Pompe Disease · GSD-II

Description

Pompe disease, also called glycogen storage disease type II (GSD-II) or acid maltase deficiency, is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in GAA, the gene encoding acid alpha-glucosidase. The enzyme breaks down lysosomal glycogen to glucose. Two damaging copies leave glycogen to accumulate in lysosomes, especially in cardiac, skeletal, and smooth muscle, with progressive cellular and tissue damage. The disease was first described by Dutch pathologist Johannes Pompe in 1932.

Pompe disease has a continuous spectrum of severity that is generally divided clinically into infantile-onset and late-onset forms. Infantile-onset Pompe disease (IOPD) presents in the first months of life with hypertrophic cardiomyopathy, profound hypotonia, feeding difficulty, and respiratory insufficiency. Untreated, the historical median survival was under one year of age, with death from cardiorespiratory failure. Late-onset Pompe disease (LOPD) presents from later infancy through adulthood with progressive proximal limb-girdle weakness and diaphragmatic weakness leading to respiratory failure. Cardiac involvement in LOPD is uncommon. Cross-reactive immunologic material (CRIM) status, determined by residual GAA protein, predicts immune response to enzyme replacement and informs immune-tolerance induction in CRIM-negative infants.

Reported live-birth incidence is approximately 1 in 40,000, with regional variation. Detection in the United States is by newborn screening on the dried blood spot using GAA enzyme activity, often paired with second-tier biomarker or sequencing. Pompe was added to the Recommended Uniform Screening Panel in March 2015 following the recommendation of Rodney Howell's ACHDNC committee. Confirmation uses GAA enzyme assay in lymphocytes or fibroblasts and GAA gene sequencing.

Treatments to date

Enzyme replacement therapy with recombinant human GAA changed the natural history of Pompe disease. Alglucosidase alfa was FDA approved as Myozyme in April 2006 for IOPD, an outcome shaped in part by John Crowley's family advocacy and the Duke University program led by Priya Kishnani. Alglucosidase alfa given every two weeks intravenously reverses cardiomyopathy in IOPD and extends ventilator-free survival, with outcomes that depend on age at treatment initiation and CRIM status (Kishnani et al., Neurology, 2007). A second branded formulation, Lumizyme, was approved in May 2010 for late-onset Pompe disease in patients 8 and older without cardiac hypertrophy, and the Lumizyme label was expanded in 2014 to cover all ages with Pompe disease.

Avalglucosidase alfa (Nexviazyme, marketed as Nexviadyme in the European Union) was FDA approved in August 2021 for LOPD ages 1 and older. The molecule is engineered with bis-mannose-6-phosphate to improve uptake into muscle, and showed noninferiority to alglucosidase alfa on respiratory function and improvement on a six-minute walk test in the COMET trial (Diaz-Manera et al., Lancet Neurology, 2021).

Cipaglucosidase alfa with miglustat (Pombiliti and Opfolda) was FDA approved in September 2023 for adults with LOPD who are not improving on their current enzyme replacement therapy. Miglustat is an orally administered enzyme stabilizer co-dosed with the recombinant enzyme to reduce inactivation in plasma.

Standard care also includes respiratory support with noninvasive ventilation, physical therapy, cardiac surveillance in IOPD, and immune-tolerance induction protocols for CRIM-negative infants starting enzyme replacement. Gene therapy programs delivering GAA by adeno-associated virus to liver or muscle are in early- and mid-phase trials.