 maintain neurological involvement. No adverse reactions to the medication were reported. Conclusions: Enzyme replacement therapy with imiglucerase (Cerezyme®) is a fundamental pillar in the treatment of patients with this disease, which positively influences quality of life, obtaining better results with its onset in pediatric age.
Subject(s)
Humans , Epidemiology, Descriptive , Longitudinal StudiesABSTRACT
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.
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Abstract Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare neurodegenerative genetic disease that affects children in early life. Its classic form is rapidly progressive, leading to death within the first 10 years. The urge for earlier diagnosis increases with the availability of enzyme replacement therapy. A panel of nine Brazilian child neurologists combined their expertise in CLN2 with evidence from the medical literature to establish a consensus to manage this disease in Brazil. They voted 92 questions including diagnosis, clinical manifestations, and treatment of the disease, considering the access to healthcare in this country. Clinicians should suspect CLN2 disease in any child, from 2 to 4 years old, with language delay and epilepsy. Even though the classic form is the most prevalent, atypical cases with different phenotypes can be found. Electroencephalogram, magnetic resonance imaging, molecular and biochemical testing are the main tools to investigateand confirm the diagnosis. However, we have limited access to molecular testing in Brazil, and rely on the support from the pharmaceutical industry. The management of CLN2 should involve a multidisciplinary team and focus on the quality of life of patients and on family support. Enzyme replacement therapy with Cerliponase α is an innovative treatment approved in Brazil since 2018; it delays functional decline and provides quality of life. Given the difficulties for the diagnosis and treatment of rare diseases in our public health system, the early diagnosis of CLN2 needs improvement as enzyme replacement therapy is available and modifies the prognosis of patients.
Resumo Lipofuscinose ceróide neuronal (CLN2) é uma doença genética neurodegenerativa rara que afeta crianças nos primeiros anos de vida. A sua forma clássica é rapidamente progressiva, levando à morte nos primeiros 10 anos. A necessidade de um diagnóstico precoce aumenta com a disponibilidade do tratamento de terapia enzimática. Um painel de nove neurologistas infantis brasileiros combinou sua experiência em CLN2 com evidências da literatura médica para estabelecer um consenso no manejo desta doença no Brasil. Eles votaram 92 questões abordando diagnóstico, manifestações clínicas e tratamento, considerando o acesso à saúde no Brasil. Deve-se suspeitar de CLN2 em qualquer criança de 2 a 4 anos de idade que apresente atraso de linguagem e epilepsia. Apesar da forma clássica ser a mais prevalente, podem ser encontrados casos atípicos com diferentes fenótipos. Eletroencefalograma, ressonância magnética, testes moleculares e bioquímicos são as principais ferramentas para investigar e confirmar o diagnóstico. No entanto, o acesso aos testes moleculares é limitado no Brasil, necessitando contar com o apoio da indústria farmacêutica. O manejo da CLN2 deve envolver uma equipe multidisciplinar e focar na qualidade de vida dos pacientes e no apoio familiar. A terapia de reposição enzimática com Cerliponase alfa é um tratamento inovador aprovado no Brasil desde 2018; ele retarda o declínio funcional e proporciona qualidade de vida. Diante das dificuldades para o diagnóstico e tratamento de doenças raras em nosso sistema público de saúde, o diagnóstico precoce de CLN2 precisa de melhorias pois a terapia de reposição enzimática está disponível e modifica o prognóstico dos pacientes.
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La enfermedad de Fabry es una afección genética producida por un déficit total o parcial de la enzima alfagalactosidasa A implicada en el catabolismo de glicoesfingolípidos. Dicha alteración genera el depósito lisosomal del residuo globotriasilceramida (Gb-3) a nivel multitisular, a predominio de los sistemas renal, cardíaco, nervioso y cutáneo. Debido a su baja prevalencia y su variada presentación clínica representa un verdadero reto diagnóstico. La combinación de antecedentes familiares de cardiopatía y afección renal, diferentes grados de hipertrofia del ventrículo izquierdo, sumado a afecciones cutáneas, neurológicas y enfermedad renal progresiva, deben hacer plantear la posibilidad de una enfermedad de Fabry. El cardiólogo que estudia un paciente con hipertrofia ventricular es quien debe sospecharla, y debe hacer un diagnóstico diferencial con miocardiopatías hipertróficas, cardiopatía hipertensiva u otras miocardiopatías por depósitos. Los aportes diagnósticos de la resonancia magnética cardíaca han sido de suma importancia en los últimos años. Los estudios enzimáticos y genéticos, antes de muy difícil adquisición en nuestro medio, son factibles en la actualidad. Un diagnóstico temprano es clave para iniciar el tratamiento enzimático sustitutivo, evitar un daño más extenso e irreversible, e identificar los familiares afectados en fases iniciales.
Fabry disease is a genetic condition caused by a total or partial deficiency of the enzyme alphagalactosidase A involved in the catabolism of glycosphingolipids. This alteration generates the lysosomal deposit of the globotriasylceramide residue (Gb-3) at the multi-tissue level, predominantly in the kidneys, heart, nervous system and skin. Due to its low prevalence and its varied clinical presentation, it represents a true diagnostic challenge. The combination of family history of heart disease and kidney disease, different degrees of hypertrophy of the left ventricle, added to skin and neurological conditions and progressive kidney disease, should raise the possibility of Fabry disease. The cardiologist who studies a patient with ventricular hypertrophy is the one who should suspect it and make a differential diagnosis of hypertrophic cardiomyopathies, hypertensive heart disease or other cardiomyopathies due to deposits. Diagnostic complementation with a cardiac resonance study has been extremely important in recent years. Enzymatic and genetic studies, previously very difficult to acquire in our environment, are currently feasible. An early diagnosis is key to starting enzyme replacement therapy, avoiding more extensive and irreversible damage, and allowing affected family members to be identified in the early stages.
A doença de Fabry é uma condição genética causada por uma deficiência total ou parcial da enzima alfagalactosidase A envolvida no catabolismo de glicoesfingolipídeos. Essa alteração gera o depósito lisossomal do resíduo globotriasilceramida (Gb-3) em nível multitecidual, predominantemente nos rins, coração, sistema nervoso e pele. Devido à sua baixa prevalência e à sua apresentação clínica variada, representa um verdadeiro desafio diagnóstico. A combinação de história familiar de cardiopatia e doença renal, diferentes graus de hipertrofia do ventrículo esquerdo, somada a condições dermatológicas e neurológicas e doença renal progressiva, deve levantar a possibilidade de doença de Fabry. O cardiologista que estuda um paciente com hipertrofia ventricular é quem deve suspeitar e fazer um diagnóstico diferencial de cardiomiopatias hipertróficas, cardiopatias hipertensivas ou outras cardiomiopatias por depósitos. A complementação diagnóstica com estudo de ressonância cardíaca tem sido de extrema importância nos últimos anos. Estudos enzimáticos e genéticos, anteriormente muito difíceis de adquirir em nosso meio, são atualmente viáveis. O diagnóstico precoce é fundamental para iniciar a terapia de reposição enzimática, para evitar danos mais extensos e irreversíveis, e permite que os familiares afetados sejam identificados nos estágios iniciais.
Subject(s)
Humans , Fabry Disease/diagnosis , Fabry Disease/drug therapy , Diagnostic Techniques and ProceduresABSTRACT
Hypertrophic cardiomyopathy (HCM) is cardiomyopathy with a clinical phenotype of cardiac hypertrophy. The etiology includes genetically defective encoding sarcomeres, congenital metabolic diseases such as lysosomal storage diseases, systemic amyloidosis such as transthyretin amyloidosis(ATTR), and Fabry disease. Previous therapies did not target the etiology and pathogenesis and therefore were less effective. In recent years, treatments targeting different mechanisms of myocardial hypertrophy have achieved good results. Mavacamten can reduce myocardial contractility by inhibiting ATP activity, thereby significantly improving left ventricular outflow tract(LVOT) obstruction, cardiac contractility, ventricular tension, and limitting myocardial damage. By inhibiting the dissociation of transthyretin(TTR) and subsequent formation and deposition of the amyloid fibril, tafamidis can reduce the mortality and morbidity of patients with transthyretin cardiac amyloidosis(ATTR-CA). Gene silencing and gene editing technology can reduce abnormal TTR levels. Synthesis of α-galactosidase A by gene recombination technology in vitro can effectively reduce left ventricular mass index(LVMi), improve cardiac function, reduce angina attacks and decrease mortality of Fabry disease.
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Fabry disease is an X-linked inherited lysosomal storage disease caused by the mutation of GLA gene that encodes α-galactosidase A (α-Gal A). GLA gene mutation causes the decline or deficiency in the activity of α-Gal A, leading to the accumulation of its substrates in the lysosomes of multiple organs and tissue that causes systemic damage and threatens the life of patients. Enzyme replacement therapy (ERT) is the standard of care for Fabry disease. ERT slows or prevents the progression of organ damage, effectively improving heart, brain, kidney functions and significantly improves quality of life. At present, there are two main ERT drugs, agalsidase alpha and agalsidase beta, which have the same amino acid sequence and different N-terminal sugars, and are used for the treatment of Fabry disease. In this paper, the efficacy and safety of ERT in the treatment of Fabry disease were summarized by reviewing the relevant literature at home and abroad and combining the results of some cases treated in Department of Nephrology, Provincial Hospital affiliated to Shandong First Medical University. Previous literature has shown that enzyme replacement therapy is the most important specific treatment for Fabry disease, which has a protective effect on important organs such as kidney, heart, and nervous system.
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There are more than 7 000 rare diseases and approximately 475 million individuals with rare diseases globally, with children accounting for two-thirds of this population. Due to a relatively small patient population and limited financial resources allocated for drug research and development in pharmaceutical enterprises, there are still no drugs approved for the treatment of several thousands of these rare diseases. At present, there are no drugs for 95% of the patients with rare diseases, and consequently, the therapeutic drugs for rare diseases have been designated as orphan drugs. In order to guide pharmaceutical enterprises to strengthen the research and development of orphan drugs, various nations have enacted the acts for rare disease drugs, promoted and simplified the patent application process for orphan drugs, and provided scientific recommendations and guidance for the research and development of orphan drugs. Since there is a relatively high incidence rate of rare diseases in children, this article reviews the latest research on pharmacotherapy for children with rare diseases.
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Humans , Child , Rare Diseases/drug therapy , Orphan Drug Production , Pharmaceutical PreparationsABSTRACT
Resumen Introducción: La enfermedad de Fabry es una entidad crónica, progresiva, poco frecuente, de origen genético y patrón de herencia recesivo ligado al cromosoma X. Se caracteriza por déficit enzimático de alfa-galactosidasa causado por mutaciones en el gen GLA, lo que produce almacenamiento anormal de esfingolípidos celulares y tisulares Caso clínico: Se describe el caso de un paciente de 53 años, con antecedente familiar y compromiso cardíaco predominante, dado por hipertrofia ventricular izquierda, arritmias auriculares e insuficiencia cardiaca congestiva secundaria, quien, adicionalmente, tiene manifestaciones multisistémicas que han evolucionado desde la infancia. Entre los pilares de tratamiento requirió implantación definitiva de marcapasos y terapia de reemplazo enzimático. Conclusiones: La enfermedad de Fabry es una entidad de compromiso sistémico y progresivo, de baja prevalencia, cuya importancia se debe reflejar en el entrenamiento del personal de salud para el adecuado diagnóstico, con miras a mejorar la calidad de vida de los pacientes.
Abstract Introduction: Fabrys disease is a chronic, progressive and a multisystemic disease of genetic origin, with a recessive pattern of inheritance tied to the X chromosome, characterized by the lisosomal deposit of globotriaosylceramide as a consequence of a deficiency in the activity of the alpha-galactosidase A enzyme. Clinical case: We present a clinical case of a 53-year old male patient carrying this disease with family history of Fabrys disease, who suffers cardiac compromise as the main clinical manifestation. He is a patient who required the implantation of a permanent pacemaker and enzyme replacement therapy. Conclusions: Fabry´s disease is a systemic and progressive disease, low fre-quency, and not well known by the health personnel, which implies a late diagnosis, being the cardiac compromise the second in frequency after renal compromise, which can lead to the patient to a hypertrophic cardiomyopathy and a rhythm and cardiac conduction disorder.
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Contexto: la enfermedad de Fabry se comporta como una enfermedad crónica con compromiso multisistémico y alto costo en salud. Objetivo: generar recomendaciones basadas en la evidencia para el diagnóstico, el tratamiento y el seguimiento de la enfermedad de Fabry con compromiso renal mediante un consenso de expertos. Metodología: a partir de la búsqueda de evidencia en Pubmed, Embase y Google Scholar entre 2010 y agosto 2020, se formulan recomendaciones sobre la definición, el diagnóstico y el tratamiento de la enfermedad de Fabry en población adulta, las cuales se consultan a un panel de expertos a través de la metodología de consenso Delphi modificado. La calidad de los documentos se evaluó por equipo metodológico aplicando herramientas en función del tipo de documento incluido. Resultados: se formularon 53 recomendaciones sobre la definición, el diagnóstico y el tratamiento. Un panel de cinco expertos clínicos nacionales e internacionales externos al grupo desarrollador participaron en la consulta preconsenso y 50 recomendaciones fueron acordadas para su inclusión, para tres de ellas se requirió una sesión formal de consenso que se dio en una ronda, incorporando tres nuevas recomendaciones. Conclusiones: las recomendaciones basadas en evidencia y experticia clínica permitirán orientar de manera estandarizada a nivel nacional y regional, el diagnóstico y el tratamiento de pacientes con sospecha o enfermedad de Fabry con compromiso renal.
Background: Fabry disease behaves like a chronic condition, with multisystem involvement and high health care costs. Objective: To generate evidence-based recommendations for the diagnosis, treatment and follow-up of the Anderson-Fabry disease with renal commitment, through an expert consensus. Methodology: Based on the search of evidence in PubMed, Embase and Google Scholar between 2010 and August, 2020, recommendations on the definition, diagnosis and treatment of Fabry Disease in adult population were formulated after consulting with an expert panel through the modified Delphi consensus methodology. The quality of the documents was assessed by methodological team applying tools according to the type of document included. Results: 53 recommendations for the definition, diagnosis and treatment were formulated. A panel of five national and international clinical experts external to the developer group participated in the pre-consensus consultation and 50 recommendations were agreed upon for their inclusion. For 3 recommendations, a formal consensus session which took place in one round was required, and 3 new recommendations were incorporated. Conclusions: The recommendations based on evidence and clinical expertise will allow us to guide the diagnosis and treatment of patients with Fabry disease with renal involvement or suspicion thereof in a standardized manner at national and regional levels.
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La hipofosfatasia es un trastorno hereditario raro causado por mutaciones en el gen ALPL. Causa defectos en la mineralización ósea y dental, función respiratoria anormal, convulsiones, hipotonía, dolor óseo y nefrocalcinosis. Las formas clínicas se reconocen según la edad al diagnóstico y la gravedad. Presentamos el caso de una lactante con fontanela anterior agrandada, bóveda craneal blanda, fracturas, dificultad respiratoria y convulsiones. El análisis bioquímico mostró hipercalcemia, fosfato sérico normal y fosfatasa alcalina sérica baja. La radiografía mostró hipomineralización, fracturas y callos. La concentración plasmática de piridoxal-5'-fosfato era de 762 mg/l (intervalo normal: 5-50) y la concentración de fosfoetanolamina en orina era de 1015 mmol/l (intervalo normal: 15-341). El análisis del gen ALPL mostró dos mutaciones heterocigotas compuestas, una de las cuales es novedosa. El diagnóstico y tratamiento tempranos de la hipofosfatasia perinatal podría mejorar los resultados y tener un impacto positivo en la sobrevida.
Hypophosphatasia (HPP) is a rare inherited disorder caused by mutations in the ALPL gene. Mineralization defect in bones and teeth, abnormal respiratory function, seizures, hypotonia, bone pain, and nephrocalcinosis can be observed. Clinical forms are usually recognized based on age at diagnosis and severity of features. We present an infant with an enlarged anterior fontanelle, soft calvarium, fractures, respiratory distress, and seizures. Biochemical analysis showed hypercalcemia, normal serum phosphate, and low serum alkaline phosphatase (ALP) levels. X-ray showed hypomineralization, fractures, and callus formations. Plasma pyridoxal 5'-phosphate (PLP) was 762 mg/L (NV : 5-50) and urine phosphoethanolamine (PEA) was 1015 mmol/L (NV : 15-341) and ALPL gene analysis showed two compound heterozygous mutations, one of which is a novel one. Early diagnosis and treatment of perinatal HPP may improve outcomes and might have a positive impact on survival.
Subject(s)
Humans , Female , Pregnancy , Infant , Hypophosphatasia/diagnosis , Hypophosphatasia/genetics , Hypophosphatasia/drug therapy , Nephrocalcinosis , Seizures , Alkaline Phosphatase/genetics , Alkaline Phosphatase/therapeutic use , MutationABSTRACT
Objective:To summarize the clinical features, gene mutations and experience of standardized enzyme replacement therapy (ERT) of Pompe disease (PD) in children.Methods:A retrospective analysis was performed on the clinical data of 13 children with PD, who were hospitalized in Qingdao Women and Children′s Hospital from December 2016 to August 2021.According to the age at onset, the children were divided into the infantile-onset Pompe disease (IOPD) group and late-onset Pompe disease (LOPD) group.At the same time, they were divided into the ERT group and non-ERT group according to whether recombinant human acid alpha-glucosidase (rhGAA) was infused.Furthermore, the ERT group was divided into the standard ERT group and non-standard ERT group.The standard ERT group received a dose of 20 mg/kg every 2 weeks for 52 weeks.The survival rate was compared between groups by using the Kaplan-Meier method.Results:Among the 13 children with PD, there were 7 males and 6 females.Ten cases belonged to the IOPD group and 3 cases belonged to the LOPD group.The most common cause of initial consultation in the IOPD group was cardiac involvement, which accounted for 60.0% (6/10 cases), while the LOPD group mainly presented with myasthenia, cardiac involvement and respiratory tract infection at the first diagnosis.The serum level of creatine kinase (CK) in all cases increased to varying degrees.Acid alpha-glucosidase (GAA) was completely deficient in 1 case and decreased in 12 cases.All the children in the IOPD group showed myocardial hypertrophy, electrocardiograph (ECG) suggested a short PR interval, increased QRS voltage and extensive T-wave inversion.Three new mutations were found by GAA gene analysis, and they were c. 1861T>G (p.Trp621Gly), c.2278A>T (p.K760X), and c. 949G>A (p.A317T). Five cases in the IOPD group were given ERT.Two of them were given standard ERT for 52 weeks, and the other 3 cases were treated with non-standard ERT.At the end of follow-up, 2 cases treated with standardized ERT survived and the remaining 8 cases died of heart failure or respiratory failure.In the LOPD group, only 1 case was given ERT one time.Finally, 2 cases survived and one died of respiratory failure.The total fatality rate was 69.2%(9/13 cases). The survival rate of the ERT group (50.0%) and standard ERT group (100.0%) was significantly higher than that of the non-ERT group (14.3%) ( Log Rank P=0.037, 0.044). Conclusions:The clinical manifestations of PD are diverse.GAA activity examination and GAA gene analysis are important for clinical diagnosis of PD.Standardized ERT can significantly delay the progression of PD and even reverse myocardial hypertrophy in children with IOPD.
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Objective:To summarize the clinical features, gene mutations and experience of standardized enzyme replacement therapy (ERT) of Pompe disease (PD) in children.Methods:A retrospective analysis was performed on the clinical data of 13 children with PD, who were hospitalized in Qingdao Women and Children′s Hospital from December 2016 to August 2021.According to the age at onset, the children were divided into the infantile-onset Pompe disease (IOPD) group and late-onset Pompe disease (LOPD) group.At the same time, they were divided into the ERT group and non-ERT group according to whether recombinant human acid alpha-glucosidase (rhGAA) was infused.Furthermore, the ERT group was divided into the standard ERT group and non-standard ERT group.The standard ERT group received a dose of 20 mg/kg every 2 weeks for 52 weeks.The survival rate was compared between groups by using the Kaplan-Meier method.Results:Among the 13 children with PD, there were 7 males and 6 females.Ten cases belonged to the IOPD group and 3 cases belonged to the LOPD group.The most common cause of initial consultation in the IOPD group was cardiac involvement, which accounted for 60.0% (6/10 cases), while the LOPD group mainly presented with myasthenia, cardiac involvement and respiratory tract infection at the first diagnosis.The serum level of creatine kinase (CK) in all cases increased to varying degrees.Acid alpha-glucosidase (GAA) was completely deficient in 1 case and decreased in 12 cases.All the children in the IOPD group showed myocardial hypertrophy, electrocardiograph (ECG) suggested a short PR interval, increased QRS voltage and extensive T-wave inversion.Three new mutations were found by GAA gene analysis, and they were c. 1861T>G (p.Trp621Gly), c.2278A>T (p.K760X), and c. 949G>A (p.A317T). Five cases in the IOPD group were given ERT.Two of them were given standard ERT for 52 weeks, and the other 3 cases were treated with non-standard ERT.At the end of follow-up, 2 cases treated with standardized ERT survived and the remaining 8 cases died of heart failure or respiratory failure.In the LOPD group, only 1 case was given ERT one time.Finally, 2 cases survived and one died of respiratory failure.The total fatality rate was 69.2%(9/13 cases). The survival rate of the ERT group (50.0%) and standard ERT group (100.0%) was significantly higher than that of the non-ERT group (14.3%) ( Log Rank P=0.037, 0.044). Conclusions:The clinical manifestations of PD are diverse.GAA activity examination and GAA gene analysis are important for clinical diagnosis of PD.Standardized ERT can significantly delay the progression of PD and even reverse myocardial hypertrophy in children with IOPD.
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Objective:To analyze the efficacy and safety of enzyme replacement therapy (ERT) in Chinese patients with Fabry disease.Methods:A retrospective analysis of the clinical manifestations, genetic variations, family screening, treatments and adverse reactions was conducted in five patients with Fabry disease admitted to the First Affiliated Hospital of Zhejiang University College of Medicine from July 2020 to May 2021. The dosage of agalsidase β was 1 mg/kg by intravenous pump once every 2 weeks.Results:Five male patients with median age of 37 years old (29-51 years old) were diagnosed based on clinical features, family history, α-galactosidase A (α-Gal A) activity, genetic analysis results and kidney biopsy. The clinical manifestations varied in these five patients. All patients had abnormal electrocardiogram, abnormal cardiac ultrasonography and abnormal urinalysis results, three experienced acroparaesthesia during childhood (one patient had persistent pain until adulthood), three had cutaneous angiokeratoma, four had renal insufficiency, four had hypohidrosis, four had diarrheas, four had cornea verticillata and two had high-frequency hearing loss. Two missense mutations of the GLA gene were identified: c.272T>C(p.I91T) and c.868A>G(p.Met290Val). Two nonsense mutations were c.1024C>T(p.Arg342*) and c.838C>T(p.Gln280*). Furthermore, the frameshift mutation c.348del p.(Ile117Phefs*4) was detected, which was not included in the known database, presented with classical Fabry disease. There was no serious adverse reaction during agalsidase β infusion in 5 patients. ERT reduced the plasma globotriaosylsphingosine (lyso-GL-3) levels after treatment of 2-10 months ( P<0.05), and the long-term diarrhea symptom were significantly improved. Conclusions:The clinical manifestations of Fabry disease are varied. Severe adverse events rarely occur in patients treated with short-term ERT. Plasma lyso-GL-3 levels decrease significantly after treatment.
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Objective:To analyze the clinical features, efficacy and adverse reactions of enzyme replacement therapy (ERT) in patients with Fabry disease (FD).Methods:The clinical data of FD patients in Shandong Provincial Hospital Affiliated to Shandong First Medical University from June 2020 to September 2021 were collected and the clinical manifestations, laboratory examinations, gene mutations, and efficacy and adverse reactions of ERT were retrospectively analyzed.Results:Sixteen patients with FD were enrolled in this study, including 12 typical cases and 4 late-onset cases, with varied clinical manifestations. Compared with late-onset patients, typical patients had younger age of onset ( P=0.001), lower activity of plasma alpha-galactosidase A ( P=0.016) and higher globotriaosylsphingosine (lyso-GL-3, P=0.030). The typical patients [(13.50±10.08) years] and late-onset patients [(10.75±7.27) years] both had long delayed time of diagnosis. In 7 patients who underwent regular 6 ERT, lyso-GL-3 was significantly lower than before ( P=0.018); after 6 treatments, the pain of 5 patients was relieved than before. Three patients with irregular ERT had aggravated symptoms, and 1 case had stroke recurrence during regular treatment. No serious adverse reaction occurred with the use of agalsidase β and α. Conclusions:ERT can effectively reduce the level of plasma lyso-GL-3 in patients with FD and relieve symptoms, and has good safety. But the efficacy of ERT is dose-dependent, and clinical benefits require long-term observation and follow-up. Patients treated with ERT should have good compliance and can receive long-term regular treatment.
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Abstract Gaucher disease (GD) is one of the most common lysosomal disorders, occurring in approximately 1 in 40,000 live births worldwide. Since 2014 enzyme replacement therapy (ERT) with taliglucerase alfa has been the treatment of choice for adult patients with GD in Brazil. The aim of this study was to evaluate the long-term efficacy and safety of taliglucerase alfa in a cohort of Brazilian patients treated at a referral center for inborn errors of metabolism. All patients who received at least one infusion of the enzyme at the study center were considered eligible to participate. Patients were followed for adverse reactions and events throughout the study period. Platelets, hemoglobin, chitotriosidase activity, bone marrow burden (BMB) score, bone mineral density, and the severity score index (SSI) were analyzed. For patients who were switched to taliglucerase alfa from imiglucerase, the same variables were compared before and after the switch. At 9-year follow-up, all parameters of interest had remained stable or improved. The overall rate of adverse events was lower than in other studies that evaluated long-term ERT with taliglucerase, and no serious adverse events were considered related to treatment. Based on our findings, ERT with taliglucerase alfa is an effective and safe approach for treatment of patients with GD.
ABSTRACT
Abstract Cardiovascular mortality (CVM) has become the major contributor to overall Fabry disease (FD) mortality in the enzyme replacement therapy (ERT) era. Our objectives were to describe causes and potential predictors of mortality in FD adult patients in Argentina, and to assess risk of major adverse cardio vascular events (MACE) in the ERT era. We retrospectively studied 93 consecutive patients treated with alpha-galactosidase A (median follow up: 9.5 years from start of ERT). Mean age at ERT starting was 35±16.3 years. Prevalence of cardiomyopathy and renal disease reached 47% and 41%, respectively. Eleven subjects (11.8%, 95%CI: 5-18%) died during follow up (1.24/100 patient-years). Mean overall survival was 71 years (95%CI: 66-75 years). Seven cases were considered as CVM; main causes were sudden death and stroke. Risk of MACE was 14% (95%CI: 6.9-21.1%; 1.47 events/100 patient-years from start of ERT). All but 2 subjects had at least one comorbid cardiovascular risk factor; however, 86% of patients remained free of MACE during follow-up. CVM remained low and our study was underpowered for detection of predictors of mortality, but it is worth noting that age at diagnosis and ERT starting, left ventricular mass index and renal disease trended to correlate with CVM. Prevalence of hypertension, diabetes and dyslipidemia were lower in FD patients when compared to population level data. As in the Argentinean general population, CVM was the leading cause of mortality among this cohort of consecutive FD patients treated with agalsidase alfa.
Resumen La mortalidad cardiovascular (MCV) se ha convertido en el principal contribuyente a la mortalidad general por enfermedad de Fabry (EF) en la era de la terapia de reemplazo enzimático (TRE). Nuestros objetivos fueron describir las causas y posibles predictores de mortalidad en pacientes adultos con EF en la Argentina, y evaluar el riesgo de eventos cardiovasculares mayores (MACE) en la actual era de TRE. Se estudiaron 93 pacientes consecutivos tratados con agalsidasa-alfa por una mediana de 9.5 años tras iniciar TRE. La edad al inicio de TRE fue 35 ± 16.3 años. La prevalencia de cardiomiopatía y enfermedad renal alcanzó 47% y 41%, respectivamente. Once sujetos (11.8%; IC95%: 5-18%) murieron durante el seguimiento (1.24/100 pacientes/año). La supervivencia global fue 71 años (IC95%: 66-75 años). Siete casos fueron considerados como MCV; las principales causas fueron muerte súbita e ictus. El riesgo de MACE fue 14% (IC95%: 6.9-21.1%; 1.47 eventos/100 pacientes/año desde la ERT). Todos menos 2 sujetos tenían al menos un factor de riesgo cardiovascular, pero el 86% permaneció libre de MACE. Los eventos de MCV fueron escasos. El estudio tuvo reducido poder estadístico para detectar predictores de mortalidad, pero la edad al diagnóstico y al iniciar la TRE, índice de masa ventricular izquierda y enfermedad renal tendieron a correlacionarse con MCV. La prevalencia de hipertensión, diabetes y dislipidemia fue menor en comparación con la población general. Como ocurre con la población general en Argentina, los eventos cardiovasculares fueron la principal causa de muerte en esta cohorte de pacientes consecutivos con EF tratados con agalsidasa-alfa.
Subject(s)
Humans , Adult , Fabry Disease/complications , Fabry Disease/drug therapy , Argentina/epidemiology , Recombinant Proteins/therapeutic use , Retrospective Studies , alpha-Galactosidase/adverse effects , Enzyme Replacement Therapy , IsoenzymesABSTRACT
La terapia de reemplazo enzimático disminuye la morbilidad y mejora la calidad de vida de los pacientes con mucopolisacaridosisii. Se han descrito reacciones de hipersensibilidad inmediata a este fármaco. La desensibilización es un tratamiento que induce la tolerancia temporaria a una droga y permite al paciente alérgico recibir la medicación.Se presenta el caso de un niño de 7 años con diagnóstico de síndrome de Hunter que, luego de 4 años de tratamiento con idursulfase, tuvo dos episodios de anafilaxia durante la infusión del fármaco. Se detectó inmunoglubulina E específica mediante pruebas cutáneas, y fue positiva la intradermorreacción con dilución 1/10 (0,2 mg/ml). Se realizó un protocolo de desensibilización de 12 pasos, sin presentar eventos adversos. La evaluación alergológica y la posibilidad de desensibilización constituyeron herramientas útiles en el manejo de nuestro paciente
Enzyme replacement therapy with idursulfase decreases morbidity and improves quality of life of patients with mucopolysaccharidosis ii. Immediate hypersensitivity reactions to this drug have been described. Desensitization is a treatment that induces temporary tolerance to a culprit drug, allowing the allergic patient to receive the medication.We present the case of a 7-year-old patient diagnosed with Hunter syndrome who presented, after 4 years of treatment, two episodes of anaphylaxis during the infusion of idursulfase. Detection of specific immunoglobulin E was carried out using skin tests, with intradermal reaction at a 1/10 dilution (0.2 mg/ml) being positive. A 12-step desensitization protocol was performed without presenting adverse events.The allergological evaluation and the possibility of desensitization were useful tools in the management of our patient.
Subject(s)
Humans , Male , Child , Desensitization, Immunologic/methods , Enzyme Replacement Therapy , Mucopolysaccharidosis II/drug therapy , Hypersensitivity, Immediate , Metabolism, Inborn ErrorsABSTRACT
Objective:To analyze the efficacy and safety of enzyme therapy in late-onset Pompe disease (LOPD) patients, so as to provide reference for the treatment and prognosis of LOPD.Methods:The effect of α-glucosidase (GAA) on a patient diagnosed with LOPD in the Affiliated Hospital of Jining Medical University was observed and analyzed. Besides, literature related to enzyme therapy in LOPD patients were searched in PubMed, Web of Science, Medline databases. Twenty-one studies containing clinical data from 910 LOPD patients related to enzyme therapy were finally included for analysis.Results:The patient developed muscle weakness since he was 16 years old. The GAA activity in peripheral blood was 0. Electromyography suggested myogenic lesions in both lower extremities. Compound heterozygous mutations of GAA gene were found by next- generation sequencing. Muscle biopsy revealed characteristic vacuolar changes. After eight years of diagnosis, the patient was given enzyme therapy for 18.5 months, 20 times in total. The symptoms of muscle weakness were slightly improved in the early stages of treatment without obvious adverse reactions. Most of the 910 LOPD patients were stabilized or had improved muscular and (or) respiratory function following treatment with GAA.Conclusion:GAA treatment is effective and well tolerated. In patients with advanced severe LOPD, enzyme replacement therapy remains effective even years after onset.
ABSTRACT
At present, there is still a lack of comprehensive diagnosis and treatment criteria for pancreatic exocrine insufficiency around the world. Pancreatic surgeons often ignore or misjudge pancreatic exocrine insufficiency secondary to pancreatic cancer, and as a result, pancreatic exocrine insufficiency is not adequately treated, which greatly affects the quality of life of patients with pancreatic cancer. This article summarizes the latest research advances in the pathogenesis, typical symptoms, and diagnostic methods of pancreatic exocrine insufficiency, as well as pancreatic enzyme replacement therapy in different stages of pancreatic cancer. It is pointed out that pancreatic enzyme replacement therapy can significantly improve the quality of life of patients with different stages of pancreatic cancer.