Abstract
BackgroundEnzyme-replacement therapy (ERT) in Pompe disease—an inherited metabolic disorder caused by acid α-glucosidase deficiency and characterized in infants by generalized muscle weakness and cardiomyopathy—can be complicated by immune responses. Infants that do not produce any endogenous acid α-glucosidase, so-called CRIM-negative patients, reportedly develop a strong response. We report the clinical outcome of our Dutch infants in relation to their CRIM status and immune response.MethodsEleven patients were genotyped and their CRIM status was determined. Antibody formation and clinical outcome were assessed for a minimum of 4 years.ResultsERT was commenced between 0.1 and 8.3 months of age, and patients were treated from 0.3 to 13.7 years. All patients developed antibodies. Those with a high antibody titer (above 1:31,250) had a poor response. The antibody titers varied substantially between patients and did not strictly correlate with the patients’ CRIM status. Patients who started ERT beyond 2 months of age tended to develop higher titers than those who started earlier. All three CRIM-negative patients in our study succumbed by the age of 4 years seemingly unrelated to the height of their antibody titer.ConclusionAntibody formation is a common response to ERT in classic infantile Pompe disease and counteracts the effect of treatment. The counteracting effect seems determined by the antibody:enzyme molecular stoichiometry. The immune response may be minimized by early start of ERT and by immune modulation, as proposed by colleagues. The CRIM-negative status itself seems associated with poor outcome.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-014-9707-6) contains supplementary material, which is available to authorized users.
Highlights
Immune responses are common in lysosomal storage disorders (LSDs) in which enzyme-replacement therapy (ERT) is applied (Brooks et al 2003; Wang et al 2008)
This study describes 11 patients with classic infantile Pompe disease (Table 1)
As previously suggested, our study indicates that the age at start of Enzyme-replacement therapy (ERT) might play a role in the immune response since none of the patients who started ERT before 2 months of age developed titers > 1:6250
Summary
Immune responses are common in lysosomal storage disorders (LSDs) in which enzyme-replacement therapy (ERT) is applied (Brooks et al 2003; Wang et al 2008). At the severe end of the spectrum, patients with classic infantile Pompe disease present with muscle weakness, hypertrophic cardiomyopathy and respiratory insufficiency in the first few months of life. If untreated, they usually succumb to cardiorespiratory insufficiency before the end of their first year (van den Hout et al 2003; Kishnani et al 2006a). Enzyme-replacement therapy (ERT) in Pompe disease—an inherited metabolic disorder caused by acid αglucosidase deficiency and characterized in infants by generalized muscle weakness and cardiomyopathy—can be complicated by immune responses.
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