Original ArticleEarly Pathologic Changes and Responses to Treatment in Patients With Later-Onset Pompe Disease
Introduction
Pompe disease (also known as glycogen storage disease type II and glycogenosis II) is a lysosomal storage disorder in which a deficiency of acid α-glucosidase causes an intralysosomal accumulation of glycogen, especially in skeletal muscle [1]. Pompe disease presents with a wide spectrum of clinical phenotypes. The severe and rapidly progressive infantile-onset Pompe disease is characterized by the presence of hypertrophic cardiomyopathy. Later-onset Pompe disease is more heterogeneous, and typically presents without cardiac manifestations [1]. Earlier manifestation of later-onset Pompe disease leads to earlier wheelchair and/or ventilator dependency [2], [3], [4].
Enzyme replacement therapy with recombinant human acid α-glucosidase (alglucosidase alpha, Genzyme, Cambridge, MA) prolongs both survival and ventilator-free survival, and reverses cardiomegaly in infantile-onset Pompe disease [5], [6], [7]. The timing of intervention and the extent of lysosomal pathology are considered critical factors that determine the outcome of therapy for infantile-onset Pompe disease [5], [6], [7]. But when patients with infantile-onset Pompe disease were diagnosed with hypotonia and cardiomyopathy, the glycogen storage in myocytes was extensive [8]. The infusion of alglucosidase alpha at the time of diagnosis reduced cardiomyopathy, but did not completely clear skeletal muscle of glycogen [8] or prevent the occurrence of autophagy [9], even in good responders.
We therefore performed a large-scale newborn screening program for the early detection and treatment of Pompe disease [10]. Patients with classic infantile-onset Pompe disease who presented with cardiomyopathy at screening were treated before age 4 weeks, and their treatment outcome was significantly improved [11].
Enzyme replacement therapy for later-onset Pompe disease has been associated with improvement in either motor capability or pulmonary function [12], [13], [14], [15]. The best outcomes occurred in young, nonventilated patients, but the mean time from onset of signs to diagnosis averaged 10 years [16]. Muscle biopsies from clinically diagnosed adult patients with later-onset Pompe disease often demonstrate advanced pathologic changes, including late, stage 4 myocytes filled with extralysosomal glycogen, autophagic debris, and fatty replacement of muscles [17]. Because of our newborn screening for Pompe disease, patients with later-onset Pompe disease were prospectively followed until symptoms or signs appeared [18]. We therefore had the opportunity to extend our knowledge of early pathologic changes in later-onset Pompe disease.
Section snippets
Newborn screening
The Newborn Screening Center at National Taiwan University Hospital initiated a screening program for Pompe disease in 2005. Acid α-glucosidase activity was measured in dried bloodspots via a fluorescence assay [10]. Newborns with lymphocyte enzyme activity <5% of the normal mean and with cardiomyopathy were defined as manifesting infantile-onset Pompe disease, and were immediately treated. Newborns with deficient enzyme activity but no cardiomyopathy at the time of screening were followed
Patients
During prospective follow-up of the 15 asymptomatic newborns with later-onset Pompe disease, five demonstrated a delay in motor development and/or an elevation of serum creatine kinase, and treatment was initiated (Table 1). Patients designated NBS1 [10], NBSL2 (Case 3), and NBSL6 (Case 6) [18] were treated at ages 14, 36, and 28 months, respectively. Patient NBSL9 (Case 9) manifested an elevation of creatine kinase at age 1.5 months [18]. Patient NBSL15 was diagnosed prenatally with acid
Discussion
In this study, we prospectively followed and subsequently treated six asymptomatic patients with later-onset Pompe disease. This study was possible because of newborn screening for Pompe disease, and we observed the pathologic changes while the signs were still very mild. We emphasize that the main early clinical manifestation of later-onset Pompe disease is hypotonia of the trunk, but not weakness of the extremities. Therefore, when any pathologic change was detected in a patient’s quadriceps
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Outcome of Later-Onset Pompe Disease Identified Through Newborn Screening
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Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies
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