Pompe disease

Priya S Kishnani MD (Dr. Kishnani of Duke University Medical Center received research and grant support and/or honorariums from Genzyme, Amicus, and Alexion, and serves on the advisory boards for Advance Liquid Logic, Baebies, Protalix/Pfizer and Shire.)
Salvatore DiMauro MD, editor. (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released January 4, 1995; last updated August 24, 2016; expires August 24, 2019

This article includes discussion of Pompe disease, AMD, acid maltase deficiency, glycogen storage disease type II, glycogenesis type II, classic infantile-onset Pompe disease, atypical (non-classic) infantile-onset Pompe disease, late-onset Pompe disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The author describes the clinical, pathological, biochemical, and molecular features of Pompe disease, an underrecognized and extremely heterogeneous glycogenosis. The most exciting developments are the advances in the field and progress since the development of enzyme replacement therapy, the first FDA-approved treatment for this otherwise lethal disorder. Success has been noted in both infantile-onset and late-onset patients, with those who begin treatment earlier in the course of disease progression tending to respond better to treatment. Other factors in treatment response have been noted, 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 polymorphisms, and the effects of defective autophagy. With the continued development of novel therapies, adjunctive treatments, and newborn screening programs, Pompe disease continues to diversify in presentation.

Key points

 

• Pompe disease is a glycogen storage, lysosomal storage, and neuromuscular disease that presents as a wide clinical spectrum divisible into 2 main categories: infantile-onset (IOPD) and late-onset Pompe disease (LOPD) (Kishnani et al 2006). Infantile-onset is further divided into classic and atypical (non-classic) based on the presence of a severe or less severe cardiomyopathy, respectively. Late-onset is defined in this manuscript as disease onset after 1 year of age, ranging from childhood to as late as the sixth decade of life, and exhibition of a slow-advancing myopathy and pulmonary compromise.

 

• “Classic infantile Pompe disease” is currently the only term exempt from debate, whereas the terminology for the rest of the clinical continuum varies. Consensus on the nomenclature is needed.

 

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

 

• 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 time of treatment initiation, cross-reactive immunological material (CRIM) status, antibody response to ERT, underlying angiotensin-converting enzyme (ACE) allele (insertion/deletion), ACTN3 polymorphism, nutritional status, and other factors.

 

•Research on enhancing therapeutic efficacy continues as the disease is better understood, including the use of noninvasive adjunctive therapies, immunomodulation to suppress or abrogate immune response, and new therapeutic targets. Investigations of Pompe disease pathology have focused on pinpointing reasons for clinical plateau in patients and the inability of ERT 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 (Pompe 1932; Putschar 1932). Thirty-three years later, Zellweger, Courtecuisse, and their respective teams recognized the “muscular form,” or the less-progressive late-onset variant (Courtecuisse et al 1965; Zellweger et al 1965). 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" (Hers 1963) and, together with Lejeune and colleagues, showed that GAA was a lysosomal enzyme (Lejeune et al 1963). Thus, Pompe disease became the prototype of inborn lysosomal diseases (Hers 1965). In the years that followed, GAA deficiency was recognized in both children and adults with myopathy, and 3 main clinical variants of GAA deficiency – infantile-onset (classic and nonclassic) and late-onset (which included childhood, juvenile, and adult presentations) – were defined (Engel 1986).

Over time, the alternate names Pompe disease, acid alpha-glucosidase (GAA) deficiency, and glycogen storage disease type II (GSD II) have eclipsed the original name, acid maltase deficiency (DiMauro et al 2007). 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 can be divided into 2 main categories: infantile-onset and late-onset Pompe disease (Kishnani et al 2006). Infantile-onset, or disease onset before 1 year of age, is further separated into classic and non-classic (atypical, infantile variant) based on the presence or absence of cardiomyopathy, respectively. On occasion, some of those who have the non-classic form do present with cardiomyopathy but typically live beyond the first 2 years of life without therapy. The late-onset form (childhood, juvenile, and adult) typically describes patients with disease onset after 1 year of age, including patients ranging from childhood age to the sixth decade of life who exhibit slow-advancing myopathy and pulmonary compromise.

Importantly, the phenotypic presentations of both the infantile- and late-onset forms continue to evolve as patients are living longer due to the approval of enzyme replacement therapy (ERT) with intravenous alglucosidase alfa (Myozyme™) in 2006. 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 1 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. 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 (Beckemeyer et al 2013; Güngör and Reuser 2013).

The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.

If you are a subscriber, please log in.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.

If you have never registered before, click Learn More about MedLink Neurology  or view available Service Plans.