Pompe Disease in Children-Early to Mid-stage

Abstract

Pompe disease is a rare neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid c~-glucosidase. It is characterized by a broad clinical spectrum, ranging from a severe infant phenotype associated with generalized muscle weakness, hypertrophic cardiomyopathy, and death within the first year of life, to a slowly progressive adult form in which the heart is not affected. Enzyme replacement therapy (ERT) with recombinant human acid c~-glucosidase (alglucosidase alfa [Myozyme ®, Genzyme Corporation, Cambridge, Massachusetts]) for the treatment of Pompe disease received marketing approval in Europe and the United States in spring 2006. Before its approval, several studies evaluating the safety and efficacy of ERT were conducted, and a placebo-controlled study involving 90 adult patients with Pompe disease is currently ongoing. The first pilot studies on the use of ERT in infants with Pompe disease started in 1999.1,2 In the following years, more studies were carried out, which finally led to the approval of ERT for the treatment of Pompe disease. 2-7 These studies showed that ERT substantially reduces cardiac hypertrophy and increases survival times. Untreated patients usually died during their first year of life, whereas life expectancy was greatly prolonged in treated patients--the oldest surviving patients are now 9 years old. Several patients who were treated with ERT also gained muscle strength and reached developmental milestones such as sitting, crawling, and walking. These results suggest that early initiation of treatment is essential for a good outcome. The best response was seen in those patients who started treatment early, before irreversible damage occurred, while the majority of patients who started treatment at a later stage in the disease became ventilator dependent or eventually died. A study assessing preand posttreatment muscle pathologic findings reported more severe ultrastructural damage of myocytes in patients who did not respond to ERT, compared with those who were responsive to therapy. 8 Reports on ERT in patients with the more attenuated form of the disease are scarce; however, 2 preliminary studies, including 3 and 5 patients, respectively, have provided the first evidence that ERT is able to change the natural course of this form of the disease. 9,1° Despite the natural course of Pompe disease being one of progressive deterioration, 6 patients showed improvements in pulmonary and/or muscle function, and 2 patients' conditions stabilized after initiation of treatment. These results corroborate those found in infants I-7 and further indicate that the best outcome is obtained when treatment is initiated before the onset of severe muscle damage. However, larger studies are required to confirm these findings. To ensure a good outcome for patients, in addition to ERT, supportive measures--including physiotherapy, training, nutrition, and timely installation of (nightly) mechanical ventilation--need to be addressed.