Management of Confirmed Newborn-Screened Patients With Pompe Disease Across the Disease Spectrum

Abstract

After a Pompe disease diagnosis is confirmed in infants identified through newborn screening (NBS), when and if to start treatment with enzyme replacement therapy (ERT) with alglucosidase alfa must be determined. In classic infantile-onset Pompe disease, ERT should start as soon as possible. Once started, regular, routine follow-up is necessary to monitor for treatment effects, disease progression, and adverse effects. Decision-making for when or if to start ERT in late-onset Pompe disease (LOPD) is more challenging because patients typically have no measurable signs or symptoms or predictable time of symptom onset at NBS. With LOPD, adequate, ongoing follow-up and assessments for onset or progression of signs and symptoms are important to track disease state and monitor and adjust care before and after treatment is started. Because numerous tests are used to monitor patients at variable frequencies, a standardized approach across centers is lacking. Significant variability in patient assessments may result in missed opportunities for early intervention. Management of Pompe disease requires a comprehensive, multidisciplinary approach with timely disease-specific interventions that target the underlying disease process and symptom-specific manifestations. Regardless of how identified, all patients who have signs or symptoms of the disease require coordinated medical care and follow-up tailored to individual needs throughout their lives. The Pompe Disease Newborn Screening Working Group identifies key considerations before starting and during ERT; summarizes what comprises an indication to start ERT; and provides guidance on how to determine appropriate patient management and monitoring and guide the frequency and type of follow-up assessments for all patients identified through NBS.

Pompe Disease: From Basic Science to Therapy

“…The consensus is that the timing of ERT initiation is of critical importance for the outcome of therapy-the earlier the better. The start of therapy in IOPD before 6 months of age has long met the definition of Bearly.^However, this paradigm was changed with the introduction of newborn screening program, and the current view is that the best time frame for the initiation of treatment is within the first days after birth [89]. Newborn screening (NBS), which marks a new era in Pompe field, will be discussed in more detail (see below).…”

“…Enzyme activity is measured in DBS using a fluorometric method [173], tandem mass spectrometry, or microfluidics combined with fluorometry [174]. The Pompe Disease Newborn Screening Working Group, an international group of experts in both NBS and Pompe disease, developed recommendations for confirmatory testing after positive NBS result and guidelines regarding monitoring and management of patients before and during ERT [40,89]. One of the unexpected findings from these studies is a much higher prevalence of the disease than previously recognized.…”

The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease

“…Pompe disease is caused by pathogenic variants in the GAA gene, which encodes acid α-glucosidase (GAA), an enzyme responsible for glycogen breakdown in the lysosome [11]. Glycogen accumulation in the lysosome can result in a clinical spectrum ranging from a rapidly progressive infantile-onset form of the disease (IOPD) to a more slowly progressive late-onset form referred to as late-onset Pompe disease (LOPD) [12]. In IOPD, the GAA activity is below 1% and infants present with severe cardiomyopathy, hypotonia, rapidly progressive muscle disease, and respiratory involvement.…”

Insight into the phenotype of infants with Pompe disease identified by newborn screening with the common c.-32-13T > G “late-onset” GAA variant

“…While immediate initiation of ERT is the standard of care for patients with variants consistent with IOPD identified by NBS, there is no consensus on if and when to initiate ERT for patients with “late-onset” GAA variants, especially with the leaky GAA splice site variant, c.-32-13T>G in intron 1 (IVS1-13T>G; IVS variant) [15]. This variant is found on at least one allele in 68–90% of Caucasian patients [16–18].…”