Algorithm for the Early Diagnosis and Treatment of Patients with Cross Reactive Immunologic Material-Negative Classic Infantile Pompe Disease: A Step towards Improving the Efficacy of ERT

OBJECTIVE: Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy. METHODS: We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy. RESULTS: Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1–1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients. CONCLUSIONS: The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD

Postmortem Findings and Clinical Correlates in Individuals with Infantile-Onset Pompe Disease

Pompe disease (OMIM 232300), a glycogen storage disorder caused by deficiency in the lysosomal enzyme acid alpha-glucosidase (EC 3.2.1.20), results in weakness and cardiomyopathy in infants affected with the classic form. Although the primary disease manifestations are due to glycogen accumulation in skeletal and cardiac muscle, glycogen also accumulates in a variety of additional tissues. To improve our understanding of disease pathogenesis in long-term survivors, we reviewed postmortem results for three infants with the classic form of Pompe disease. We have observed a number of new complications in long-term survivors of infantile-onset Pompe disease, and we focused this postmortem study on pathological correlates. Findings in survivors include cardiac arrhythmias, which may be related to glycogen accumulation in cardiac conduction tissue; urinary incontinence, likely due to glycogen accumulation in smooth muscle; and refractory errors, possibly related to accumulation in ocular structures. These observations provide potential pathophysiologic correlates for complications in long-term survivors of infantile Pompe disease