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  • Updated 08.07.2020
  • Released 01.04.1995
  • Expires For CME 08.07.2023

Pompe disease



The author describes the clinical, pathological, biochemical, and molecular features of Pompe disease, which is an underrecognized and extremely heterogeneous glycogen storage disease. Tremendous advances in infantile-onset Pompe disease have occurred since the development of enzyme replacement therapy (ERT)—the first FDA-approved treatment for this otherwise lethal disorder. Therapeutic success has subsequently been noted in both infantile-onset and late-onset patients, with those who begin enzyme replacement therapy earlier in the course of disease progression tending to respond better to treatment. Other factors in treatment response are now recognized, including negative impact of high and sustained antibody titers on the infused enzyme, the role of cross-reactive immunological material (CRIM) status in the mounting of immune response, variable treatment efficacy due to muscle fiber type, angiotensin-converting enzyme (ACE) insertion/deletion, ACTN3 variants, and the effects of defective autophagy. With the continued development of novel therapies, adjunctive treatments, and newborn screening programs, advancements in the treatment and management of Pompe disease continue to push the boundaries of modern medicine.

Key points

• Pompe disease is a glycogen storage, lysosomal storage, and neuromuscular disease that has a wide clinical spectrum, with 2 main categories: infantile-onset (IOPD) and late-onset Pompe disease (LOPD) (121). Infantile-onset is further divided into classic and nonclassic based on the presence of a severe or less severe cardiomyopathy in the first year of life, respectively. Late-onset is defined in this manuscript as 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 currently the only term exempt from debate. However, in the past few years, there has been some consensus on the nomenclature for the rest of the clinical continuum.

• The advent of enzyme replacement therapy (ERT) with intravenous alglucosidase alfa in 2006 marked the beginning of a shifting natural history, including new phenotypic manifestations, disease complications, and understanding of the spectrum of Pompe disease (122). 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 (159; 127; 128).

• 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 (CRIM) status, antibody response to ERT, underlying angiotensin-converting enzyme (ACE) 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, immunome 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

The infantile form of Pompe disease, also known as glycogen storage disease type II, was first described in 1932 in separate papers by Pompe and Putschar, who each called attention to the fatal glycogen storage in the heart (185; 190). Thirty-three years later, Zellweger, Courtecuisse, and their respective teams recognized the “muscular form,” or the less-progressive late-onset variant (45; 255). 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" (94) and, together with Lejeune and colleagues, showed that GAA was a lysosomal enzyme (143). Thus, Pompe disease became the prototype of inborn lysosomal diseases (95). In the years that followed, GAA deficiency was recognized in both children and adults with myopathy, and the main clinical variants of GAA deficiency – infantile-onset (classic and nonclassic) and late-onset (which included childhood, juvenile, and adult presentations) – were defined (66).

Over time, the alternate names Pompe disease, acid alpha-glucosidase deficiency (107), and glycogen storage disease type II (GSD II) have eclipsed the original name, acid maltase deficiency (57). The disease is more accurately attributed to a deficiency of lysosomal acid alpha-glucosidase rather than acid maltase because acid alpha-glucosidase functions generally by breaking down glycogen into glucose, whereas acid maltase specifically dismantles maltose into glucose. The eponym Pompe disease was originally limited to the infantile form of the disease, but is now utilized to describe all clinical variants.

A glycogen storage, lysosomal storage, and neuromuscular disease, Pompe disease represents a wide clinical spectrum that is now considered a clinical continuum with 2 subtypes, delineated by presence or absence of cardiomyopathy in the first year of life: infantile-onset (IOPD) and late-onset Pompe disease (LOPD) (121). IOPD is further classified as classic and nonclassic. Patients with classic IOPD 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 compared to the classic form without left ventricular outflow tract obstruction and typically live beyond the first 2 years of life without 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 the approval of enzyme replacement therapy with intravenous alglucosidase alfa (Myozyme™) in 2006 and the advent of newborn screening for Pompe disease (119; 188; 40). 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, infantile patients who are surviving with ERT have an emerging phenotype that seems to reflect features in the late-onset cohort, but also show very specific manifestations unique to their group. Based on these features, it is unclear whether the group should be labeled infantile survivors or late-onset. Since the advent of newborn screening, patients with LOPD are also now being identified with features of the disease in the first year of life. 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 (16; 80).

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