Treatment Success in Pompe Disease
Abstract & Commentary
By Michael Rubin, MD, FRCP(C) Professor of Clinical Neurology, Weill Cornell Medical College, New York, NY. Dr. Rubin reported he has received grant/research support from Pfizer and is on the speaker's bureau for Athena Diagnostics.
Synopsis: Enzyme replacement therapy appears safe and effective for this rare genetic muscle disease.
Source: van Capelle IC, Winkel LP, Hagemans ML, et al. Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease. Neuromuscul Disord 2008;18:447-452.
Pompe disease, caused by mutation of the alpha-glucosidase gene on chromosome 17q and resulting in alpha-glucosidase (acid maltase) deficiency, is a rare (incidence 1:40,000), autosomal recessive, glycogen storage disease that, depending on the amount of functioning enzyme present, can present from infancy (no enzyme activity detectable) to adulthood (some enzyme activity detectable). Definitive diagnosis is achieved by documenting alpha-glucosidase deficiency in muscle, blood, or cultured fibroblasts from skin biopsy. Enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (Myozyme) was approved in 2006. How well does it work?
Two children and one adult have been receiving ERT since 1999 under the care of a Dutch group in Rotterdam, The Netherlands. A 16-year-old girl, both wheelchair and ventilator dependant with severe scoliosis, had over 4 previous years experienced an annual 4% decline in vital capacity. For 3 years following initiation of therapy, and with surgical correction of the scoliosis, total muscle strength did not change, but pulmonary function stabilized and mechanical ventilation hours were reduced from 18 to 12 hours/day. During 5 subsequent years, muscle strength increased and pulmonary function and ventilation hours remained stable. Based on the Rotterdam 9-item Handicap scale, handicap level improved, and the patient was able to conclude a Master's degree and begin law school in 2007.
A quadriplegic, bed-ridden, ventilator-dependent, 32-year-old man, who from 8 years of age had lost an average of 2.6% vital capacity per year, experienced minimal but significant improvement of total muscle strength with stabilization of respiratory function during the first 3 years of ERT. Over 5 subsequent years, muscle strength and function and pulmonary function remained stable. Handicap level improved slightly and by 2007 he was able to perform outdoor domestic and leisure activities independently.
An 11-year-old boy with normal pulmonary function and some weight-bearing potential in his legs became wheelchair dependent at age 9. During the first 3 years of ERT, muscle strength increased significantly (p<0.01) in all muscles except elbow extensors, and muscle function reached 100% as measured by Gross Motor Function Measure,1 although squatting and rising were problematic. Over the following 5 years, muscle strength normalized in all muscles, rising from a squat was no longer difficult, cycling improved, and he presently works as a gardener with no limitations in sport or social activities.
Muscle pathology improved after 3 and 5.5 years of ERT in the last patient only, demonstrating fewer acid phosphatase reactive foci, diminished PAS positive glycogen deposits, and normal cross-striations. ERT was well tolerated over the entire treatment period and 2 patients continue to receive home ERT infusions. Long-term ERT is both well tolerated and safe, showing promise to benefit patients with Pompe disease.
Commentary
Despite identifying almost 200 mutations in the alpha-glucosidase gene on chromosome 17q25.3-q25.3 causing Pompe disease, we have yet to understand how myopathy results from reduced enzyme activity.2 Autophagia may be triggered by accumulation of glycogen in the enzyme deficient muscle cells. Vesicular abnormalities may play a role, as enlargement and decreased mobility of endosomes and lysosomes are seen in knockout-mouse models of Pompe disease. Vesicles with elevated pH are increased in number and can affect lysosomal enzyme function. Simple mechanical interruption of the sarcomere due to the increased numbers of lysosomes may result in weakness. Theories abound but the final word awaits more rigorous science.
Reference
1. Russell DJ, et al. Gross Motor Function Measure (GMFM-66 and GMFM-88): Users Manual. Cambridge University Press, 2002.
2. Katzin LW, Amato AA. J Clin Neuromuscl Dis 2008;9:421-431.
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