New therapeutic approaches for Pompe disease: enzyme replacement therapy and beyond.

Pompe disease is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Prior to 2006, therapy was palliative. Severely affected infants with Pompe succumbed to cardiomyopathy or respiratory failure by one year of age. Enzyme replacement therapy (ERT) with alglucosidase alfa (Genzyme, Cambridge, MA, USA) is currently the only approved treatment for Pompe disease which has improved overall survival, ventilator-free survival, cardiomyopathy, and motor development in infants. In patients with late onset Pompe disease, ERT has resulted in disease course stabilization with motor and pulmonary improvements. Factors impacting outcome include age at start of ERT, muscle fiber type, underlying genotype and a multidisciplinary approach to care. This article highlights the lessons learned from infants and adults treated with ERT, limitations of ERT, and the development of adjunctive and alternative therapies, including immune modulation, upregulation of receptor expression, diet and exercise, second-generation recombinant ERT, chaperone therapy, substrate reduction therapy and gene therapy.

Infantile Pompe disease on ERT: update on clinical presentation, musculoskeletal management, and exercise considerations.

Enzyme replacement therapy (ERT) with alglucosidase alpha, approved by the FDA in 2006, has expanded possibilities for individuals with Pompe disease (glycogen storage disease type II, GSDII, or acid maltase deficiency). Children with infantile Pompe disease are surviving beyond infancy, some achieving independent walking and functional levels never before possible. Individuals with late-onset Pompe disease are experiencing motor and respiratory improvement and/or stabilization with slower progression of impairments. A new phenotype is emerging for those with infantile Pompe disease treated with ERT. This new phenotype appears to be distinct from the late-onset phenotype rather than a shift from infantile to late-onset phenotype that might be expected from a simple diminution of symptoms with ERT. Questions arise regarding the etiology of the distinct distribution of weakness in this new phenotype, with increasing questions regarding exercise and musculoskeletal management. Answers require an increased understanding of the muscle pathology in Pompe disease, how that muscle pathology may be impacted by ERT, and the potential impact of, and need for, other clinical interventions. This article reviews the current state of knowledge regarding the pathology of muscle involvement in Pompe disease and the potential change in muscle pathology with ERT; the newly emerging musculoskeletal and gross motor phenotype of infantile Pompe disease treated with ERT; updated recommendations regarding musculoskeletal management in Pompe disease, particularly in children now surviving longer with residual weakness impacting development and integrity of the musculoskeletal system; and the potential impact and role of exercise in infantile Pompe survivors treated with ERT.

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

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.