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Glycogen storage disease type II (Pompe disease) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in GAA (acid α-glucosidase). The association between GAA and Pompe disease is supported by hundreds of case reports and large cohort studies, demonstrating that biallelic loss-of-function and missense variants lead to absent or severely reduced enzyme activity, characteristic infantile-onset cardiomyopathy, hypotonia and progressive muscle weakness ([PMID:9266392], [PMID:22644586]).
The clinical validity of GAA in Pompe disease is Definitive. Over 867 patients with biallelic GAA variants have been reported in the literature, spanning the full spectrum from classic infantile to late-onset forms, with multiple families showing segregation of variants with disease and concordant functional defects in patient cells and animal models ([PMID:22644586]).
Inheritance is autosomal recessive, with compound heterozygotes or homozygotes exhibiting disease. Segregation has been demonstrated in at least 19 families with multiple affected relatives. Case series report over 500 distinct GAA variants, including missense (e.g., c.1726G>A (p.Gly576Ser)), nonsense (e.g., c.118C>T (p.Arg40Ter)), splice (e.g., c.-32-13T>G), small indels and large deletions ([PMID:11738358]). Founder alleles such as c.-32-13T>G are prevalent in Caucasians, while c.1935C>A (p.Asp645Glu) is common in Southern Han Chinese ([PMID:36517654]). Phenotypes range from hypertrophic cardiomyopathy and hypotonia in infancy to proximal muscle weakness and respiratory insufficiency in adults.
Functional assays in patient fibroblasts and transfected cells show that missense variants impair enzyme processing, stability and catalytic activity. Splicing studies reveal that c.-32-13T>G abrogates U2AF65 binding and exon 2 inclusion, reversible by antisense morpholinos and small molecules ([PMID:24150945]). A knock-in mouse model carrying c.1935C>A (p.Asp645Glu) recapitulates infantile cardiomyopathy, hypotonia, and glycogen storage, confirming haploinsufficiency as the pathogenic mechanism ([PMID:36517654]). Pharmacological chaperones and proteasome inhibitors enhance mutant GAA folding, trafficking and activity in vitro, and reduce glycogen burden in vivo.
No robust refutations have been reported. Pseudodeficiency alleles (e.g., c.1726G>A; c.2065G>A) can lower enzyme assays in screening but do not cause clinical disease when homozygous ([PMID:19362502]).
Genetic and functional data converge to establish GAA as the definitive cause of Pompe disease. The breadth of phenotypic presentations—from lethal infantile cardiomyopathy to slowly progressive adult myopathy—correlates with residual enzyme activity dictated by variant type. Functional studies guide therapeutic strategies including enzyme replacement, pharmacological chaperones and antisense rescue of splicing. Further variants continue to be catalogued, but current evidence fully supports clinical genetic testing and early intervention.
Key Take-home: Biallelic pathogenic GAA variants cause Pompe disease with a spectrum of severity; molecular diagnosis enables timely treatment and genetic counseling.
Gene–Disease AssociationDefinitive867 patients across >400 families, extensive segregation and functional concordance Genetic EvidenceStrongOver 500 distinct variants in compound heterozygous or homozygous state in >800 patients; autosomal recessive inheritance with segregation Functional EvidenceModerateIn vitro and in vivo assays demonstrate defective GAA processing and activity and rescue by chaperones, ASOs, and mouse models |