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Condition report · Metabolic

Pompe Disease

Whole genome sequencing reads the complete GAA gene, identifying all variant types including the common intronic pseudodeficiency allele that confounds enzyme assay-based carrier and newborn screening in Pompe disease.

A condition report looks for rare variants known to cause the conditions it covers.

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About this condition

An inherited lysosomal storage disorder caused by variants in the GAA gene, in which glycogen builds up in muscle. It ranges from a severe infantile form affecting the heart to a later-onset form with progressive muscle and breathing weakness.

Pompe disease (glycogen storage disease type II, GSDII, acid maltase deficiency) is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in GAA (acid alpha-glucosidase) on chromosome 17q25.3. GAA encodes the enzyme responsible for lysosomal glycogen degradation; its deficiency leads to progressive glycogen accumulation in muscle cells, causing skeletal muscle weakness, respiratory failure, and cardiac involvement. Pompe disease presents as a clinical spectrum ranging from classic infantile-onset Pompe disease (IOPD), characterized by rapidly progressive hypertrophic cardiomyopathy, profound hypotonia, and respiratory failure in the first months of life, to late-onset Pompe disease (LOPD), presenting from early childhood to the eighth decade with progressive proximal muscle weakness and respiratory insufficiency without cardiac involvement.

The molecular genetics of Pompe disease are complex. Over 900 GAA variants have been documented. The most common disease-causing variant in individuals of European ancestry is c.-32-13T>G (IVS1), a leaky splice site variant that allows approximately 10-20% normal GAA mRNA production and is associated with late-onset disease. The most common pathogenic variant in African-ancestry patients is p.Arg854X. A critical molecular complexity is the GAA pseudodeficiency allele (c.1726G>A; p.Gly576Ser and c.2065G>A; p.Glu689Lys, usually in cis forming the c.[1726G>A;2065G>A] haplotype), which reduces GAA enzyme activity on biochemical assay without causing disease. This pseudodeficiency allele confounds newborn screening programs and carrier assays, creating false-positive results that require molecular confirmation to resolve.

Alglucosidase alfa (Myozyme/Lumizyme) has been the standard enzyme replacement therapy (ERT) for Pompe disease since 2006 and substantially slows progression, particularly in LOPD patients treated before irreversible muscle loss. In 2022, cipaglucosidase alfa (Pombiliti) combined with miglustat (a pharmacological chaperone) received FDA approval, demonstrating superiority to standard alglucosidase alfa in LOPD in the PROPEL trial. Gene therapy approaches using AAV vectors are in clinical trials. The window of maximum treatment benefit in LOPD is early in the disease course, before diaphragmatic and limb-girdle muscle fibrosis develops, making early molecular diagnosis critical.

Classic infantile Pompe and late-onset Pompe are phenotypically distinct. The IVS1 (c.-32-13T>G) variant allows some residual GAA expression and is strongly associated with late-onset disease. Compound heterozygotes for IVS1 plus a null allele have variable but typically late-onset presentations.

The condition we analyse

Pompe Disease (Glycogen Storage Disease II)

Autosomal recessive

Glycogen storage disease due to acid maltase deficiency (AMD) is an autosomal recessive trait leading to metabolic myopathy that affects cardiac and respiratory muscles in addition to skeletal muscle and other tissues. AMD represents a wide spectrum of clinical presentations caused by an accumulation of glycogen in lysosomes: Glycogen storage disease due to acid maltase deficiency, infantile onset, non-classic infantile onset and adult onset. Early onset forms are more severe and often fatal.

What a diagnosis changes

Enzyme replacement therapy (alglucosidase alfa; cipaglucosidase alfa + miglustat, superior in late-onset disease); respiratory support (BiPAP/CPAP/mechanical ventilation); physiotherapy; gene therapy in clinical trials

Genes analysed

Also known as

acid maltase deficiency; acid maltase deficiency disease; Aglucosidase alfa; Alpha-1,4-glucosidase acid deficiency; deficiency of alpha-glucosidase; deficiency of lysosomal alpha-glucosidase; GAA glycogen storage disease; generalised glycogenosis; glycogen storage disease caused by mutation in GAA; glycogen storage disease type 2; glycogen storage disease type II; glycogenosis due to acid maltase deficiency; glycogenosis type 2; glycogenosis type II; GSD due to acid maltase deficiency; GSD II; GSD type 2; GSD type II; GSD2; Pompe Disease

Includes 2 related subtypes ↓
  • glycogen storage disease due to acid maltase deficiency, infantile onset
  • glycogen storage disease due to acid maltase deficiency, late-onset
MONDO:0009290Orphanet 365MedGen 5340

Example variants this report looks at

For each condition, a few of the variants ClinVar classifies under it, those with most review stars. Each page describes ClinVar's public record of the variant, never a result.

VariantGeneClinVar classificationReview status
A14Rfs*18GAAPathogenic3 stars out of 4 reviewed by expert panel
A150Gfs*27GAALikely pathogenic3 stars out of 4 reviewed by expert panel
A382Lfs*10GAAPathogenic3 stars out of 4 reviewed by expert panel

482 more variants under Pompe Disease (Glycogen Storage Disease II) have a page. Every variant, by gene:

Why whole genome sequencing

The GAA pseudodeficiency allele causes false-positive results on enzyme assays and newborn screens. Only molecular genotyping can distinguish true Pompe disease from pseudodeficiency, and the complete GAA genotype determines which ERT protocol is optimal.

Pseudodeficiency alleles cause false-positive Pompe screening results that only molecular testing can resolve

Newborn screening programs that detect low acid alpha-glucosidase (GAA) enzyme activity on dried blood spots generate false-positive results in infants who carry one or two GAA pseudodeficiency alleles, alleles that reduce enzyme activity on assay without causing disease. The pseudodeficiency allele (c.[1726G>A;2065G>A]) is present in approximately 3-4% of the general population and is particularly common in Asian ancestry groups. Distinguishing a true Pompe disease newborn from a pseudodeficiency-positive newborn requires molecular GAA genotyping. Whole genome sequencing identifies all GAA variants including the pseudodeficiency haplotype, resolving ambiguous newborn screen results and preventing both over-treatment of pseudodeficiency carriers and under-treatment of true Pompe disease cases.

The cipaglucosidase alfa + miglustat combination has variant-specific response characteristics

Cipaglucosidase alfa (Pombiliti) is a next-generation recombinant GAA with improved mannose-6-phosphate receptor-mediated uptake and superior muscle delivery compared to standard alglucosidase alfa. Miglustat co-administration stabilizes the enzyme during blood transit. Clinical trial data from PROPEL showed overall superiority to standard ERT, with the greatest benefit in patients who had not previously been on ERT and those with higher anti-drug antibody titers. The GAA genotype, particularly whether a patient has residual GAA mRNA production (such as IVS1/null compound heterozygotes), influences anti-drug antibody development risk, which is a key determinant of ERT response. Complete GAA characterization informs this immune response risk prediction.

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