• adult-onset acid maltase deficiency;
  • muscle function deterioration;
  • natural history of acid maltase deficiency;
  • nutrition and exercise therapy


  1. Top of page
  2. Abstract
  6. Acknowledgements

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.


  1. Top of page
  2. Abstract
  6. Acknowledgements


Thirty-four patients with adult-onset disease, 16 women and 18 men, with histologically and biochemically proven AMD, were referred to us for evaluation and treatment from 1994 to 2004. All the patients were Caucasian and all but two were from various parts of the United States. One patient was from Spain and one from Canada. Although some were referred by their physicians, most patients were self-referred, frequently having become aware of NET from other patients via the internet. At the time of presentation, a full history and examination was obtained, including details of age of onset of symptoms, distribution and severity of muscle weakness, muscle function, pulmonary function, and nutritional status. There were three sets of siblings (patients 7 and 8; 14, 15, and 34; 28 and 29), with patients 14 and 15 being identical twins.

Study Design.

The rate of pre-therapy deterioration in muscle function, as measured by a modified Walton scale10 (Table 1), from the time of disease onset to the time of presentation at our center, was determined from the patient's history and medical records. Muscle function, as measured by this Walton scale, was monitored at each visit. Pulmonary function, in the form of vital capacity (VC), was measured by spirometry in the seated position at the time of presentation and at each follow-up visit. In most patients, pulmonary function measurements prior to therapy were not consistently available. Yearly follow-up visits were recommended, but were not accomplished in all patients. Written informed consent was obtained from all subjects. The research protocol was approved by the institutional review board of North Shore University Hospital.

Table 1. Modified Walton scale of muscle function.*
  • *

    The Walton scale was further subdivided between scores 2 and 4, to include 2.5 and 3.5 as designated.

Grade 0: Preclinical. All activities normal.
Grade 1: Walks normally. Unable to run freely.
Grade 2: Detectable defect in posture or gait. Climbs stairs without using the bannister.
Grade 2.5: Sometimes needs to use bannister to climb stairs.
Grade 3: Climbs stairs only with the bannister.
Grade 3.5: Sometimes climbs stairs with bannister, but at other times unable to climb stairs even with bannister.
Grade 4: Walks without assistance. Unable to climb stairs.
Grade 5: Walks without assistance. Unable to rise from a chair.
Grade 6: Walks only with calipers or other aids.
Grade 7: Wheelchair bound.

Nutrition and Exercise Therapy (NET).

Submaximal Aerobic Exercise.

Apart from patient 5, all the patients were ambulatory and were evaluated during incremental exercise on a treadmill. The goal was to achieve 60%–65% of maximal oxygen consumption (VO2 max), or maximal heart rate for age, which has been shown to correlate well with the comparable percent of VO2 max.6 During the exercise, patients were encouraged to work up to, but not exceed, a rate of perceived exertion of 11–12 (mildly hard) as defined by the Borg scale.4 Once a suitable aerobic exercise program was determined, patients were instructed to undertake that treadmill program daily for 45–50 min, followed by upper-body aerobic exercise for 10–15 min, using an upper-body ergometer. Patients who were not ambulatory, or who had difficulty exercising on a treadmill, were exercised on a bicycle for a similar period of time or were strongly encouraged to walk with a walker if possible.

Low-Carbohydrate and High-Protein Nutrition.

Prior to starting therapy and at each revisit, total daily caloric intake and percent caloric distribution were calculated from a 3-day food diary (Food Processor, version 7.6; Esha, Salem, Oregon). Patients were instructed to consume the recommended dietary allowance with a caloric distribution of 25%–30% protein, 30%–35% carbohydrate, and 35%–40% fat. Patients were also instructed to ingest oral L-alanine, 1.5 g, 4 times/day.3, 28 Body mass index (BMI) was calculated, and body composition, lean body mass, and fat mass were measured at each visit by bioelectric impedance analysis using BI-101Q RJL Systems, software 3.1b (Clinton Township, Michigan).

Compliance with NET.

The need for full compliance with NET was emphasized to patients. Frequent contact with patients via telephone and internet was undertaken in an attempt to enhance compliance. Although patients were encouraged to return for initial review after 6 months and then every 12 months, this was not always achieved. A compliance scale was devised to measure patient compliance (Table 2). The degree of compliance was graded from 0 to 16, with 8 points allotted to exercise and 8 to nutrition and body composition. A score of <8 was considered poor compliance, 8–11 moderate compliance, and >11 good compliance. Twenty-six of the 34 patients were considered to be in moderate–good compliance, whereas 8 were considered not to be compliant consistently.

Table 2. Compliance scale of adherence to nutrition and exercise therapy (NET).*
  • *

    The compliance scale was formulated in which 0–8 points were allocated for compliance to exercise protocol and 0–8 points for compliance to nutrition protocol (including body composition), with a maximum total compliance score of 16. A total score of <8 was considered to indicate poor compliance; 8–11, moderate compliance; and >11, good compliance.

Exercise: 0–8 points
 1 point for each day of the week that patient performs prescribed submaximal aerobic exercise (0–7).
 1 point for regular additional exercise, e.g., upper body exercise.
Nutrition: 0–8 points
 Percent protein intake:
  0, never reaches requirement; 1, sometimes reaches requirement; 2, always reaches requirement.
 Percent carbohydrate intake:
  0, always exceeds recommendation; 1, sometimes exceeds recommendation; 2, never exceeds recommendation.
 Adequate caloric intake:
  0, <85% daily requirement; 1, 85%–95% daily requirement; 2, 95%–110% daily requirement; 1, >110% daily requirement.
 Body mass index:
  −2, BMI <18; 0, BMI 18–20; 1, BMI 20–23; 2, BMI 23–27; 1, BMI 27–30; 0, BMI >30.
Statistical Evaluation of Muscle Function.

For each patient, the Walton score was evaluated at the following three time points: at the onset of symptoms as determined from the medical history, at the start of NET, and at the patient's most recent visit. These three scores were used for statistical evaluation. The slope of the line from onset of symptoms to start of NET (pre-therapy slope) was computed, as was the slope of the line from the start of NET to the most recent measurement (post-therapy slope). For each patient, the difference between the pre-therapy and post-therapy slopes was computed. Paired t-tests were performed on the data of the compliant and noncompliant group of patients. A P-value of <0.05 was considered statistically significant. If the null hypothesis that the treatment has no effect on the Walton score is true, the difference between pre-therapy and post-therapy slopes should be zero. Although this was not a placebo controlled trial, the noncompliant patients did form a small group to which the response of the compliant patients was compared.

Statistical Evaluation of Respiratory Function.

Comparison of the rate of change of respiratory function before and after institution of NET was not possible, as sequential respiratory function evaluation from the onset of symptoms to the start of NET was unavailable in the records of most patients. After starting NET, respiratory function as measured by VC was monitored at each visit. The response to NET was evaluated by calculating the percent change in VC from the time of starting NET to the most recent VC measurement. Each percent change was then divided by the time in years, from the start of NET to the most recent measurement, to obtain the rate of change. The average rate of change for the compliant and noncompliant groups was compared by a t-test, with a P-value of <0.05 considered significant.


  1. Top of page
  2. Abstract
  6. Acknowledgements

Clinical Data.

Thirty-four patients, aged 25–66 (mean 44.1 ± 10.5) at the time of presentation to our center, were evaluated and instructed on how to implement NET. The age of onset of clinical symptoms ranged from 18 to 56 (mean 32.4 ± 11.0). Onset of symptoms occurred between 20 and 45 years of age in 79% of patients; three had onset prior to 20 years, and four had onset after 50 years. The usual initial symptoms were difficulty in running, walking, and climbing stairs; nine patients (27%) also manifested some degree of respiratory insufficiency at the onset of symptoms. In two patients, acute respiratory insufficiency was the initial symptom. Myalgia, burning pain, and muscle cramping was experienced by many patients during exercise, and a number of patients experienced myalgia at rest or during sleep. Four patients presented to our center with a Walton score of 1, 1 with a score of 2, 24 (71%) with a score between 2.5 and 3.5, 4 with a score of 6, and 1 with a score of 7. As illustrated in Figure 1, there was progressive muscle function deterioration from the onset of symptoms to the time of presentation. Four of the more severely affected patients (Walton score 6 or 7) developed symptoms before age 26, and all presented to our center more than 20 years later. Of the other 30 patients, 2 presented with a history of >20 years, 7 with a history of ≥10 years, and 21 with a history of <10 years. All but two patients, whose onset of symptoms occurred after the age of 25, presented with a Walton score between 2.0 and 3.5.

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Figure 1. Rate of deterioration in muscle function over years in compliant patients with adult-onset acid maltase deficiency (Walton scale) from time of onset of symptoms to time of presentation (pre-therapy), and from time of institution of nutrition and exercise therapy to the most recent evaluation (post-therapy). The numbers above line 1 indicate individual patients. Continuous and interrupted lines were used to assist the identification of muscle-function progression of individual patients.

Download figure to PowerPoint

Muscle Function following Institution of NET.

All 22 fully compliant patients (compliance score ≥11) demonstrated a plateauing of their deterioration in muscle function, and 6 of these patients showed a slight improvement in their Walton score (Fig. 1). Two moderately compliant patients also demonstrated plateauing of their Walton score. Two patients, who initially were fully compliant and demonstrated an early improvement in muscle function, later became less compliant (compliance score 8–10) with subsequent mild deterioration in their Walton score. The mean length of time since NET was instituted in the 26 compliant patients was 4.0 ± 1.5 years, with length of treatment ranging from 2 to 8 years. The rate of deterioration in muscle function continued unabated in the eight noncompliant patients (compliance score < 8) (Fig. 2). Mean length of time from presentation in these patients was 6.4 ± 2.3 years. Four had initially been compliant and their clinical status had stabilized, but later they became exercise noncompliant and Walton scores deteriorated. Two patients never complied and showed progressive deterioration. One patient, who was moderately compliant with the exercise program, was nutritionally noncompliant as a result of her inability to ingest adequate calories and achieve a BMI >18; another patient, who had an initial Walton score of 3, was exercise noncompliant after sustaining a leg injury.

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Figure 2. Rate of deterioration in muscle function over years in noncompliant patients with adult-onset acid maltase deficiency (Walton scale) from time of onset of symptoms to time of presentation (pre-therapy), and from time of institution of nutrition and exercise therapy to the most recent evaluation (post-therapy). The numbers above line 1 indicate individual patients. Continuous and interrupted lines were used to assist the identification of the muscle-function progression of individual patients.

Download figure to PowerPoint

Statistically, the mean difference between pre-therapy and post-therapy slope for the 26 compliant subjects was −0.29 (95% CI −0.36, −0.19) (P < 0.0001), i.e., the post-therapy annual increase (deterioration) in Walton score was 0.29 less than the pre-therapy annual increase. Thus, the paired t-test of the compliant group rejected the null hypothesis that the true difference between pre-therapy and post-therapy slopes was zero. The mean difference between pre-therapy and post-therapy slope for the eight noncompliant subjects was −0.01 (95% CI −0.36, 0.34) (P = 0.95), i.e., the post-therapy annual increase in Walton score was 0.01 less than was the pre-therapy increase. Rate of change in muscle function of the compliant group was compared to that of the noncompliant group, and the difference was significant (P = 0.02).

Respiratory Function following Institution of NET.

At the time of presentation to our center, the VC was <50% of predicted in 9 patients and between 50%–65% of predicted in 8 patients, i.e., 17 of the 34 (50%) patients had moderate–severe respiratory insufficiency. Of the 12 compliant patients with moderate–severe respiratory insufficiency, 2 showed marked (15%) improvement, 2 had modest (≥5%) improvement, 3 had slight improvement (1%–4%), 3 showed modest (<7%) deterioration, 1 showed moderate (10%) deterioration, and 1 who recently became noncompliant showed marked (>25%) deterioration. Of the 14 compliant patients who at presentation had normal or near-normal respiratory function (>75% predicted) or mild respiratory insufficiency (65%–75% predicted), 2 showed moderate improvement (≥10%), 6 were unchanged, 3 showed modest deterioration (5%–10%), and 3 showed moderate deterioration (10%–15%). The two noncompliant patients who presented with respiratory insufficiency (<50% predicted) showed further moderate (5%–10%) deterioration. Of the two noncompliant patients who presented at 59% of predicted VC, one showed 4% improvement and the other showed 7% deterioration. Of the four noncompliant patients who presented with normal or near-normal respiratory function, one deteriorated by 20% and three improved by 4%–8%.

Statistically, there was little annual percent change in the mean (± SE) VC in the 26 compliant patients (−0.21 ± 0.50), which was considerably different from that of the 8 noncompliant patients (−1.70 ± 0.81), but the difference between the two groups did not reach statistical significance (P = 0.14).


Strict compliance to both aspects of NET is necessary for the therapy to be effective. The more recently treated patients were more intensely counseled and frequent contact was maintained with these patients, which resulted in better exercise compliance. Some of the earlier treated patients, who were initially instructed to exercise two to three times a week, and who in many cases exercised less frequently, found it difficult to adjust to the later recommended daily exercise program. Likewise, as our experience with the use of NET increased, it became apparent that adequate caloric intake and an adequate BMI >18 was necessary for NET to be effective. Four patients who were grossly underweight, with BMIs <18, were unable to increase their weight by ingesting adequate calories. Shortly after presentation, percutaneous endoscopic gastrostomies were inserted in two patients. To increase their caloric intake, one third of their daily caloric requirements were administered overnight by continuous infusion of Resource Diabetic (Novartis, Minneapolis, Minnesota), a high-protein and low-carbohydrate formula. Since we were initially unaware of the critical need to maintain a satisfactory BMI, there was considerable delay in instituting nocturnal tube feedings in one of the earlier diagnosed underweight patients who had presented in the mid-1990s. Her BMI continued to decrease, despite strong encouragement to increase her oral caloric intake, with concurrent muscle and pulmonary function deterioration.

In all patients, the serum creatine kinase (CK) levels were elevated above the normal range of 30–200 IU/L, with levels ranging from 276 to 1,302 IU/L, with the exception of one patient whose initial CK level was 121 IU/L. There was no significant change in the mean CK levels following introduction of NET; the mean initial level was 744 ± 458 and following NET was 698 ± 387 IU/L. There was no significant correlation between CK level and muscle or respiratory dysfunction.


  1. Top of page
  2. Abstract
  6. Acknowledgements

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.


  1. Top of page
  2. Abstract
  6. Acknowledgements

This research was supported in part by The Children's Pompe Foundation, and Genzyme Corporation.


  1. Top of page
  2. Abstract
  6. Acknowledgements
  • 1
    Amalfitano A, Bengur AR, Morse RP, Majure JM, Case LE, Verrling DL, et al. Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med 2001; 3: 132138.
  • 2
    Bodamer OA, Leonard JV, Halliday D. Dietary treatment in late-onset acid maltase deficiency. Eur J Pediatr 1997; 156: 539542.
  • 3
    Bodamer OA, Halliday D, Leonard JV. The effects of L-alanine supplementation in late-onset glycogen storage disease type II. Neurology 2000; 55: 710712.
  • 4
    Borg GAV. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14: 377381.
  • 5
    Brown DH. Glycogen metabolism and glycolysis in muscle. In: EngelAG, Franzini-ArmstrongC, editors. Myology, Vol 1. New York: McGraw-Hill; 1994. p 648664.
  • 6
    Dunbar CC, Robertson RJ, Baum R, Blandin MF, Metz K, Burdett R, et al. The validity of regulatory exercise intensity by ratings of perceived exertion. Med Sci Sports Exerc 1992; 24: 9499.
  • 7
    Engel AG, Hirschhorn R, Huie ML. Acid maltase deficiency. In: EngelAG, Franzini-ArmstrongC, editors. Myology, Vol 1, 3rd ed. New York: McGraw-Hill; 2004. p 15591586.
  • 8
    Ferrer X, Coquet M, Saintarailles J, Ellie E, Deleplanque B, Desnuelle C, et al. Myopathy in adults caused by acid maltase deficiency. A trial of treatment with high protein diet. Rev Med Interne 1992; 13: 149152.
  • 9
    Fukuda T, Ewan L, Bauer M, Mattaliano RJ, Zaal K, Ralston E, et al. Dysfunction of endocytic and autophagic pathways in a lysosomal storage disease. Ann Neurol 2006; 59: 700708.
  • 10
    Gardner-Medwin D. Management of muscular dystrophy. Physiotherapy 1977; 63: 4651.
  • 11
    Gollnick PD, Armstrong RB, Saubert CW, Piehl K, Saltin B. Enzyme activity and fiber composition in skeletal muscle of untrained and trained men. J Appl Physiol 1973; 34: 107111.
  • 12
    Hagemans MLC, Winkel LPF, Van Doorn PA, Hop WJC, Loonen MCB, Reuser AJJ, et al. Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain 2005; 128: 671677.
  • 13
    Harber MP, Schenk S, Barkan, AL, Horowitz JF. Effects of dietary carbohydrate restriction with high protein intake on protein metabolism and the somatoropic axis. J Clin Endocrin Metab 2005; 90: 51755181.
  • 14
    Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: acid α-glucosidase (acid maltase) deficiency. In: ScriverCR, BeaudetAL, SlyWS, ValleD, ChildsB, VogelsteinB, editors. The metabolic and molecular bases of inherited diseases, Vol 2, 8th ed. New York: McGraw-Hill; 2001. p 33893420.
  • 15
    Hurley BF, Nemeth PM, Martin WH III, Hagberg JM, Dalsky GP, Holloszy JO. Muscle triglyceride utilization during exercise: effect of training. J Appl Physiol 1986; 60: 562567.
  • 16
    Isaacs H, Savage N, Bodenhorst M, Whistler T. Acid maltase deficiency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J Neurol Neurosurg Psychiatry 1986; 49: 10111018.
  • 17
    Laforet P, Nicolino M, Eymard PB, Puech JP, Caillaud C, Poenaru L, et al. Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 2000; 55: 11221128.
  • 18
    Majeski AE, Dice JF. Mechanisms of chaperone-mediated autophagy. Int J Biochem Cell Biol 2004; 36; 2435–2444.
  • 19
    Margolis ML, Hill AR. Acid maltase deficiency in an adult. Evidence for improvement in respiratory function with high-protein dietary therapy. Am Rev Respir Dis 1986: 134; 328331.
  • 20
    Martiniuk F. Alpha glucosidase deficiency syndromes. In: KarpatiG, editor. Structural and molecular basis of skeletal muscle disease, Vol 2. Lawrence, KS: Allen Press; 2002. p 2128.
  • 21
    Martiniuk F, Chen A, Mack A, Arvanitopoulos E, Chen Y, Rom WM. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet 1998: 79; 6972.
  • 22
    Mobarhan S, Pintozzi RL, Damle P, Friedman H. Treatment of acid maltase deficiency with a diet high in branched chain amino acids. J Parenter Enteral Nutr 1990; 14: 210212.
  • 23
    Motlagh B, MacDonald JR, Tarnopolsky MA. Nutritional inadequacy in adults with muscular dystrophy. Muscle Nerve 2005; 31: 713718.
  • 24
    Padberg GW, Wintzen AR, Giesberts MA, Sterk PJ, Molenaar AJ, Hermans J. Effects of a high-protein diet in acid maltase deficiency. J Neurol Sci 1989; 90: 111117.
  • 25
    Pelligrini N, Laforet P, Orlkowski D, Pelligrini M, Caillaud C, Eymard B, et al. Respiratory insufficiency and limb muscle weakness in adults with Pompe's disease. Eur Respir J 2005; 26: 10241031.
  • 26
    Raben N, Fukuda T, Gilbert AL, de Jong D, Thurberg BL, Mattaliano RJ, et al. Replacing acid alpha-glucosidase in Pompe disease: recombinant and transgenic enzymes are equipotent, but neither completely clears glycogen from type II muscle fibers. Mol Ther 2005; 11: 4856.
  • 27
    Slonim AE, Goans PJ. Myopathy in McArdle's syndrome: improvement with a high-protein diet. N Engl J Med 1985; 312: 355359.
  • 28
    Slonim AE, Coleman RA, McElligot MA, Nassar J, Hirschhorn K, Labadie GU. Improvement of muscle function in acid maltase deficiency by high-protein therapy. Neurology 1983; 33: 2438.
  • 29
    Slonim AE, Coleman RA, Moses WS. Myopathy and growth failure in debrancher enzyme deficiency: improvement with high-protein nocturnal enteral therapy. J Pediatr 1984; 105: 906911.
  • 30
    Slonim AE, Rosenthal H, O'Connor MR, Goldberg T, Schwenk WR, Haymond MW. High protein and exercise therapy (HPET) for childhood acid maltase deficiency (AMD). J Neurol Sci 1990; 98(Suppl): A465.
  • 31
    Slonim AE, Bulone L, Minikes J, Hays AP, Shanske S, Tsujino S, et al. Benign course of glycogen storage disease type IIb in two brothers: nature or nurture. Muscle Nerve 2006; 33: 571574.
  • 32
    Umpleby AM, Wiles CM, Trend PS, Scobie IN, Macleod AF, Spencer GT, et al. Protein turnover in acid maltase deficiency before and after treatment with a high-protein diet. J Neurol Neurosurg Psychiatry 1987; 50: 587590.
  • 33
    Umpleby AM, Trend PS J, Chubb D, Conaglen JV, Williams CD, Heps R. The effect of a high protein diet on leucine and alanine turnover in acid maltase deficiency. J Neurol Neurosurg Psychiatry 1989; 52: 954961.
  • 34
    Winkel LP, Kamphoven JH, Van Den Hout HJ, Severijnen LA, Van Doorn PA, Reuser AJ, et al. Morphological changes in muscle tissue of patients with infantile Pompe's disease receiving enzyme replacement therapy. Muscle Nerve 2003; 27: 743751.
  • 35
    Winkel LP, Van Den Hout JM, Kamphoven JH, Disseldorp JA, Remmerswaal M, Arts WF, et al. Enzyme replacement therapy in late-onset Pompe's disease: a three-year follow up. Ann Neurol 2004; 55: 495502.