The new era of Pompe disease: Advances in the detection, understanding of the phenotypic spectrum, pathophysiology, and management

Abstract

Pompe disease is an autosomal recessive neuromuscular disorder marked by progressive muscle weakness due to lysosomal buildup of glycogen. Presentation is described as a spectrum, varying by age of onset, organ involvement, and degree of myopathy. Given the phenotypic variability, Pompe disease is broadly classified into an infantile form and a late onset (juvenile, childhood, adult onset) form. Prior to the advent of enzyme replacement therapy (ERT) with alglucosidase alfa and approval for human use in 2006, the natural history was limited due to death before age 2 years for infantile onset cases and significant morbidity and early mortality for late onset Pompe disease (LOPD). ERT with alglucosidase alfa redefined the once fatal outcome in infantile Pompe, establishing an emergent phenotype. Treatment in late onset patients resulted in improved outcomes, enhancing understanding of the phenotype, presentation, and extent of organ involvement. This Issue of the Seminars seeks to enumerate the recent advancements in the field of Pompe disease, including newborn screening, novel therapeutic targets, new insights in the pathophysiology including role of autophagy, and impacts of long-term disease burden and CNS glycogen accumulation on cognition in infantile survivors. It also addresses immunological challenges and the critical role of immunomodulation in ERT treatment outcome. Other topics discussed include the role of biomarkers in monitoring disease progression and treatment responses, the role of genotype in defining phenotype and treatment response, better insights into the clinical presentations in LOPD and finally the importance of a multidisciplinary approach to care with the role of physical therapy as an example. Many gaps in our scientific understanding of this disease still remain; however, we hope the next decade will bring new knowledge and therapies to the horizon.

Hypertrophic Cardiomyopathy in Pompe Disease Is Not Limited to the Classic Infantile-Onset Phenotype

“…Slonim et al defined "nontypical" infantile-onset Pompe disease as those with less severe cardiomyopathy and longer survival of 1-2 years (Slonim et al 2000). Others have used "atypical infantile-onset Pompe disease" to characterize patients who have symptom onset before 1 year of age but with no cardiomyopathy (Bembi et al 2008;Kishnani et al 2012). Gungor and Reuser suggested using the term "childhood" Pompe disease to cover the gap between "classic infantile" and "adult" Pompe disease (Gungor and Reuser 2013).…”

“…About 75% of patients with classic infantile-onset Pompe disease die before 12 months of age with a median age at death of 8.7 months (Kishnani et al 2006a). Patients with the heterogeneous and more slowly progressive late-onset Pompe disease, which includes childhood-, juvenile-, and adult-onset subgroups (Kishnani et al 2012), typically present with muscle weakness and respiratory failure but no cardiac manifestations (Hirschhorn and Reuser 2001;Kroos et al 2007). However, Pompe disease is a continuum of disease with variable age of onset, organ involvement, and degree of myopathy, and therefore, not all patients can be categorized according to the aforementioned classification.…”

Особливості Клініко-Лабораторної Діагностики Хвороби Помпе У Дітей

“…За даними американських і європейських дослід-ників, ХП становить близько 15 % у структурі усіх хвороб накопичення глікогену, яких на сьогодні ви-діляють 14 типів [2].…”

Antibody-mediated enzyme replacement therapy targeting both lysosomal and cytoplasmic glycogen in Pompe disease

“…Measurement of tissue glycogen contents, GAA activity, and urinary Hex 4 Frozen tissues were homogenized in cold water and centrifuged. The clear lysates were used for the following assays.…”

“…Infantile-onset Pompe disease is characterized by muscle weakness, hypotonia, and a hypertrophic cardiomyopathy, and most patients die from cardiorespiratory failure in the first year of life. Late-onset Pompe disease features progressive skeletal muscle weakness without significant cardiomyopathy [2][3][4]. Pompe disease is currently treated by enzyme replacement therapy (ERT) with recombinant human Haiqing Yi and Tao Sun contributed equally to this work.…”