ABSTRACT
Clinical trials have demonstrated beneficial effects of enzyme replacement therapy (ERT) with alglucosidase alfa in infants, children and adults with Pompe disease. Recent studies have shown that high antibody titers can occur in patients receiving ERT and counteract the effect of treatment. This particularly occurs in those patients with classic-infantile Pompe disease that do not produce any endogenous acid α-glucosidase (CRIM-negative). It is still unclear to what extent antibody formation affects the outcome of ERT in adults with residual enzyme activity. We present the case of a patient with adult-onset Pompe disease. He was diagnosed at the age of 39years by enzymatic testing (10.7% residual activity in fibroblasts) and DNA analysis (genotype: c.-32-13T>G/p.Trp516X). Infusion-associated reactions occurred during ERT and the patient's disease progressed. Concurrently, the antibody titer rose to a similarly high level as reported for some CRIM-negative patients with classic-infantile Pompe disease. Using newly developed immunologic-assays we could calculate that approximately 40% of the administered alglucosidase alfa was captured by circulating antibodies. Further, we could demonstrate that uptake of alglucosidase alfa by cultured fibroblasts was inhibited by admixture of the patient's serum. This case demonstrates that also patients with an appreciable amount of properly folded and catalytically active endogenous acid α-glucosidase can develop antibodies against alglucosidase alfa that affect the response to ERT.
Subject(s)
Antibodies/blood , Glycogen Storage Disease Type II/drug therapy , Glycogen Storage Disease Type II/immunology , alpha-Glucosidases/immunology , alpha-Glucosidases/therapeutic use , Adult , Antibodies/immunology , Enzyme Replacement Therapy , Female , Fibroblasts/drug effects , Glycogen Storage Disease Type II/enzymology , Glycogen Storage Disease Type II/physiopathology , Humans , Immunologic Tests , Male , Middle Aged , Muscle Strength/physiology , Respiratory Function Tests , Treatment Outcome , alpha-Glucosidases/adverse effectsABSTRACT
Globotriaosylceramide (GL3) is a heterogeneous glycosphingolipid that is elevated in the blood plasma of patients diagnosed with Fabry disease. GL3 consists of numerous isoforms, some of which are distinctly specific to human plasma. An electrospray-ionization LC/MS/MS method has been developed that has the capacity to monitor the GL3 isoform profiles in plasma extracts. Total GL3 is extracted from human plasma via chloroform/methanol liquid-liquid extraction, purified by C(18) solid-phase extraction and analyzed by multiple reaction monitoring LC/MS/MS. The relative responses of eight selected isoforms are calculated on the basis of the total GL3 response and the isoform responses are subsequently utilized to construct isoform profile plots.
