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Acid alpha-glucosidase deficiency (pompe disease)Tokiko Fukuda, MD, PhD, Ashley Roberts, BS, Paul H. Plotz, MD, and Nina Raben, MD, PhD Corresponding author
enlarged lysosomes. Recent efforts have brought about the Nina Raben, MD, PhDArthritis and Rheumatism Branch, National Institute of Arthritis development and production of the recombinant human and Musculoskeletal and Skin Diseases, National Institutes of GAA (rhGAA) for enzyme replacement therapy (ERT). Health, 9000 Rockville Pike, Clinical Center, Building 10/9N244, Pompe disease is one of several lysosomal storage disorders (LSD) being treated by ERT [3•], but it is the only one in this class in which skeletal muscle is the pri- Current Neurology and Neuroscience Reports 2007, 7:71–77
mary target. The success of ERT in other diseases (eg, Current Medicine Group LLC ISSN 1528-4042Copyright 2007 by Current Medicine Group LLC the non-neuropathic form of Gaucher disease) turned out to be hard to replicate in Pompe disease; the rever-sal of pathology in skeletal muscle is more difficult than The development and recent approval of recombinant anticipated. The emerging data from the first clinical acid alpha-glucosidase for enzyme replacement therapy trials with rhGAA suggested that the most critical factor have been major milestones in Pompe disease research. defining the outcome of therapy is the underlying skeletal Acid alpha-glucosidase is the enzyme responsible muscle pathology at the start of therapy. The view of the for degradation of glycogen polymers to glucose in pathology as the accumulation of glycogen within swol- the acidic milieu of the lysosomes. Cardiac and skel- len lysosomes and probable lysosomal rupture has not etal muscles are the two major tissues affected by the changed since the earliest studies, and the literature has accumulation of glycogen within the lysosomes. Both been remarkably silent regarding the secondary events cardiomyopathy and skeletal muscle myopathy are that may occur in skeletal muscle as a result of substrate observed in patients with complete enzyme deﬁciency; accumulation in the lysosomes. In this review, we focus this form of the disease is fatal within the ﬁrst year of life. on the results of the clinical trials, the latest methods for Skeletal muscle myopathy eventually leading to respira- early diagnosis, and the studies in knockout (KO) mouse tory insufﬁciency is the predominant manifestation of models that shed new light on the pathogenesis of the partial enzyme deﬁciency. The recombinant enzyme disease and the mechanisms of muscle damage. alglucosidase alfa is the ﬁrst drug ever approved for this devastating disorder. This review discusses the beneﬁts and the shortcomings of the new therapy. Clinical Manifestations Clinical manifestations of the disease depend largely on the level of residual enzyme activity, which, in turn, depends on the nature of the genetic defect. Over 200 Pompe disease owes its name to the Dutch pathologist mutations scattered across the gene have been found in J.C. Pompe , who first described the disease in 1932. Pompe patients. The mutations result in various out-This first report on the nosologic entity was a postmortem comes ranging from a complete lack of the enzyme to a description of pathology in an infant who died from what near-normal amount of enzyme with reduced activity. was thought to be pneumonia. Two critical observations Because the enzyme undergoes complex post-translational were made: 1) the disease is a vacuolar myopathy, and 2) modifications while trafficking to the lysosomes, multiple there is a massive accumulation of glycogen, primarily abnormalities along this pathway add to the variability of affecting cardiac and skeletal muscle. The vacuoles were the level of residual enzyme activity. later identified as lysosomes, and the cause of the glyco- The age of onset, organ involvement, and rate of gen accumulation was found to be a defect in lysosomal disease progression are heterogeneous . Traditional acid alpha-glucosidase (GAA) . These early studies classification of infantile, juvenile, and adult forms has established the primary underlying pathology in muscle given way to the view that there is a continuum of disease of Pompe patients, which is accumulation of glycogen in severity. Recently, a group of experts agreed to classify the disease into two broad categories: infantile and problems, wheelchair dependence, and use of respiratory late-onset forms . support [11,12]. In most patients, initial symptoms were The infantile form includes classic and nonclassic related to mobility and limb-girdle weakness. Respiratory variants. Classic infantile disease is a rapidly progres- insufficiency was observed in patients of any age, even in sive disorder manifesting as cardiomegaly, hypotonia, those without limb-girdle weakness . or mild hepatomegaly, resulting in death within the first year due to cardiorespiratory failure. In the nonclassic infantile form, the symptoms are still evident in the first ERTyear of life but the disease is characterized by a slower The concept of ERT for Pompe disease and other LSDs is progression and less severe cardiomyopathy . A com- based on experimental evidence indicating that lysosomal plete or near-complete GAA deficiency is typical for the enzymes can be taken up by the cells through receptor-infantile form . mediated endocytosis. In Pompe disease, the recombinant The late-onset form includes childhood, juvenile, and enzyme is a precursor containing mannose-6-phosphate adult-onset variants. Both childhood and juvenile disease groups that enable the enzyme to bind the receptor on the present any time after infancy with mild or no cardiac cell surface. Cation-independent mannose 6-phosphate involvement. The adult-onset form usually presents receptor (MPR) is responsible for binding and directing between the second and sixth decade of life and manifests the lysosomal enzymes into the endocytic pathway . as a slowly progressive skeletal muscle myopathy. The pre- The receptor-enzyme complexes enter the cells in trans- dominant manifestations of the late-onset form include port vesicles that fuse with endosomes. The acidic pH of proximal muscle weakness with respiratory muscle late endosomes induces the dissociation of the complexes; involvement. Respiratory failure is the cause of signifi- the receptor is recycled back, whereas the enzyme is trans- cant morbidity and mortality in this form. Some residual ported to the lysosomes. Numerous proteins participate enzyme activity can be found in late-onset patients.
in the sorting and trafficking of the lysosomal enzymes . Like the endogenous GAA precursor, the rhGAA is expected to undergo proteolytical cleavage along the transport route to yield intermediate forms followed by Pompe disease is a rare disorder with a total combined conversion to the fully active lysosomal species [15,16].
incidence estimated at one in 40,000 . The development of ERT underscores the value of studies on the natural history of the disease. First, these data provide a critical Clinical Trialsreference for the efficacy of ERT. Second, the ability to Currently, more than 280 patients in 30 countries are conduct prospective studies will dwindle as more patients receiving alglucosidase alfa (Myozyme; Genzyme Corpo-get access to therapy.
ration, Framingham, MA), which is a Chinese hamster A study of the classic infantile form with 20 origi- ovary (CHO)-derived rhGAA. However, the published nal cases and 133 cases from the literature showed that data include only the results of the first clinical trials for a the median age of death was 7.7 months for the origi- small group of infantile and late-onset patients. nal group and 6 months for the retrospective study. Nine patients (six infantile and three late-onset Motor development in the original group was severely patients) began therapy with a product purified from the impaired; milestones, such as the ability to turn, sit, milk of transgenic rabbits (trGAA), which was the first or stand, were not achieved or were quickly lost after clinically applicable rhGAA. Eventually, the production acquisition. The majority of patients died before 1 year of the milk product was discontinued (the method was not of age (only 5% of the original cases and 8% of all sustainable) and all surviving patients were transitioned reported cases survived) . When nonclassic infantile patients were included in Of the six severely affected infants who started the a retrospective study of 168 patients, slightly different therapy on trGAA, four were followed for 3 years. They data were obtained . Median age of death was 8.7 began therapy at a dosage of 15 to 20 mg/kg weekly, months, and the survival rate was 25.7% at 12 months which was later increased to 40 mg/kg weekly because the and 12.3% at 18 months. The frequencies of presenting level of enzyme activity in skeletal muscle still remained symptoms and signs were similar in both studies. Symp- significantly below normal on a lower dosage. Increase toms included cardiomegaly, cardiomyopathy, congestive in the dosage resulted in the normalization of the level heart failure, hypotonia, muscle weakness, respiratory of GAA activity [17,18]. However, glycogen in muscle distress, feeding difficulties, failure to thrive, gastro- decreased in only one patient (who was 3 months of age at start) who made remarkable progress and reached mile- Studies of the natural course of late-onset disease dem- stones never observed in untreated patients. His motor onstrated a significant variability in terms of age of onset, score normalized at the age of 2 years and he remained rate of disease progression, development of respiratory ventilator-free after 3 years of follow-up . However, Acid Alpha-Glucosidase Deficiency Fukuda et al. 73 this patient may have regressed because a later observa- alive; however, as of July 2006 only the best responder tion (Raben, Personal observation) clearly indicates that was still alive [22••]. this child still has a myopathy. Two older patients in this The second open-label phase II trial with CHO-derived study (7 and 8 months of age at start) became ventilator rhGAA was conducted in eight severely affected infan-dependent before or soon after the therapy began, and tile patients (age 2.7 months to 14.6 months) [22••]. All one patient (2.5 months of age at start) became ventila- patients fit the criteria of classic infantile form. They were tor dependent at the age of 2 years and died at the age of on 10 mg/kg weekly for the 52-week initial stage, and the 4 years, 3 months after a short period of fever, unstable surviving patients continued on 10 to 20 mg/kg weekly blood pressure, and coma. or biweekly for up to 153 weeks. GAA activity in skeletal Based on the results of this first study, two other muscle increased in all patients. As in all previous studies, patients (aged 3.1 and 5.9 months at start) began ther- the most dramatic effect of ERT was on cardiac muscle. apy with the trGAA at a dosage of 40 mg/kg weekly. The effect on skeletal muscle, however, was extremely As in the first study, the level of GAA activity in muscle variable. Two patients died during the initial stage, and increased significantly in both, but glycogen reduction four additional patients died during the extension phase, was observed in only one patient who showed significant bringing the total number of deaths to six. The deaths improvement of motor function over the course of a 10- were attributed to complications of the disease. Median month follow-up . In both studies [18,19] anti-GAA age at death or treatment withdrawal for all patients was antibody did not seem to correlate with clinical decline 21.7 months, significantly later than would be expected or lesser effect of therapy. for untreated patients. The two surviving children showed Data for a 3-year follow-up have been reported for significant reduction in skeletal muscle glycogen level on three late-onset patients (aged 11, 16, and 32 years) who therapy and were over 3 years of age at the time the study started therapy with trGAA [20•]. Weekly infusions of was published. 10 mg/kg resulted in only a slight increase in GAA activ- The safety and efficacy of alglucosidase alfa were ity in muscle; after 12 to 24 weeks of therapy the dosage assessed in two additional open-label trials. The results was increased to 20 mg/kg weekly. However, even on of these trials have not yet been published in a peer-a higher dosage the level of GAA activity remained reviewed journal; therefore, we will not discuss the below the normal range and glycogen was only slightly details of these studies but present a brief outline and decreased. At the start of therapy all the patients were the mortality rates. One study (conducted between 2003 wheelchair bound and two older patients were ventila- and 2005) involved 18 patients aged 6 months or younger tor dependent. The best clinical response was observed with cardiac hypertrophy who were ventilator free at in the youngest patient who was least affected at start start of therapy. Within the first 12 months of treatment, of therapy. This patient gained normal muscle strength there were no deaths. As of July 2006, four patients and function. Two other patients remained wheelchair had died. The second is an ongoing study of 21 patients bound, but they too showed a lower degree of disability aged 6 months to 3.5 years at the start of therapy. Five and improved quality of life [20•]. deaths were reported by the end of the 104-week study; Two studies with CHO-derived rhGAA have been one additional death has occurred during the extension reported so far. First, an open-label phase I/II study (5 phase (Kishnani, Personal communication).
mg/kg twice weekly) was conducted in three patients (2.5, Clinical trials have demonstrated that the stron- 3, and 4 months of age at start) with infantile Pompe gest and most consistent effect of ERT was on cardiac disease . Prior to ERT, two patients had severe car- pathology: all patients showed remarkable decreases diomyopathy typical for classic infantile form. The third in the left ventricular mass index, left ventricular pos-patient, who was the youngest at the enrollment and terior wall thickness, and improvements in cardiac least severely affected, fit the criteria of the nonclassic function regardless of disease severity. The reduction infantile form because he had less severe cardiomyopathy in cardiac size has been observed in patients who do and normal baseline cardiac evaluation despite virtually not show a decrease in the amount of accumulated absent GAA activity. This patient did well on therapy, skeletal muscle glycogen or improvement in muscle showed significant improvement in motor function, and function. Abnormal ECG parameters, which reflect began walking independently at 12 months of age. Two conduction abnormalities and hypertrophic cardiomy-other patients showed steady decrease in heart size and opathy, such as shortened PR interval, increased QT maintained normal cardiac function for more than 1 dispersion, and large left ventricular voltages, have also year. Both patients had some improvement in muscle been significantly improved on ERT . However, function, but both subsequently deteriorated and became recent data suggest that Pompe patients may be at risk ventilator dependent after episodes of viral pneumonia. for arrhythmias despite the significant improvement in In both cases, the decline coincided with the rising titers cardiomyopathy and conduction on ERT . of antibodies against rhGAA. Data for 16 to 18 months Thus, it is very clear that it is the dramatic effect of treatment were reported, at which time all three were on cardiac function that results in longer survival of all patients when compared with the age at death in untreated Autophagy is a highly conserved process of degrada- Pompe patients. However, mortality from disease compli- tion of most long-lived proteins and damaged organelles cations was very high, and only a small subset of patients [33••]. The process starts with the formation of double-achieved significant gains in physical performance. The membrane vesicles, called autophagosomes, which reasons for the variability in skeletal muscle response to sequester various constituents of cytoplasm, including therapy remain unclear.
glycogen. Autophagosomes fuse with and discharge their So far, only one study has attempted to correlate content into late endosomes and lysosomes; the autopha- the morphology of skeletal muscle and the outcome of gosomal membrane and cytoplasmic components are therapy. Winkel et al.  have examined the morpho- logic changes in muscle tissues in the first four infantile Apart from the increase in the number of AVs, other patients who received the trGAA. The authors came to vesicular compartments linked to lysosomes were found the conclusion that at each time point muscle pathol- to be affected in Pompe skeletal muscle . Analysis ogy correlated with the severity of clinical symptoms, of muscle biopsies from several patients with late-onset and that the degree of the impairment of muscle func- disease indicated proliferation of multiple vesicles of the tion plays the decisive role in the outcome. In the best endocytic pathway, such as early and recycling endosomes. responder, skeletal muscle striation and architecture Thus, these clinical studies suggest that the abnormalities were relatively well preserved at start of therapy, and in Pompe disease go beyond the expansion of the lyso-this patient had the least glycogen accumulation . somes. Studies in animal models give insight to the role Thus, the important lesson here is that the effect on of these secondary events in the progressive nature of the motor performance is highly dependent on the condi- disease and their effect on the outcome of therapy. tion of the patient at start of treatment. Although this study is informative, more details are needed regarding the skeletal muscle pathology and how it correlates with Studies in Knockout Mouse Models response to therapy. Since this review was submitted, a Preclinical studies with ERT in a mouse model of the dis-second study has been published analyzing the morphol- ease were very consistent with the results of the clinical ogy of skeletal muscle before and after ERT . trials. rhGAA reduced cardiac glycogen to undetectable levels but the reduction of glycogen in skeletal muscle was modest, and some fibers, in particular glycolytic fast twitch type II fibers, showed little or no glycogen clear- A lysosomal rupture hypothesis has long been proposed ance [35,36]. The rhGAA was taken up more efficiently to account for skeletal muscle destruction in Pompe by cardiac muscle than by skeletal muscle, but most of the disease [27,28]. The hypothesis, based on electron micros- administered enzyme was targeted to the liver. copy observation, suggests that muscle contraction causes Analysis of vesicular compartments in myoblasts iso- enlarged glycogen-filled lysosomes to rupture, result- lated from the KO mice demonstrated that the cellular ing in the release of free glycogen and potentially toxic pathology in Pompe disease spreads to affect both the endo-components into the cytosol. Skeletal muscle differs from cytic and autophagic pathways as shown by staining with other cells in that the expanded lysosomes are located in specific markers. Expansion of endocytic and autophagic a limited inter-myofibrillar space, thus creating a condi- vesicles profoundly affected the mobility and fusion of these tion for the physical rupture of the lysosomal membrane. vesicles in Pompe myoblasts [37••,38]. The autophagic Ruptured lysosomes eventually lead to loss of myofibril- vacuoles were easily identified in isolated single myofibers lar material and complete fiber destruction [27,28]. If this of the KO mice by staining with a specific autophagosomal hypothesis is true, the fibers at the later stages of disease marker. Furthermore, the entire core of the fibers was filled progression would be beyond repair with the current with multiple vesicular structures of the autophagic and therapeutic approach. endocytic pathways, and often contained autofluorescent Another pathologic finding in skeletal muscle in material. This autophagic buildup was limited to therapy- Pompe disease has been the presence of areas with large resistant type II fibers [36,37••] and was found in virtually numbers of autophagic vacuoles (AV). This observation every type II KO fiber, even in young animals. The extent was made by Engel  as early as 1970; glycogen accu- of autophagic buildup was enormous; in some fibers, the mulation was found not only in the lysosomes, but also volume occupied by the autophagic area reached approxi-in AVs with cytoplasmic degradation products. Exces- mately 40% of the total volume of a particular segment sive accumulation of AVs in skeletal muscle was later . The large autophagic mass interrupted the contractile confirmed by electron microscopy of muscle biopsies proteins in myofibers. Thus, it appears that it is not the from a number of Pompe patients [30–32]. Surprisingly, primary defect (ie, intralysosomal glycogen accumulation) however, the extent of autophagy, its role in the patho- that is responsible for muscle damage and wasting, but genesis of disease, and its implications for therapy have rather the secondary accumulation of what is sometimes been largely ignored. referred to as “biologic garbage” . Acid Alpha-Glucosidase Deficiency Fukuda et al. 75 Similar morphologic changes in skeletal muscle ferent genes: glucosidase II and neutral alpha-glucosidase fibers were observed in another mouse model of Pompe (with pH optimum of 7.5), and maltase-glucoamylase disease. Hesselink et al. [40,41•] found enhanced depo- (with pH optimum of 5 to 5.5). Maltase-glucoamylase sition of lipofuscin and large areas of centrally localized poses the greatest problem because it contributes signifi-debris in muscle of the KO mouse. Additionally, our own cantly to the total GAA activity measured at acidic pH. studies with labeled rhGAA have demonstrated that the Maltase-glucoamylase is expressed in neutrophils but bulk of the endocytosed therapeutic enzyme ends up in not in lymphocytes . Thus, purified lymphocytes are the autophagic areas within the fibers . Thus, exces- a better diagnostic material, but potential contamination sive autophagy sets up the conditions for the disruptive with neutrophils may result in false-negative results. buildup and diversion of the therapeutic enzyme away Recently, a major effort has been directed toward the development of methods for measuring GAA activity using The cause of the excessive autophagy in Pompe muscle dry blood spots (DBS), with the idea that these methods is still unclear. Nutritional deprivation is a well-known can be utilized for newborn screening. Blood spots can be trigger of autophagy. A hypothetical cascade may involve collected by the standard heel-stick procedure or the drop-local glucose starvation (a result of the failure of lysosomal wise addition of whole blood onto filter paper or Guthrie glycogen break-down to glucose) followed by induction cards, which can be stored for a long period of time and of autophagy, which then leads to buildup because of the easily transported. Two approaches show promise for the inability of the lysosomes to fuse with or digest the con- The first approach is immuno-quantification of GAA Excessive and early accumulation of lipofuscin, which protein in DBS . The assay takes advantage of the fact normally accumulates in aging post-mitotic cells , that in Pompe disease, like in most LSDs, the amount of points to another potential trigger of autophagy: oxida- the mutant enzyme is reduced; the exception is a subset tive stress. Oxidative damage in the KO fibers may affect of patients who produce a significant amount of protein the permeability of the lysosomal membrane, resulting in with reduced activity . A two-tiered screening strat-the leakage of lysosomal components even before the lyso- egy involving an initial protein determination followed by an immuno-capture enzyme activity assay would address the issue . Another strategy is competitive inhibition of maltase- glucoamylase activity using maltose  or acarbose . Maltose has been shown to have much higher affinity to Currently, GAA assay in skin fibroblasts or muscle biopsy maltase-glucoamylase than to GAA . Direct compari-remain the standard and most reliable diagnostic methods. son of the two inhibitors (maltose and acarbose) in DBS GAA has an optimum activity at pH of 3.75 to 4.5, and extracts using 4-MU showed that acarbose was superior the enzyme activity is measured using natural substrate, to maltose because there was no overlap in the level of glycogen, or the fluorescent synthetic substrate 4-methy- GAA activity between heterozygous and infantile Pompe lumbelliferyl-alpha-D-glucosidase (4-MU). However, patients . Acarbose has been successfully used for culturing fibroblasts takes weeks and significantly delays GAA activity measurement in mixed leukocytes  and the diagnosis. Muscle biopsy is a direct and rapid way in lymphocytes . In mixed leukocytes , acarbose of measuring GAA activity and provides a valuable his- completely inhibited the maltase-glucoamylase at pH of tologic material. However, the risk of anesthesia should 4.0 but inhibited the GAA by less than 5%, and there be considered in infantile patients. In late-onset cases, was a clear separation between the Pompe patients and the site of muscle biopsy may greatly affect the results of the control group when glycogen was used as a substrate. histologic analysis, and some samples may show little or The two groups were less well separated when 4-MU no glycogen accumulation. Mutation detection is still not was used, and the separation was significantly improved a trivial procedure, and as such is not suitable for routine by taking the ratio of inhibited over uninhibited activity. diagnostic purposes. Using 4-MU over glycogen is justified to exclude GAA None of these techniques can be used for the mass pseudo-deficiency caused by a polymorphism that lowers screening of newborns, which is the most promising the activity for glycogen but not for 4-MU . strategy for diagnosis of asymptomatic individuals and Considering that Pompe disease is a rare disorder, a early therapeutic intervention. Early diagnosis in clini- practical approach would be a multiplex assay for new- cally affected individuals is equally important, because born screening of multiple LSDs, especially those for the degree of skeletal muscle involvement at the start of which ERT is available or in development. A multiplex ERT has a major impact on the outcome of therapy. An immuno-quantification assay was used in a retrospec-ideal source of the enzyme for diagnostic purposes would tive study to simultaneously quantify individual proteins be leukocytes. However, in addition to GAA, leukocytes for 11 LSDs using DBS . 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