Enzyme replacement therapy (ERT) with alglucosidase alfa has led to significant improvement in clinical outcomes in patients with infantile Pompe disease (IPD) with the oldest IPD survivors now reaching teenage years. A new natural history of Pompe disease (PD) is unfolding. Recognition of factors that negatively impact response to ERT include cross-reactive immunological material (CRIM)-negative status (no endogenous acid ?-glucosidase (GAA) on Western Blot), immune responses against ERT, and delayed start of ERT. ERT does not cross the blood-brain barrier, and the impact of glycogen deposition in the nervous system is unknown. Immune tolerance induction (ITI) has helped prevent immune responses and newborn screening (NBS) for Pompe disease has led to the early diagnosis, both significant advances in the field. In this multi-center study, there are three specific aims: 1) Assess the safety and efficacy of ERT in IPD patients with and without ITI; 2) Describe the early phenotype of patients with Pompe disease diagnosed via NBS and their treatment response to ERT with and without ITI; and 3) Understand cognitive and neurological involvement in long-term IPD survivors.
For aim 1, via our multi-center collaboration systematic data on IPD patients ? who receive ERT and ITI will be compared to patients who receive ERT alone by the following measures ? IgG antibody response, left ventricular mass index (LVMI), and overall survival. Safety to the ITI will be evaluated by markers of immune tolerance including CD19 counts, vaccination status and antibody response to vaccines, infections around the time of ITI, ANC, AST, and ALT levels.
For aim 2, patients diagnosed via NBS will undergo extensive clinical and laboratory evaluations including a clinic visit, physical therapy evaluations, biochemical tests to detect muscle damage, muscle ultrasounds, speech and swallow evaluation, heart assessments, hearing assessments, and sleep questionnaires. These measures will be compared with Pompe patients who were diagnosed clinically (and not via NBS) to identify early features of the disease and to establish benefits of early initiation of ERT.
For aim 3, patients will undergo state-of-the-art brain imaging, assessments to evaluate the peripheral nervous system (PNS) involvement, and cognitive assessments to test for cognitive function, behavior/executive function, academic skills/education, language, motor function including physical therapy evaluation, audiology evaluation and, speech evaluation. This multi-center study will expand on the early data on the role of ITI in establishing immune tolerance, it will result in the capture of data on patients diagnosed via NBS for the development of evidence-based guidelines and the ability to treat patients with IPD in a timely manner. It will allow us to truly understand the impact of glycogen accumulation in the brain and the PNS, currently an unknown.
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