Abstract
Pompe disease is caused by the accumulation of glycogen in the lysosomes due to a deficiency of the lysosomal acid-α-glucosidase (GAA) enzyme. Depending on residual enzyme activity, the disease manifests two distinct phenotypes. In this study, we assess an enzymatic and genetic analysis of Hungarian patients with Pompe disease. Twenty-four patients diagnosed with Pompe disease were included. Enzyme activity of acid-α-glucosidase was measured by mass spectrometry. Sanger sequencing and an MLPA of the GAA gene were performed in all patients. Twenty (83.33%) patients were classified as having late-onset Pompe disease and four (16.66%) had infantile-onset Pompe disease. Fifteen different pathogenic GAA variants were detected. The most common finding was the c.-32-13 T > G splice site alteration. Comparing the α-glucosidase enzyme activity of homozygous cases to the compound heterozygous cases of the c.-32-13 T > G disease-causing variant, the mean GAA activity in homozygous cases was significantly higher. The lowest enzyme activity was found in cases where the c.-32-13 T > G variant was not present. The localization of the identified sequence variations in regions encoding the crucial protein domains of GAA correlates with severe effects on enzyme activity. A better understanding of the impact of pathogenic gene variations may help earlier initiation of enzyme replacement therapy (ERT) if subtle symptoms occur. Further information on the effect of GAA gene variation on the efficacy of treatment and the extent of immune response to ERT would be of importance for optimal disease management and designing effective treatment plans.
Highlights
Glycogen storage disease type II (Pompe disease or acid maltase deficiency) is an autosomal recessive metabolic disorder characterized by the accumulation of glycogen in the lysosomes due to a deficiency of the lysosomal acid alpha-glucosidase (GAA) enzyme.The gene encoding the enzyme is located on chromosome 17q25.2-q25.3
The greater the extent and number of autophagosomal and lipofuscin inclusions are before enzyme replacement therapy (ERT) treatment, the less clinical improvement is achieved [20]
This finding indicates that earlier disease onset and later-initiated ERT favors the accumulation of secondary pathological materials, which impair the clinical response to treatment [20]
Summary
Glycogen storage disease type II (Pompe disease or acid maltase deficiency) is an autosomal recessive metabolic disorder characterized by the accumulation of glycogen in the lysosomes due to a deficiency of the lysosomal acid alpha-glucosidase (GAA) enzyme. In Pompe disease, beside the primary lysosomal pathology, large amounts of non-contractile lipofuscin inclusion and autophagosomal buildup were found in the muscle fibers of LOPD patients, contributing to their clinical status. These pathological findings showed progression over time, even in patients on ERT treatment [20]. The greater the extent and number of autophagosomal and lipofuscin inclusions are before ERT treatment, the less clinical improvement is achieved [20] This finding indicates that earlier disease onset and later-initiated ERT favors the accumulation of secondary pathological materials, which impair the clinical response to treatment [20]. We assessed the protein domain involvement linked to different disease-causing alterations with the possible effect these variants may have on protein structure, GAA enzyme activity and phenotypes
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