Newborn Screening for Pompe Disease: Pennsylvania Experience

Fıçıcıoğlu, Can; Ahrens‐Nicklas, Rebecca C.; Joshua, Joshua; Cuddapah, Sanmati; DiBoscio, Brenda; DiPerna, James C.; Gordon, Patricia L.; Henderson, Nadene; Menello, Caitlin; Luongo, Nicole; Ortiz, Damara; Xiao, Rui

doi:10.3390/ijns6040089

Cited by 32 publications

(32 citation statements)

References 34 publications

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“…We also analyzed the effect of these genotypes on disease manifestation and the potential alteration they make on the GAA enzyme structure, resulting decreased enzyme activity. Consistent with the results reported in the literature, in our cohort, the GAA enzyme activity measured in the IOPD group is significantly lower compared to the LOPD cases (Figure 1A-C; Table 1) [30,43,44]. Fifteen…”

Section: Discussionsupporting

confidence: 92%

“…Based on our data, the GAA enzyme activity in c.-32-13T > G homozygous cases are significantly higher when compared to cases with the c.-32-13T > G alteration is present in compound heterozygous form with another pathogenic variant. Similar results were obtained in newborn GAA screening reported in Pennsylvania, where enzyme activity of GAA was significantly higher in homozygous cases compared to compound heterozygous ones [30]. This difference may be due to the fact that, in c.-32-13T > G homozygous cases, only exon 2 of GAA gene is misspliced while, in cases of other variants, the protein may be truncated or its conformation may be significantly altered.…”

Section: Discussionsupporting

confidence: 84%

“…In her case, the disease is characterized by earlier onset (AOO 23 years) and relatively low enzyme activity (0.16 µmol/L/h) (Table 1, Figure 1A,B). Compared to a comprehensive study in Pennsylvania, where 21 LOPD patients featured the c.-32-13T > G alteration, the mean GAA activity of patients did not differ significantly from the group carrying the c.-32-13T > G variant at least on one allele [30]. One of our patient was compound heterozygous for the c.925 G > A (p.Gly309Arg) and the c.1468 T > C (p.Phe490Leu) alteration involving the N-terminal-β-sheet and catalytic CH31 (α/β)8 barrel domains (Table 1, Figure 1A).…”

Section: Discussioncontrasting

confidence: 83%

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Correlation of GAA Genotype and Acid-α-Glucosidase Enzyme Activity in Hungarian Patients with Pompe Disease

Gál

Grosz

Borsos

et al. 2021

Life

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 84%

Section: Discussioncontrasting

confidence: 83%

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Correlation of GAA Genotype and Acid-α-Glucosidase Enzyme Activity in Hungarian Patients with Pompe Disease

Gál

Grosz

Borsos

et al. 2021

Life

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“…Notably, the pathogenic variant c.-32-13T > G, which is frequently detected in patients with LOPD in Europe and the United States (24), was not detected in our screening program. The total recall rate in this program was 0.1%, which was approximately ve times higher than that of the United States (17,19). We attribute the high false-positive rate to the high frequency of the pseudode ciency variant c.[1726G > A; 2065G > A] in East Asia.…”

Section: Discussionmentioning

confidence: 82%

Current Status of Newborn Screening for Pompe Disease in Japan

Sawada

Kido

Sugawara

et al. 2021

Preprint

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Background: Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (AαGlu). Pompe disease manifests as an accumulation of lysosomal glycogen in the skeletal and heart muscle. We conducted newborn screening (NBS) for Pompe disease in Japan from April 2013 to October 2020 to determine the feasibility and utility of NBS for Pompe disease.Results: From the 296,759 newborns whose enzyme activity was measured, 107 of which underwent GAA analysis, we found one patient with infantile-onset Pompe disease (IOPD) and seven with potential late-onset Pompe disease (LOPD). We identified 34 pseudodeficient individuals and 65 carriers or potential carriers. The frequency of patients with IOPD was similar to that in the United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years.Conclusions: The frequency of IOPD in Japan was similar to that in the United States, where NBS for Pompe disease is recommended. This indicates that NBS for Pompe disease may also be useful in Japan. Therefore, it should be used over a wider region in Japan.

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“…Reduced GAA activity in DBS is reported in both IOPD and LOPD patients [ 10 ], but second tier testing is required to confirm a diagnosis due to pseudodeficiency alleles which result in a reduction in GAA activity in vitro but no active disease [ 11 ]. Molecular screening for GAA genetic variants can be used as confirmation of PD but is complicated by a high number of genetic variants of uncertain significance (VUS) [ 12 , 13 ] that still require phenotype confirmation.…”

Section: Introductionmentioning

confidence: 99%

Experience with the Urinary Tetrasaccharide Metabolite for Pompe Disease in the Diagnostic Laboratory

Saville

Fuller

2021

Metabolites

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Following clinical indications, the laboratory diagnosis of the inherited metabolic myopathy, Pompe disease (PD), typically begins with demonstrating a reduction in acid alpha-glucosidase (GAA), the enzyme required for lysosomal glycogen degradation. Although simple in concept, a major challenge is defining reference intervals, as even carriers can have reduced GAA, and pseudodeficiencies complicate interpretation. Here, we developed a mass spectrometric assay for quantification of a urinary glycogen metabolite (tetrasaccharide) and reported on its utility as a confirmatory test for PD in a diagnostic laboratory. Using two age-related reference intervals, eight returned tetrasaccharide concentrations above the calculated reference interval but did not have PD, highlighting non-specificity. However, retrospective analysis revealed elevated tetrasaccharide in seven infantile-onset (IOPD) cases and sixteen late-onset (LOPD) cases, and normal concentrations in one heterozygote. Prospective tetrasaccharide analysis in nine individuals with reduced GAA confirmed IOPD in one, LOPD in six and identified two heterozygotes. Using this metabolite as a biomarker of therapeutic response was not overly informative; although most patients showed an initial drop following therapy initiation, tetrasaccharide concentrations fluctuated considerably and remained above reference intervals in all patients. While useful as a confirmation of PD, its utility as a biomarker for monitoring treatment warrants further investigation.

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Newborn Screening for Pompe Disease: Pennsylvania Experience

Cited by 32 publications

References 34 publications

Correlation of GAA Genotype and Acid-α-Glucosidase Enzyme Activity in Hungarian Patients with Pompe Disease

Correlation of GAA Genotype and Acid-α-Glucosidase Enzyme Activity in Hungarian Patients with Pompe Disease

Current Status of Newborn Screening for Pompe Disease in Japan

Experience with the Urinary Tetrasaccharide Metabolite for Pompe Disease in the Diagnostic Laboratory

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