Abstract

PURPOSE: To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date.METHODS: Patients aged =1 year with confirmed Pompe disease previously receiving 160L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments.RESULTS: Of 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n=23), c.-32-13T>G (n=13), and c.525delT (n=12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean±SD, median, range): overall 46.3±33.0% (47.9%, 0.0-100.0%), IOPD 41.6±31.64% (38.9%, 0.0-99.7%), LOPD: 61.8±33.2 (70.9%, 0.0-100.0%).CONCLUSION: ADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.

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