Table 4. GAA mutations and enzyme activities in various tissues in patients with Pompe disease.
Four novel (predicted to be pathogenic) were identified including “p.I468F” which was found in 2 unrelated individuals. Amniocytes in patient 1 showed undetectable GAA activity, which predicts severe classical IOPD, while postnatal DBS showed detectable but markedly reduced GAA activity.
| Patient | GAA mutation | GAA enzyme activity | Order of diagnostic studies | Maximum anti-Lumizyme IgG antibody titer* | |||
|---|---|---|---|---|---|---|---|
| Alelle 1 | Allele 2 | Muscle | Skin | DBS (normal) | Ist-2nd-3rd | ||
| 1 | c.1979G>A (p.R660H) | VUS [c.-32-17_-32-10del8ins30] | nd | nd | <2.5 (>7.5) | Amniocytes GAA activity-DBS-DNA | negative |
| 2 | c.1979G>A (p.R660H) | VUS [c.32-17_32-10del8ins30] | 0.023 (0.42 ± 0.2) | nd | 1.9 (10-49) | MBx-DBS-DNA | negative |
| 3 | c.1843G>A (p.Gly615Arg) | c.1843G>A p.Gly615Arg | low | low | 0# | DBS-MBx-DNA | 1:1600 |
| 4 | VUS [c.-1402A>T (p.I468F)] | unknown (negative GAA deletion/duplication) | 0.08 (0.42 ± 0.2) | 88.77 (260 ± 82.2) | 4.8 (10-49) | Skin fibroblast GAA MBx Muscle GAA -DBS-DNA | na |
| 5 | nd | nd | nd | nd | 2.8 (10-49) | DBS | na |
| 6 | c.655G>A (p.G219R), exon 3 | c.546G>A (p.T182T), exon 2 (splice site) | nd | nd | 2.9 (10-49) | MBx-DBS-DNA | na |
| 7 | c.-32-13T>G ((IVS1-13T>G) | Multiple VUS (R527F) | nd | nd | 4 (10-49) | MBx-DBS-DNA | 1:1600 |
| 8 | nd | nd | nd | nd | 2.85 (10-49) | MBx-DBS | 1:1600 |
| 9 | c.-32-13T>G (IVS1-13T>G) | VUS [c.1402A>T (p.I468F)] | nd | nd | <2.5 (10-49) | MBx-DBS-DNA | nd |
| 10 | nd | nd | 29.23 (260 ± 82.2) | nd | nd | MBx-Muscle GAA | 1:12,800 |
| 11 | nd | nd | 38.54 (260 ± 82.2) | 38.54 (177.8-342.2) | nd | MBx-Muscle GAA-Skin fibroblast | 1:200 |
| 12 | nd | nd | 17.7 (63-123 | nd | nd | MBx-Muscle GAA-DNA | 1:1600 |
Abbreviations: DBS dried blood spot, GAA acid α glucosidase, MBx muscle biopsy, na not applicable, nd not done, VUS variant of unknown significance.
*
Anti Lumizyme antibody titers were reported by Genzyme,
#
GAA activity was measured in blood lymphocytes (mean 35 nmol/hr/mg protein). Units: GAA enzyme activity in muscle/skin fibroblasts (μmol/min/gm tissue), DBS (pmol/hr/punch).