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  • Updated 12.21.2021
  • Released 01.04.1995
  • Expires For CME 12.21.2024

Pompe disease

Introduction

Overview

The authors describe the clinical, pathological, biochemical, and molecular features of Pompe disease, which is a heterogeneous glycogen storage disease. Tremendous advances in infantile Pompe disease have occurred since the development of enzyme replacement therapy--the first FDA-approved treatment for this otherwise lethal disorder. Therapeutic success has subsequently been noted in both infantile and late-onset Pompe disease; those who begin enzyme replacement therapy earlier in the course of disease progression tend to respond better to treatment. However, there are new emerging phenotypes among the survivors of Pompe disease, and therapies must be improved. With the continued development of novel therapies and newborn screening programs, advancements in the management of Pompe disease continue to push the boundaries of modern medicine.

Key points

• Pompe disease is a glycogen storage disease that has a wide clinical spectrum and is broadly classified as infantile and late-onset Pompe disease (93). Infantile Pompe disease is further divided into classic and non-classic, based on the presence of a severe (classic) or less severe (non-classic) cardiomyopathy in the first year of life. Late-onset Pompe disease is defined in this article as that which occurs in patients with no cardiac involvement in the first year of life, with an age at diagnosis and a clinical presentation ranging from infancy to as late as the sixth decade of life.

• “Classic infantile-onset Pompe disease” is the only term exempt from debate. However, there has been some consensus on the nomenclature for the rest of the clinical continuum in the past few years.

• The advent of enzyme replacement therapy with intravenous alglucosidase alfa in 2006 marked the beginning of a shifting natural history, including new phenotypic manifestations, disease complications, and understanding of the clinical spectrum of Pompe disease (94). Presentation continues to diversify by age at onset, extent of organ involvement, and degree of myopathy.

• There has been increasing evidence of central nervous system involvement in children with infantile-onset Pompe disease (125; 99; 101).

• Across the clinical spectrum, treatment response in patients continues to vary based on several factors, including muscle fiber type, defective autophagy, the degree of disease progression at the time of treatment initiation, cross-reactive immunological material status, antibody response to enzyme replacement therapy, underlying angiotensin-converting enzyme allele (insertion/deletion), ACTN3 variants, nutritional status, and other factors.

• Research on enhancing therapeutic efficacy continues as the disease is better understood, including the use of noninvasive adjunctive therapies, immune modulation to suppress or abrogate immune response, and new therapeutic targets. Investigations of the pathology have focused on pinpointing reasons for clinical plateau and the inability of enzyme replacement therapy to minimize the buildup of lysosomal and cytoplasmic glycogen, presence of autophagic material, especially in type 2 muscle fibers, and lipofuscin in late-onset patients.

Historical note and terminology

In 1932, Pompe and Putschar described case studies on infants with fatal “enlarged heart.” Thirty-three years later, Zellweger, Courtecuisse, and their respective teams recognized the less progressive “muscular form” (143; 148; 36; 202). In 1963, Hers documented the defect of the enzyme acid maltase (alpha-1,4- glucosidase, acid alpha-glucosidase, GAA) in liver, heart, and skeletal muscle of children with "cardiomegalic glycogenosis" and, together with Lejeune and colleagues, showed that GAA was a lysosomal enzyme (114; 74). Thus, Pompe disease became the prototype of inborn lysosomal diseases.

In the years that followed, GAA deficiency was recognized in both children and adults with myopathy, and the main clinical variants of GAA deficiency were categorized as infantile and late-onset forms (53). Over time, the alternate names “Pompe disease,” “acid alpha-glucosidase deficiency,” and “glycogen storage disease type II (GSD II)” have eclipsed the original name, “acid maltase deficiency” (47). The eponym Pompe disease was originally limited to the infantile form of the disease as described by JC Pompe but is now utilized to describe all clinical variants. The disease is more accurately attributed to a deficiency of lysosomal GAA rather than acid maltase because GAA generally functions by breaking down glycogen into glucose, whereas acid maltase specifically dismantles maltose into glucose.

Pompe disease represents a wide clinical spectrum that is now considered a clinical continuum with two subtypes, delineated by presence or absence of cardiomyopathy in the first year of life: infantile-onset Pompe disease and late-onset Pompe disease (93). IPD is further classified as classic and nonclassic. Patients with classic IPD present with severe cardiomyopathy and left ventricular outflow tract obstruction in the first year of life, which is fatal if untreated. Patients with the nonclassic form present with less severe cardiomyopathy than those with the classic form and typically live beyond the first 2 years of life without enzyme replacement therapy. Patients with LOPD (childhood, juvenile, and adult) typically do not have any cardiac involvement in the first year of life, and the age at symptom-onset typically ranges from infancy to the sixth decade of life. Patients with LOPD exhibit variable rates of progression of myopathy and pulmonary compromise.

Importantly, the phenotypic presentations of both the infantile-onset and late-onset forms continue to evolve as patients are living longer due to enzyme replacement therapy with intravenous alglucosidase alfa (rhGAA, Myozyme™) in 2006, the advent of newborn screening for Pompe disease (91; 146; 32), and immune modulation (43; 115). As the phenotypic spectrum continues to evolve, the nomenclature for the disease is struggling to keep pace. The definition of “classic infantile Pompe” is the only term that is currently exempt from criticism. In contrast, the true terminology for the rest of the clinical continuum continues to be debated as the characteristics that at one point helped delineate the groups, namely cardiac involvement, are being proven to exist across the categories. In particular, patients with IPD who are surviving with enzyme replacement therapy have an emerging phenotype that seems to reflect features in the LOPD cohort but also show specific manifestations unique to their group. Based on these features, it is unclear whether the IPD subgroups should be labeled as infantile survivors or a late-onset infantile subgroup. Since the advent of newborn screening, children with LOPD are also now being identified early, and a subset of these children present with subtle clinical signs in infancy. Similarly, it is unclear if this subset should be labeled as an infantile-onset late form of Pompe disease. Consensus on the nomenclature is needed and will continue to be an issue as the full clinical spectrum of Pompe disease is solidified and understood (10; 65).

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