Pompe disease (GSDII / acid maltase deficiency)

What changes during this transition

Pompe disease (glycogen storage disease type II, acid maltase deficiency) is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in the GAA gene (chromosome 17q25.3) encoding acid α-glucosidase. Deficient GAA enzyme activity causes progressive glycogen accumulation in lysosomes — affecting cardiac muscle, skeletal muscle, diaphragm, liver, smooth muscle, and CNS. Two clinical subtypes anchor the spectrum: infantile-onset Pompe disease (IOPD) — null GAA mutations, generalized hypotonia, massive hypertrophic cardiomyopathy, macroglossia, hepatomegaly, respiratory failure, historically fatal by age 1 pre-ERT; and late-onset Pompe disease (LOPD) — partial enzyme activity, presenting childhood through adulthood with proximal limb-girdle weakness and diaphragmatic weakness (often the load-bearing presenting symptom — dyspnea, orthopnea, sleep-disordered breathing), with mortality from respiratory failure. Many LOPD patients are diagnosed late through limb-girdle muscular dystrophy workup. Combined incidence ~1/40,000-100,000 varying by population. Newborn screening for Pompe is universal in many US states since 2015 (Taiwan pioneered the first universal program) — transforming early diagnosis and access to treatment. Diagnostics: GAA enzyme activity in dried blood spot, leukocytes, or fibroblasts (diagnostic); GAA gene sequencing confirms with genotype-phenotype correlation; CRIM (cross-reactive immunological material) status determination for IOPD predicts anti-drug antibody response; cardiac workup with echo, EKG, cardiac MRI (IOPD); pulmonary function with FVC supine vs upright to capture diaphragmatic weakness; muscle biopsy if diagnosis remains unclear. Standard of care is enzyme replacement therapy — three FDA-approved peptide/protein therapies anchor the modern era: alglucosidase alfa (Myozyme / Lumizyme, Sanofi/Genzyme, FDA-approved April 2006) — recombinant human GAA, the first ERT approved for Pompe, IV every 2 weeks at 20 mg/kg, transformed IOPD survival from death by 1 year to long-term survival typically with significant residual disability; CRIM-negative infants require immune tolerance induction protocols (rituximab + methotrexate + IVIG) to manage high anti-drug antibody titers. Avalglucosidase alfa (Nexviazyme, Sanofi, FDA-approved August 2021) — next-generation ERT with enhanced mannose-6-phosphate residues for improved muscle uptake; the COMET trial demonstrated improved FVC and functional outcomes vs alglucosidase alfa in late-onset Pompe. Cipaglucosidase alfa + miglustat (Pombiliti + Opfolda, Amicus Therapeutics, FDA-approved September 2023) — recombinant GAA with enhanced bis-phosphorylated M6P glycan paired with an oral enzyme stabilizer (miglustat) dosed just before infusion to prevent enzyme degradation in blood; the PROPEL trial demonstrated improved FVC and 6MWT vs alglucosidase alfa in LOPD adults. Multiple AAV-based gene therapy programs are in trials. Multidisciplinary Pompe center care is the standard — neuromuscular specialist, cardiologist (acutely for IOPD), pulmonologist, geneticist, physical and respiratory therapy, speech and swallowing, nutrition, with NIV / BiPAP / tracheostomy as respiratory decline progresses. Lifelong ERT carries substantial cost (~$300–700k/year) and family genetic counseling with cascade screening is part of standard care. The Pompe community is anchored by the Acid Maltase Deficiency Association (AMDA), International Pompe Association (IPA), Pompe Disease Foundation, Muscular Dystrophy Association (MDA), and the broader lysosomal storage disease patient organizations internationally. Editorially: the three FDA-approved ERTs are the peptide/protein therapies that engage Pompe biology — they are named here as standard of care. Community peptides reach Pompe patients through generic 'muscle weakness', 'healing', and 'myostatin' framing — none engage GAA enzyme activity or lysosomal glycogen clearance, and none are appropriate substitutes for ERT or for the multidisciplinary Pompe center care model. Seventy-ninth deliberate non-elevation of community peptides.