Pompe disease is an autosomal recessive lysosomal storage disorder caused by disease‐associated variants in the acid alpha‐glucosidase (GAA) gene. The current Pompe mutation database provides a ...severity rating of GAA variants based on in silico predictions and expression studies. Here, we extended the database with clinical information of reported phenotypes. We added additional in silico predictions for effects on splicing and protein function and for cross reactive immunologic material (CRIM) status, minor allele frequencies, and molecular analyses. We analyzed 867 patients and 562 GAA variants. Based on their combination with a GAA null allele (i.e., complete deficiency of GAA enzyme activity), 49% of the 422 disease‐associated variants could be linked to classic infantile, childhood, or adult phenotypes. Predictions and immunoblot analyses identified 131 CRIM negative and 216 CRIM positive variants. While disease‐associated missense variants were found throughout the GAA protein, they were enriched up to seven‐fold in the catalytic site. Fifteen percent of disease‐associated missense variants were predicted to affect splicing. This should be confirmed using splicing assays. Inclusion of clinical severity rating in the Pompe mutation database provides an invaluable tool for diagnosis, prognosis of disease progression, treatment regimens, and the future development of personalized medicine for Pompe disease.
Aim
To examine the long‐term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy.
Method
Using neuropsychological ...tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years.
Results
From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white‐matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white‐matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities.
Interpretation
As treatment enables patients with classic infantile Pompe disease to reach adulthood, white‐matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow‐up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next‐generation therapeutic strategies for classic infantile Pompe disease.
What this paper adds
In our long‐term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white‐matter abnormalities.
Cognitive development varied from stable and normal to declines towards intellectual disabilities.
Resumen
Pacientes con la enfermedad de Pompe infantil clásico aproximándose a la adultez: un estudio de cohorte acerca de las consecuencias para el cerebro
Objetivo
Examinar las consecuencias a largo plazo del depósito de glucógeno en el sistema nervioso central (SNC) por la enfermedad de Pompe infantil clásico usando terapia de reemplazo enzimático.
Método
Usando test neuropsicológicos y resonancia nuclear magnética (RMN) de cerebro, nosotros valoramos prospectivamente una cohorte de 11 pacientes con Pompe infantil clásico de hasta 17 años de edad.
Resultados
Desde aproximadamente los dos años de edad en adelante, la RMN de cerebro mostró compromiso de la sustancia blanca periventricular y centro semioval. Después de los 8 años de edad, se agregaron anormalidades en la sustancia blanca a nivel del cuerpo calloso, cápsula interna y externa y áreas subcorticales. Desde los 11 años de edad se encontraron anormalidades de la sustancia blanca en tronco cerebral. A pesar de que parece haber un patrón característico de compromiso en el tiempo, hubo considerables variaciones entre pacientes reflejadas por variaciones en el desarrollo neuropsicológico. El desarrollo cognitivo varió desde estable y normal hasta declinaciones que condujeron a la discapacidad intelectual
Interpretacion
Así como el tratamiento posibilita a los pacientes con la enfermedad de Pompe infantil clásico alcanzar la adultez, las anormalidades de la sustancia blanca se tornan progresivamente evidentes, afectando el desarrollo neuropsicológico. Por lo tanto, aconsejamos que los programas de seguimiento sean extendidos para evidenciar compromiso del SNC en cohortes de pacientes más numerosas e internacionales, para incorporar nuestros hallazgos al asesoramiento de los padres antes de comenzar el tratamiento, y para incluir al cerebro como un objetivo adicional en el desarrollo de nuevas generaciones de próximas estrategias terapéuticas para la enfermedad de Pompe infantil clásico.
Resumo
Pacientes com a doença de Pompe infantil clássica conforme se aproximam da vida adulta: um estudo de coorte sobre as consequências para o cérebro
Objetivo
Examinar as consequências de longo prazo do armazenamento de glicogênio no sistema nervosa central (SNC) para a doença de Pompe infantil clássica usando terapia de reposição enzimática
Método
Usando testes neuropsicológicos e imagens por ressonância magnética (IRM), avaliamos prospectivamente uma coorte de 11 pacientes com Pompe infantil clássica com até 17 anos de idade.
Resultados
De aproximadamente 2 anos de idade em diante, a IRM do cérebro mostrou envolvimento da substância branca periventricular e do centrum semioval. Após os 8 anos de idade, anormalidades adicionais da substância branca ocorreram no corpo caloso, cápsula interna e externa, e áreas subcorticais. A partir dos 11 anos, anormalidades da substância branca também foram encontradas no tronco cerebral. Embora pareça ser um padrão característico de envolvimento com o passar do tempo, houve variações consideráveis entre pacientes, refletidas por variações no desenvolvimento neuropsicológico. O desenvolvimento cognitivo variou de estável e normal para declínios levando a incapacidade intelectual.
Interpretação
Conforme o tratamento permite que pacientes com doença de Pompe infantil clássica atinjam a vida adulta, anormalidades da substância branca se tornam crescentemente evidentes, afetando o desenvolvimento neuropsicológico. Portanto, aconselhamos que programas de acompanhamento sejam expandidos para captar o envolvimento do SNC em coortes de pacientes maiores e internacionais, para incorporar nossos achados no aconselhamento dos pais antes do início do tratamento, e para incluir o cérebro como um alvo adicional do desenvolvimento da próxima geração de estratégias terapêuticas para a doença de Pompe infantil clássica.
What this paper adds
In our long‐term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white‐matter abnormalities.
Cognitive development varied from stable and normal to declines towards intellectual disabilities.
This article is commented on by Schoser on page 536 of this issue.
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Mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma are rare autosomal recessive lysosomal storage disorders. Data on the natural course of the diseases are scarce. These data are important for ...counseling, therapies development, and improvement of outcome. The aim of this study is to gain knowledge on the natural history of ML by obtaining data on survival, symptom onset, presenting symptoms, diagnosis, and pathogenic variants associated with the MLII or MLIII phenotype.
A systematic review on all published MLII and MLIII cases between 1968 and August 2019 was performed.
Three hundred one articles provided data on 843 patients. Median age at diagnosis: 0.7 for MLII and 9.0 years for MLIII. Median survival: 5.0 for MLII and 62.0 years for MLIIIII. Median age of death: 1.8 for MLII and 33.0 years for MLIII. Most frequent causes of death in all ML were pulmonary and/or cardiac complications. Pathogenic variants were described in 388 patients (GNPTAB: 571, GNPTG 179).
This review provides unique insights into the natural history of MLII and MLIII, with a clear genotype-phenotype correlation with the most frequent pathogenic variant c.3503_3504del in MLII and in MLIII alpha/beta c.22A>G for GNPTAB. All pathogenic GNPTG variants resulted in MLIII gamma.
Pompe's disease van der Ploeg, Ans T, Dr; Reuser, Arnold JJ, PhD
The Lancet (British edition),
2008-Oct-11, Letnik:
372, Številka:
9646
Journal Article
Recenzirano
Summary Pompe's disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait ...characterised by acid α-glucosidase deficiency leading to lysosomal glycogen storage. Pompe's disease is also regarded as a muscular disorder, but the generalised storage of glycogen causes more than mobility and respiratory problems. The clinical spectrum is continuous and broad. First symptoms can present in infants, children, and adults. Cardiac hypertrophy is a key feature of classic infantile Pompe's disease. For a long time, there was no means to stop disease progression, but the approval of enzyme replacement therapy has substantially changed the prospects for patients. With this new development, the disease is now among the small but increasing number of lysosomal storage disorders, for which treatment has become a reality. This review is meant to raise general awareness, to present and discuss the latest insights in disease pathophysiology, and to draw attention to new developments about diagnosis and care. We also discuss the developments that led to the approval of enzyme replacement therapy with recombinant human α-glucosidase from Chinese hamster ovary cells (alglucosidase alfa) by the US Food and Drug Administration and European Medicines Agency in 2006, and review clinical practice.
Identification of variants in the acid α‐glucosidase (GAA) gene in Pompe disease provides valuable insights and systematic overviews are needed. We report on the number, nature, frequency, and ...geographic distribution of GAA sequence variants listed in the Pompe Registry, a long‐term, observational program and the largest global repository of Pompe disease data. Variant information was reviewed and compared with publicly available GAA databases/resources. Among 1,079 eligible patients, 2,075 GAA variants (80 unique novel) were reported. Variants were listed by groups representing Pompe disease phenotypes. Patients were classified as Group A: Symptom onset ≤ 12 months of age with cardiomyopathy; Group B: Symptom onset ≤ 12 years of age (includes patients with symptom onset ≤ 12 months of age without cardiomyopathy); or Group C: Symptom onset > 12 years of age. Likely impact of novel variants was predicted using bioinformatics algorithms. Variants were classified by pathogenicity using ACMG guidelines. Data reported from the Pompe Registry provide new information about the distribution of GAA variants globally and across the clinical spectrum, add to the number and diversity of GAA variants registered in public databases through published data sharing, provide a first indication of the severity of novel variants, and assist in diagnostic practice and outcome prediction.
Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and ...GNPTG encode the α/β‐precursor and the γ‐subunit of N‐acetylglucosamine (GlcNAc)‐1‐phosphotransferase, respectively, the key enzyme for the generation of mannose 6‐phosphate targeting signals on lysosomal enzymes. Defective GlcNAc‐1‐phosphotransferase results in missorting of lysosomal enzymes and accumulation of non‐degradable macromolecules in lysosomes, strongly impairing cellular function. MLII‐affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc‐1‐phosphotransferase, but also helped to define genotype‐phenotype correlations to predict the clinical outcome in patients.
The lysosomal storage disorders mucolipidosis (ML) type II and III, trafficking of lysosomal enzymes in health and disease, and geographical distribution of disease‐associated GNPTAB and GNPTG mutations.
Pompe disease is an inherited disorder caused by disease‐associated variants in the acid α‐glucosidase gene (GAA). The Pompe disease GAA variant database (http://www.pompevariantdatabase.nl) is a ...curated, open‐source, disease‐specific database, and lists disease‐associated GAA variants, in silico predictions, and clinical phenotypes reported until 2016. Here, we provide an update to include 226 disease‐associated variants that were published until 2020. We also listed 148 common GAA sequence variants that do not cause Pompe disease. GAA variants with unknown severity that were identified only in newborn screening programs were listed as a new feature to indicate the reason why phenotypes were still unknown. Expression studies were performed for common missense variants to predict their severity. The updated Pompe disease GAA variant database now includes 648 disease‐associated variants, 26 variants from newborn screening, and 237 variants with unknown severity. Regular updates of the Pompe disease GAA variant database will be required to improve genetic counseling and the study of genotype–phenotype relationships.
This article describes an update of the Pompe disease GAA variant database (http://www.pompevariantdatabase.nl) providing new variants and findings related to the genetics of Pompe disease. The update includes genotypes and phenotypes obtained from clinical and/or research studies published between 2016 and 2020, as well as data from large registries and newborn screening programs. Variants that were already present in the previous version of the database have been retrospectively analyzed and updated. This information is freely accessible for clinicians, councilors and researchers in an open‐access database in order to improve the diagnostic process and to aid in decision making on the treatment of patients with Pompe disease worldwide.
The aim of this study was to compare the long‐term outcome of classic infantile Pompe patients treated with 20 mg/kg alglucosidase alfa every other week (eow) to those treated with 40 mg/kg/week, and ...to study the additional effect of immunomodulation. Six patients received 20 mg/kg eow and twelve 40 mg/kg/week. Five patients were cross‐reactive immunologic material (CRIM)‐negative, two in the 20 mg, three in the 40 mg group. We compared (ventilator‐free) survival, motor outcome, infusion associated reactions (IARs), and antibody formation. From 2012 on patients >2 months in the 40 mg group also received immunomodulation with rituximab, methotrexate, and intravenous immunoglobulin (IVIG) in an enzyme replacement therapy (ERT)‐naïve setting. Survival was 66% in the 20 mg group and 92% in the 40 mg group. Ventilator‐free survival was 50% and 92%. Both CRIM‐negative patients in the 20 mg group died, whereas all three are alive in the 40 mg group. In the 20 mg group, 67% learned to walk compared with 92% in the 40 mg group. At the age of 3 years, 33% and 92% were able to walk. Peak antibody titers ranged from 1:1250 to 1:31 250 in the 20 mg group and from 1:250 to 1:800 000 in the 40 mg group. Five patients of the 40 mg group of whom two CRIM‐negative also received immunomodulation. B‐cell recovery was observed between 5.7 and 7.9 months after the last dose of rituximab. After B‐cell recovery titers of patients with and without immunomodulation were similar (ranges 1:6 250‐1:800 000 and 1:250‐1:781 250). This study shows that classic infantile patients treated with 40 mg/kg/week from the start to end have a better (ventilator‐free) survival and motor outcome. Immunomodulation did not prevent antibody formation in our study.
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