High-dose enzyme replacement therapy (ERT) along with continuously adjusted immunomodulation may seem to be an efficient approach for infantile-onset Pompe disease (IOPD), according to a study recently published in Molecular Genetics and Metabolism Reports.

“The combination of early onset high dose weekly ERT, off label extended-release albuterol and successful long term immune tolerance based on monthly monitoring of anti-rhGAA [recombinant human acid alpha glucosidase] antibody levels provided a personalized approach that was safe and effective in our [cross-reactive immunological material]-negative IOPD patient resulting in a favorable outcome,” Curelaru et al explained.

This case report describes a 30-month-old female that presented with fever, dyspnea, cough, and feeding impairment. Physical evaluation detected normal vital signs except low oxygen saturation in room air of 90% and other abnormal findings such as axial hypotonia and a systolic ejection murmur.

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Perinatal history included an uneventful bichorionic twin pregnancy that ended at 31 weeks of gestation due to early contractions, leading to respiratory distress syndrome that kept the patient hospitalized and receiving supplemental oxygen for 5 weeks. Laboratory tests upon admission revealed high liver transaminases and creatinine kinase levels.

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An echocardiogram reported important hypertrophic cardiomyopathy with a left ventricular mass of 60 g and a left ventricular mass index 157 g/m^2 above the normal value, with severe outflow obstruction. Given these findings, the patient underwent genetic testing that confirmed IOPD with homozygous acid alpha glucosidase (GAA) mutation, further classifying the disease as cross-reactive immunological material-negative.

The healthcare providers initiated a therapeutic scheme according to the Duke protocol, consisting of ERT at 20 mg/kg every other week, and an immunosuppressive course of 5 weeks with rituximab, methotrexate, and intravenous immunoglobulin administered with the first dose of ERT.

Nonetheless, after 4 weeks of using this approach, the providers noticed a sustained increase of recombinant human GAA antibody titers in serum hence the scheme switched to high dose ERT of 40 mg/kg weekly for 4 more weeks and a second course of the previous immunomodulating drugs and bortezomib.

After 14 months, immunotherapy was completely discontinued gradually, and anti-rhGAA antibodies were consistently negative for up to 5 months after. At 30 months of age, the patient exhibited a normal cardiac profile, with immune tolerance and CD19 recovery.

“Our recommendation for rituximab and methotrexate administration following bortezomib treatment are as follows (1) Continue maintenance rituximab and methotrexate for six months with monthly monitoring of anti-rhGAA IgG [immunoglobulin] antibody titers, (2) If antibody titers remains <12,800 while on maintenance rituximab and methotrexate then start tapering rituximab and methotrexate for another six months, and (3) if patient continues to maintain titers of <12,800 then discontinue rituximab and methotrexate and continue to monitor anti-rhGAA IgG
antibody titers monthly,” the authors concluded.


Curelaru S, Desai A, Fink D, Zehavi Y, Kishnani P, Spiegel R. A favorable outcome in an infantile-onset Pompe patient with cross reactive immunological material (CRIM) negative disease with high dose enzyme replacement therapy and adjusted immunomodulation. Mol Genet Metab Rep. Published online July 6, 2022. doi:10.1016/j.ymgmr.2022.100893