Fast Five Quiz: Late-Onset Pompe Disease
Multiple genetic variants have been associated with LOPD. However, the c.-32-13T>G splice site variant is found in up to 90% of adults and 50% of pediatric patients. Patients with LOPD often have compound heterozygous genotypes, with one allele carrying the common c.-32-13T>G splice-site variant and the other harboring a more deleterious GAA mutation (eg, nonsense, frameshift, or large deletion).
Other variants— such as p.Arg854*, p.Asp645Glu, and c.1935C>A — are more commonly seen in infantile forms of Pompe disease.
Learn more about the pathophysiology of LOPD.
Diagnosis of LOPD typically follows a two-step approach: first, measuring GAA enzyme activity (often via dried blood spot assay) followed by confirmatory molecular genetic testing to identify pathogenic GAA variants.
Although once considered a first-line diagnostic tool for LOPD, muscle biopsy is no longer preferred due to its invasive nature and the non-specificity of histologic findings. Muscle biopsy may still be considered in rare, ambiguous cases when enzyme and genetic testing are inconclusive or conflicting.
CK levels might be elevated in some patients but are nonspecific and primarily serve to raise clinical suspicion.
Learn more about the workup for LOPD.
Enzyme replacement therapy (ERT) has significantly changed the natural history of the disease by improving survival and stabilizing motor and respiratory function. However, key limitations in skeletal muscle uptake and variability in clinical response remain. This is due to low expression of the mannose-6-phosphate receptor in muscle tissue, which hampers enzyme internalization. As a result, patients might experience a limited or plateaued response. Newer approaches, including modified ERT and gene therapy, are being developed to address this issue.
High toxicity to cardiac muscle, uniform patient response, and development of cardiac hypertrophy have not been reported as key limitations.
Learn more about treatment options for LOPD.
NBS programs have reshaped the understanding of Pompe disease, particularly LOPD. A significant proportion of screen-positive newborns harbor genetic variants associated with LOPD, including pseudo deficiency alleles and variants of uncertain significance. These individuals are often asymptomatic at birth and might not develop symptoms for years, if at all. This has raised important clinical questions around monitoring, counseling, and when (or whether) to initiate therapy; expanded screening has also revealed that the true prevalence of LOPD might be higher than historical estimates suggested.
Learn more about the management of LOPD.
Editor's Note: This article was created using several editorial tools, including generative AI models, as part of the process. Human review and editing of this content were performed prior to publication. Lead image: UCSF/Science Source
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