The approval of enzyme replacement therapy (ERT) for treating infantile-onset Pompe disease (IOPD) changed it from a life-threatening disease within the first years of life into a chronic condition. Although ERT is not a cure for the disease, it definitely changes its course.

For instance, ERT has been shown to have a positive impact not only on patients’ survival, but also on their motor development and hypertrophic cardiomyopathy (HCMP). However, data on patients’ outcomes is still scarce.

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“The acute and long-term follow-up of patients on ERT is necessary to better understand the variable response and the challenges that hinder its effectiveness and explore the unmet needs,” Bar-Yoseph et al wrote in a recent publication in the Journal of Personalized Medicine.

On the other hand, the extension in patients’ life expectancy had undoubtedly uncovered an even more complex and multisystemic IOPD phenotype, which includes cardiac, respiratory, neurocognitive, speech, musculoskeletal, swallowing, and hearing symptoms.

Therefore, the follow-up of IOPD patients is also crucial to improving comprehension of the disease phenotype.

Early Diagnosis Is Essential

Early identification of IOPD is very important, as ERT increases lifespan and treats HCMP, hepatomegaly, and elevated liver transaminases despite persistent respiratory distress,” wrote Kim et al in the Korean Journal of Pediatrics.

In their study, they demonstrated that patients with IOPD showed a stable disease course during a median of 10 years of follow-up. According to them, the effect of ERT in IOPD patients’ survival is likely due to improvements in cardiomegaly and thickness of the left ventricle.

Early Enzyme Replacement Therapy May Improve Hearing in Infant-Onset Pompe Disease

Recently, Bar-Yoseph et al analyzed the acute and long-term effects of ERT on exercise in IOPD patients. They confirmed that blood enzyme levels increased 2 days after treatment initiation; however, they did not observe alterations in exercise parameters.

On the other hand, long-term evaluations showed stabilization in young patients, but not in adolescents. Clinical deterioration in adolescents was primarily observed in peak pulmonary oxygen uptake (VO2), followed by 6-min walking distance (6MWD), forced vital capacity (FVC), and Gross Motor Function Measure Score Sheet (GMFM-88).

According to the authors, “Individualized assessment of the peak VO2 by means of [cardiopulmonary exercise testing] may provide a more sensitive assessment of clinical severity and long-term response to treatment.”

The ERT Dosing Dilemma

ERT, the only treatment currently approved for the treatment of Pompe disease, aims to provide patients with functional acid alpha-glucosidase (GAA). To that end, synthetic recombinant human GAA (rhGAA) is administered at a recommended dose of 20 mg/kg every two weeks.

However, as discussed by Hanh and Schänzer in a review article published in the Annals of Translational Medicine, this recommendation was suggested after 1 study comparing 2 small groups of patients. Therefore, there is no robust scientific evidence to support the adoption of this or any other dosing schedule in IOPD patients. In fact, several patients end up being treated with higher doses.

“Although there is some evidence that high doses up to 40 mg/kg every week are more effective, no larger study has systematically analyzed the efficacy of alternative dosing schedules,” Hanh and Schänzer recalled.

According to Chien et al, early initiation of the treatment is key to the success of ERT. “We previously demonstrated that patients diagnosed through newborn screening were treated very early and presented more favorable outcomes than patients who were diagnosed by clinical symptoms,” they said.

In a new study published in the journal Molecular Genetics and Metabolism Reports, Chien et al evaluated the response of 28 patients receiving alglucosidase alpha as follows: labeled dosage followed by a high dosage (n=23) or high dosage exclusively (n=5).

Their study enrolled IOPD patients from 7 centers, who were divided into a newborn-screened cohort (n=24) and a clinically identified cohort (n=6). The median age of each cohort at ERT initiation was 0.5 and 4.5 months, respectively. The initial ERT regimen was 20 mg/kg every other week and 40 mg/kg every other week in the second group.

From the patients receiving the labeled dosage, 96% had their dosages increased as follows: to 30 mg/kg every other week and then 40 mg/kg every other week, directly to 40 mg/kg every other week, or 20 mg/kg weekly. From the patients who initiated with a 40 mg/kg every other week regimen, 40% had a further increase in dosage.

The study found that IOPD patients late in ERT initiation (P =.006) or late in high-dosage ERT initiation (P =.044) had a higher risk of motor decline. Among the 28 patients included in the data analysis, 27 were alive at the end of data collection (median age, 8.3 years, age range, 0.8–17.3).

“We suggest that a high dosage of ERT such as 40 mg/kg every other week as the starting dosage, may be more effective than the labeled dose in stabilizing and improving the clinical prognosis of patients with IOPD even if they were identified through newborn screening,” Chien et al said. “Close monitoring of biomarkers and antibody titers as well as planning for an individualized dosage may further improve clinical outcomes.”


Kim M-S, Song A, Im M, et al. Clinical and molecular characterization of Korean children with infantile and late-onset Pompe disease: 10 years of experience with enzyme replacement therapy at a single center. Korean J Pediatr. 2019;62(6):224-234. doi:10.3345/kjp.2018.06968

Chien Y-H, Tsai W-H, Chang C-L, et al. Earlier and higher dosing of alglucosidase alfa improve outcomes in patients with infantile-onset Pompe disease: evidence from real-world experiences. Mol Genet Metab Rep. 2020;23:100591. doi:10.1016/j.ymgmr.2020.100591

Bar-Yoseph R, Tal G, Dumin E, et al. Individualized assessment of exercise capacity in response to acute and long-term enzyme replacement therapy in pediatric Pompe disease. J Pers Med. 2021;11(11). doi:10.3390/jpm11111105

Hahn A, Schänzer A. Long-term outcome and unmet needs in infantile-onset Pompe disease. Ann Transl Med. 2019;7(13):283. doi:10.21037/atm.2019.04.70