Elsevier

Pediatric Neurology

Volume 46, Issue 3, March 2012, Pages 168-171
Pediatric Neurology

Original Article
Early Pathologic Changes and Responses to Treatment in Patients With Later-Onset Pompe Disease

https://doi.org/10.1016/j.pediatrneurol.2011.12.010Get rights and content

Abstract

The treatment of later-onset Pompe disease with enzyme replacement therapy may not lead to significant improvement in muscle function, probably because of the irreversible muscle destruction caused by glycogen storage. A prospective study was performed to understand early muscle pathology in patients and the response of these pathologic changes to treatment. Five newborns and one child with later-onset Pompe disease but no signs at time of diagnosis were prospectively followed, and treatment was initiated when signs appeared. Six pretreatment biopsies taken at ages 1.5 months to 7 years indicated glycogen storage, lipid storage, stage 4 myocytes, and autophagic debris. Four 6-month posttreatment biopsies revealed glycogen clearance, but stage 4 myocytes and autophagic debris were still evident in three. In conclusion, among patients with later-onset Pompe disease and very mild signs, advanced pathologic changes were evident in a small portion of their myocytes. Because these pathologic changes may not respond to treatment, early treatment is necessary to achieve the best outcomes.

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

References (22)

  • J.H. Wokke et al.

    Clinical features of late-onset Pompe disease: A prospective cohort study

    Muscle Nerve

    (2008)
  • Cited by (20)

    • Outcome of Later-Onset Pompe Disease Identified Through Newborn Screening

      2022, Journal of Pediatrics
      Citation Excerpt :

      Motor performance (GMFM-66, PDMS-2 gross motor, and Pompe-PEDI mobility) also improved in all subjects, and they could maintain average physical endurance as measured by the 6MWT (Figure 3). The elder sibling of subject 9 (9a), who already had lordosis and elevated CK levels at age 7 years,15 was also stabilized (Figure 3, E). In contrast, subject 25, who started ERT at age 4 months but withdrew at 10 months due to family issues, showed worsening biochemical variables and GMFM-66 after that (Figure 3, F).

    • Safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of the novel enzyme replacement therapy avalglucosidase alfa (neoGAA) in treatment-naïve and alglucosidase alfa-treated patients with late-onset Pompe disease: A phase 1, open-label, multicenter, multinational, ascending dose study

      2019, Neuromuscular Disorders
      Citation Excerpt :

      Muscle pathology in LOPD is characterized by progressive muscle damage starting with intralysosomal glycogen to accumulation of storage material [8], autophagic build-up [9], loss of contractile structure [10], muscle atrophy and replacement by fat [11–13], and concomitant progressive loss of function [14]. This process may already start in early life [15] and clinically diagnosed symptomatic patients’ health and functional status may already be severely impaired at presentation [15–17]. For symptomatic patients with LOPD, the risk of wheelchair use increases by 13% and the risk of ventilator dependency increases by 8% for each additional post-diagnosis year without treatment [18].

    • Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T &gt; G “late-onset” GAA variant

      2017, Molecular Genetics and Metabolism
      Citation Excerpt :

      The management and treatment of infants diagnosed with this “late-onset” GAA variant following NBS remains unclear, due to diagnostic delay and the paucity of published literature on this patient population [16,22–26]. Data from the Taiwan Pompe NBS program, which began in 2005 is a valuable resource [27–29]; however, absence of the IVS c.-32-13T > G splice site variant in Taiwan as compared to Caucasian populations, limits our ability to extrapolate conclusions from Taiwan's LOPD program [30]. We present seven consecutive patients with “late-onset” GAA variants identified by NBS, consisting of three patients with c.-32-13T > G variant in compound heterozygosity and a second pathogenic variant and four patients with c.-32-13T > G variant in homozygosity.

    • Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease

      2017, Molecular Genetics and Metabolism Reports
      Citation Excerpt :

      Fourteen IOPD patients older than 2 years of age were enrolled in the trial (Supplement Table 1). All patients exhibited severe GAA deficiency and two pathologic GAA mutations in trans and were cross-reactive immunological material positive [7,14–16]. All patients had presented symptoms before 12 months of age and were treated with rhGAA with dosages of 20–40 mg/kg/2 weeks (or 20 mg/kg every week), and none of them exhibited sustained high levels of anti-rhGAA antibodies.

    • Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies

      2013, Molecular Genetics and Metabolism
      Citation Excerpt :

      Delay from onset of symptoms to diagnosis has been reported to be 7 years on average, and misdiagnosis before a final diagnosis of Pompe disease is very common [2,3]. There is evidence to suggest that onset of treatment with enzyme replacement therapy is more effective if given early in the disease course, and therefore a delay in diagnosis should be minimized as much as possible [4]. At the time of the study preparation, in 2009, we were aware of only six known cases of Pompe disease in Denmark, two of whom had the classical infantile form of the disease.

    View all citing articles on Scopus
    View full text