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- MATERIALS AND METHODS
Adult-onset acid maltase deficiency is an inherited lysosomal skeletal-muscle disease characterized by progressive myopathy and respiratory failure, for which there is no known therapy. In an uncontrolled, prospective study, we evaluated whether adherence to high-protein and low-carbohydrate nutrition and exercise therapy (NET) can slow the progressive deterioration of muscle function in this disease. Thirty-four patients have been treated with NET for periods of 2–10 years (mean 4.5 ± 2.5). Pre-NET rate of muscle function deterioration, as measured by the Walton scale, was compared to post-NET rate. Twenty-six patients were deemed to be consistently compliant with NET. Difference between pre-NET slope of muscle function deterioration to that of post-NET slope in compliant patients was −0.29 (95% CI −0.19, 0.39) (P < 0.0001). We conclude that compliance with NET can slow deterioration of muscle function and improve the natural history of adult-onset acid maltase deficiency. Muscle Nerve, 2006
Acid maltase deficiency (AMD), also known as type II glycogen storage disease, is caused by a genetic defect of acid alpha-glucosidase (GAA), a lysosomal hydrolase that degrades glycogen to glucose. The structural gene is located on chromosome 17 (17q25), contains 20 exons, and has a length of 25 kb7; 60 disease-specific mutations have been identified.20 AMD is an autosomal-recessive disease, believed to have an incidence of 1 in 40,000 births.21 Infantile, juvenile, and adult variants of AMD are distinguished by age of onset, rate of progression, and extent of tissue involvement.7, 14 In general, there is an inverse correlation between amount of residual GAA activity and disease severity.14 Clinical presentation ranges from the rapidly fatal infantile form with cardiomyopathy and severe myopathy to the late-onset forms manifesting as slowly progressive myopathies of childhood and adulthood.7, 14 Both juvenile-onset patients who present in early childhood or towards puberty, and adult-onset patients who present after the age of 18, demonstrate proximal muscle weakness and wasting, frequently associated with diaphragmatic and respiratory muscle weakness, without cardiomyopathy.7, 12, 25 Recently, Laforet et al.,17 utilizing the Walton scale of muscle function, portrayed the progressive muscle function deterioration in 21 late-onset AMD patients, 18 of whom had adult-onset disease.
The pathogenesis of late-onset AMD has been attributed to disruption of cell integrity by increasing accumulation of glycogen.7, 14 However, Slonim et al.28 noted that the severity of myopathy was out of proportion to the degree of glycogen deposition and suggested that an increase in proteolysis contributes to the weakness. An increase in proteolysis was suggested by the rapid fall in plasma amino-acid levels following ingestion of a protein load,28, 30 and confirmed by isotope turnover studies.30, 32 Although enzyme replacement therapy (ERT) with recombinant human enzyme (rhGAA) has recently been approved as therapy for adult-onset AMD in the USA and Europe, there are no studies that demonstrate that rhGAA or any other therapy can slow the progressive deterioration in muscle function of this disorder.6 However, we observed that nutrition and exercise therapy (NET), formulated to decrease muscle glycogen deposition and increase muscle fatty acid utilization, does slow the progression of this disease. Over the last 10 years, we have prospectively monitored the muscle function and respiratory function of 34 patients treated for varying lengths of time with NET. Twenty-six of these patients were considered to be compliant with the NET protocol. To assess whether NET slowed deterioration in muscle function, the rate of deterioration since instituting NET was compared to each patient's reported rate of deterioration prior to starting NET.
- Top of page
- MATERIALS AND METHODS
The natural history of adult-onset AMD has been well described7, 12 and the rate of deterioration in muscle function delineated by Laforet et al.17 in a recent large cohort of patients. Clinically, the progressive proximal muscle weakness mimics limb-girdle dystrophy and Becker's muscular dystrophy, with frequent additional early involvement of respiratory muscle weakness.25 Prior to starting NET, the rate of muscle deterioration of our patients (pre-therapy in Figs. 1 and 2) was similar to that observed by Laforet et al.17 However, following NET there was a significant slowing in the rate of deterioration in compliant patients (Fig. 1), whereas the noncompliant patients continued to show progressive deterioration (Fig. 2). Although the evidence is less clear and not statistically significant, the pulmonary function deterioration that had taken place in 50% of our patients prior to presentation also seemed to have slowed following institution and compliance with NET, whereas pulmonary function continued to deteriorate in most of the noncompliant patients.
The need for full compliance to both the nutrition and exercise elements of NET has been consistently and repeatedly demonstrated in our patients. As our experience in the use of NET increased, it became apparent that patients who exercised daily and remained active responded far better than those who became less active and exercised less frequently. Although all forms of aerobic exercise were encouraged, a prescribed daily treadmill exercise program was found to be the most effective means of achieving the goal of a sustained conditioned state. Exercise on an upper-body ergometer for 10–15 min following the 45–50 min of lower-limb exercise, as well as the use of light–moderate weights, were also beneficial in maintaining muscle function. Likewise, it became increasingly apparent that a low-carbohydrate and high-protein diet, consisting of adequate calories distributed evenly throughout the day, was maximally beneficial, as previously demonstrated in the childhood form of AMD.28, 31 The lack of adequate caloric intake, resulting in a low BMI, was particularly detrimental and required urgent correction by the use of nocturnal gastric tube feeding to supplement the inadequate oral nutritional intake.
Prior to institution of NET, 14 of the 26 compliant patients had decided to discontinue working and intended to apply for disability benefits. Following institution of NET, nine of these patients continued work in a normal schedule, and in a number of cases were able to take up additional activities that they previously believed would not be possible. Three patients continued to work, but at reduced hours, while two patients discontinued work. Following the earlier publication that NET was beneficial in childhood-onset AMD,28, 30 a number of investigators showed that a high-protein diet produced clinical improvement in adult-onset AMD patients, including improvement in respiratory function,16, 19, 22 whereas others reported no improvement in skeletal-muscle function.2, 8, 24 In their summary analysis of published studies, Bodamer et al.2 concluded that only 25% of patients showed improvement in muscle or respiratory function on a high-protein diet, while noting at the same time that compliance with the nutrition protocol was poor in most studies. Exercise was not a part of the treatment protocol in any of these studies.
The pathogenesis of late-onset AMD has been attributed to intralysosomal accumulation of glycogen and the presence of autophagic vacuoles, causing disruption of muscle fibers.7 The net muscle protein degradation, shown to occur in late-onset AMD,2, 8, 32, 33 is now believed to be a major contributing factor to the muscle weakness and wasting of this disease. However, both the cause and mechanism of the increased muscle proteolysis are uncertain, although proteolysis is believed to take place via lysosomal autophagy.19 Conceptually, when the lysosomal hydrolytic glycogenolytic pathway is interfered with,5 as occurs in acid α-glucosidase deficiency, it is likely that increased proteolysis occurs33 to provide amino acids for use as an alternative source of muscle fuel. Although muscle lysosomal α-glucosidase has only one sixth the glycogenolytic activity that is potentially available from cytosolic phosphorylation,5 glycogenolysis derived from lysosomal hydrolysis is constantly active in normal resting muscle,5 for example during sleep, whereas muscle glycogenolysis via phosphorylation only takes place during muscle contraction and is minimal or absent during sleep. The combination of a high-protein, low-carbohydrate diet and conditioning aerobic exercise therapy was devised to counteract the pathogenic effect of increased muscle glycogen deposition and decreased muscle protein synthesis.13 The low-carbohydrate intake is geared to minimize both intra- and extralysosomal glycogen accumulation, whereas protein and alanine supplementation is intended to increase muscle protein synthesis and minimize net muscle degradation, modifying the two pathogenic processes occurring in late-onset AMD.7, 32, 33 In addition, the daily submaximal aerobic exercise is geared to decrease the demand for muscle glycogenolysis and increase the utilization of intramuscular fatty acids, as occurs in normal subjects as a consequence of daily conditioning exercise.15 A decrease in demand for muscle glycogenolysis should also decrease the demand for amino acids as an alternative source of fuel and further decrease muscle proteolysis.
Recent studies on the mechanisms of skeletal-muscle destruction and resistance to ERT in the murine knock-out AMD model by Raben and coworkers9, 26 highlights the important differences between type I and type II muscle fibers in AMD. Type II fibers, but not type I fibers, contain large regions of autophagic vacuoles that are believed to be responsible for skeletal-muscle damage and for interfering with efficient trafficking of replacement enzyme to lysosomes.9 These investigators postulate that the failure to hydrolyze glycogen to glucose, a fundamental lesion in AMD, may set up a nutritionally deprived state that induces a continuous autophagic buildup in type II fibers, resulting in profound disorganization of the microtubular structure and resultant muscle dysfunction.9 Reversal of this pathogenic process may further explain how NET slows the deterioration in muscle function. It has long been recognized that mammalian skeletal muscle has the potential to alter its phenotype, and that regular submaximal aerobic exercise is the most effective means of increasing type I skeletal-muscle fibers and decreasing type II fibers.11 At the same time, the enhanced nutritional state and frequent supplementation with alanine provided by NET would be expected to minimize periods of muscle nutritional deprivation.18 Both these therapeutic interventions should minimize the development of autophagic vacuoles and thereby minimize muscle destruction, as was histochemically demonstrated in two sibling patients with juvenile AMD.31 Assuming the above postulates to be true, NET should also slow the deterioration of both muscle function and respiratory function in adult-onset AMD. Indeed, once NET was complied with by our patients, the rate of deterioration in muscle function slowed significantly; the rate of deterioration in respiratory function appears also to have been slowed, but the data are less clear.
This uncontrolled prospective study demonstrates that the relentless deterioration in muscle function of adult-onset AMD can be slowed, thus significantly improving the natural history of this disease. Furthermore, this study demonstrates that a genetically inherited myopathic disease can be significantly modified by attempting to correct the disturbed intermediary metabolism resulting from the inherited enzyme deficiency, in this case by nutritional and exercise therapy. This is a further example of how appropriate nutrition and exercise can be utilized as effective therapy for the muscle glycogen storage diseases.27, 29 This study reinforces the recent observation of Motlagh et al.,23 who observed that a substantial number of adult patients with various forms of muscular dystrophy failed to meet their dietary and protein requirements, thus further impairing their muscle strength.
The beneficial effect of NET for adult-onset AMD needs to be confirmed in a large prospective randomized multicenter study, where caregivers would need to emphasize and monitor the importance of therapeutic compliance. Other questions that need to be addressed are whether continued compliance with NET slows the progression of the disease process indefinitely, and whether institution of NET soon after the onset of symptoms prevents or minimizes muscle deterioration. Now that rhGAA enzyme is commercially available, it is pertinent to determine whether ERT can improve skeletal muscle function in adult-onset AMD and whether the concurrent use of NET may enhance the effect of ERT. Data from clinical trials in the infantile form of AMD indicate that cardiac muscle responds well to ERT, whereas the response of skeletal muscle is highly variable.1, 34 The skeletal-muscle response to ERT in late-onset patients (3 years' administration in three juvenile patients), was also variable.35 Similarly, ERT administration in the murine knock-out model of the disease reversed the pathology in cardiac muscle and type I skeletal-muscle fibers, but type II fibers were resistant to ERT.9, 26 If indeed NET acts by decreasing the number of type II fibers and minimizes the number and size of autophagic vacuoles, then institution of NET should theoretically enhance the action of the exogenously administered GAA enzyme.