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Lysosomal Storage Disease 2 Pompe’s disease Ans T van der Ploeg, Arnold J J Reuser Lancet 2008; 372: 1342–53 This is the second in a Series of three papers about lysosomal storage disease Department of Paediatrics, Division of Metabolic Diseases and Genetics, Erasmus MC, Sophia Children’s Hospital, University Medical Centre, Rotterdam, Netherlands (A T van der Ploeg MD); and Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, Netherlands (A J J Reuser PhD) Correspondence to: Dr Ans T van der Ploeg, Erasmus MC, Sophia Children’s Hospital, University Medical Centre, Department of Paediatrics, Division of Metabolic Diseases and Genetics, Dr Molewaterplein 60, 3015 GJ Rotterdam, Netherlands [email protected]

Pompe’s disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait characterised by acid α-glucosidase deficiency leading to lysosomal glycogen storage. Pompe’s disease is also regarded as a muscular disorder, but the generalised storage of glycogen causes more than mobility and respiratory problems. The clinical spectrum is continuous and broad. First symptoms can present in infants, children, and adults. Cardiac hypertrophy is a key feature of classic infantile Pompe’s disease. For a long time, there was no means to stop disease progression, but the approval of enzyme replacement therapy has substantially changed the prospects for patients. With this new development, the disease is now among the small but increasing number of lysosomal storage disorders, for which treatment has become a reality. This review is meant to raise general awareness, to present and discuss the latest insights in disease pathophysiology, and to draw attention to new developments about diagnosis and care. We also discuss the developments that led to the approval of enzyme replacement therapy with recombinant human α-glucosidase from Chinese hamster ovary cells (alglucosidase alfa) by the US Food and Drug Administration and European Medicines Agency in 2006, and review clinical practice.

Introduction Pompe’s disease (Online Mendelian Inheritance in Man [OMIM] number 232300) is an inherited metabolic myopathy. It is a generalised glycogenosis characterised by lysosomal glycogen storage caused by deficiency of the lysosomal enzyme acid α-glucosidase. Pompe’s disease has an estimated frequency of one in 40 000 in African-American, one in 50 000 in Chinese, one in 40 000 in Dutch, and one in 146 000 in Australian populations.1–6 Synonyms for the disease are glycogen-storage disease type II and acid-maltase deficiency. This disease has been untreatable, but approval in 2006 of enzyme replacement therapy with recombinant human acid α-glucosidase has shown the potential to substantially alter its prognosis. This review addresses the latest insights into Pompe’s disease, with a focus on diagnostic and therapeutic challenges.

Clinical features Pompe’s disease presents as a spectrum of features in which symptoms can manifest at any age (figure 1).7 At the severe end of the spectrum is a subgroup of patients with a clearly defined course. This classic infantile form was first described by Pompe in 1932 and usually presents in patients within the first months of life. The median age of onset ranges from 1·6 to 2·0 months.8–10 Presenting symptoms are feeding difficulties, failure to thrive, respiratory infections, hypotonia, and very few movements.11 The heart is characteristically affected. For example, cardiac ultrasound shows a hypertrophic cardiomyopathy with thickening of the ventricular walls and septum, which could lead to outflow tract obstruction and cardiac failure.12 The electrocardiogram (ECG) shows high voltages, repolarisation disturbances, and frequently a short PR interval.13,14 Motor development is delayed and major motor milestones such as rolling over, sitting, or standing are usually not achieved. 1342

On clinical examination, patients show slipping through on vertical suspension and prominent head lag. Tendon reflexes are often decreased. Additional clinical features can be enlargement of the tongue and moderate enlargement of the liver. Hearing deficit might be present and has been attributed to pathological changes in the middle ear, inner ear, and auditory nervous system.15–17 This last feature remained unnoticed for a long time because patients died early, but it should be addressed adequately if patients survive longer than expected with enzyme replacement therapy. The same is also true for the recently recognised osteopenia and osteoporosis in affected children.18 The mean age of death in studies of large groups of patients was 6·0–8·7 months.8–10 Patients with classic infantile Pompe’s disease rarely survive beyond 1 year of age. In patients with less progressive forms of Pompe’s disease, onset of symptoms in this group can range from infancy to late adulthood, and a clear distinction of subtypes cannot be made.1,2,7,16,19–21 A questionnaire study in an international cohort of 255 children and adults with Pompe’s disease showed an

Search strategy and selection criteria We searched Pubmed for articles with the terms ”Pompe disease”, ”acid alpha-glucosidase deficiency”, ”acid maltase deficiency”, “glycogenosis type II”, and “enzyme (replacement) therapy”. We mainly selected publications in English from the past 7 years, but did not exclude commonly referenced and highly regarded older publications. For treatment, we focused on enzyme therapy. Articles on gene therapy were excluded, because they were beyond the scope of this review. For detailed information about the full range of mutations in the GAA gene, we refer to the website http:// www.pompecenter.nl, which provides frequent updates.

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Enzymatic and molecular diagnosis All patients have a deficiency of the lysosomal enzyme acid α-glucosidase, and can be diagnosed on the basis of this feature.34 However, the sensitivity and specificity of the enzymatic procedure depends on the choice of tissue specimen, type of substrate, and assay conditions. Of the www.thelancet.com Vol 372 October 11, 2008

Patients with the common c. –32–13T>G mutation in one GAA allele Patients with other mutations

Patient profile

age range of first complaints from birth to 62 years.22 Disease severity, as measured by wheelchair and ventilator use, was more related to disease duration than to age. Notably in this study, six of 23 patients younger than 15 years had a more rapid course of disease than did the others. All six patients who were ventilator dependent also needed a wheelchair and were fed via nasogastric tube or percutaneous gastrostomy. These six patients presented with symptoms before the age of 2 years, as did the children classified as having a non-typical infantile form of Pompe’s disease.10 Symptoms of children and adults with a non-classic presentation are predominantly related to skeletal muscle dysfunction, resulting in both mobility and respiratory problems. The heart is sporadically affected.2,21,23–25 Presenting symptoms analysed in 54 adults were difficulties in participating in sports, climbing stairs, rising from an armchair, walking, and rising from a lying position. Other first symptoms were fatigue and muscle cramps.26 Mobility and respiratory problems might progress at a different pace. Patients who are still ambulant might need ventilation at night and those with normal pulmonary function might become dependent on a wheelchair. Various cases have been described in which patients presented with sudden respiratory failure, although mobility problems were not evident or had remained unnoticed,27–29 which emphasises the importance to monitor pulmonary function irrespective of the motor disorder. Involvement of the diaphragm could lead to low vital capacities in the supine position although pulmonary function in the upright position is still adequate. Therefore, pulmonary function should be assessed in both positions. Patients might have excessive daytime sleepiness, sleep-disordered breathing, and nightly hypoventilation and might need (non)-invasive ventilation.16,28 Pompe’s disease in adults is regarded as a slowly progressive disorder. Many adults show symptoms during childhood.19,20,22 However, a study done in 52 affected adults recorded a substantial deterioration in mobility, degree of handicap, and need for respiratory support during 2-years follow-up.30 During this period, four of the 52 patients died at a relatively young age (44–68 years), indicating that this disease is life threatening in adults, as it is in infants and children. Apart from frequently encountered pulmonary complications, the possible episode of an aneurysm due to accumulation of glycogen in vascular smooth-muscle cells is a potential risk factor.31–33

0

10

20

30

40

50

60

70

Age (years)

Figure 1: Age at onset of symptoms and the current age of a cohort of 36 patients with Pompe’s disease Each horizontal bar represents the disease duration of an individual patient. *Patients have died.

various tissue specimens that are used for diagnosis, cultured skin fibroblasts have by far the highest acid α-glucosidase activity and do not contain neutral α-glucosidase activities that interfere with the assay when done at pH 4·0–4·3. The use of 4-methylumbelliferyl-α-D-glucopyranoside as an artificial substrate provides an assay that is sufficiently specific and sensitive to detect as little as 1–2% of residual enzyme activity. This test can distinguish infants with the classic infantile form of the disease from children and adults with residual activity (figure 2).20,35–38 Infants with classic Pompe’s disease have less than 1% residual activity; children and adults have residual activity, but usually no more than 30% of average normal activity. On the basis of the data, enzyme deficiency might be easier to correct in children and adults than in infants, provided that young and aged muscle respond equally well. Full correction of enzyme activity is not needed, because carriers with about 50% of average normal activity are unaffected. A supplemental advantage of cultured fibroblasts is that they can serve as a longlasting source of material for various investigations, whereas a disadvantage is the need for tissue-culture facilities and 1343

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the 4–6 weeks’ delay between obtaining the tissue (skin biopsy) and the actual assay. Moreover, culture conditions need special attention, since the height of the acid α-glucosidase activity is sensitive to the degree of cell density and type of culture media.37 Strict adherence to standardised cell-culture procedures has to be maintained. The same artificial substrate can be used for the enzymatic diagnosis of Pompe’s disease in muscle 160 155 150 145 140 135 130 125 120 115 110

Lysosomal α-glucosidase activity (nmol/h/mg protein)

105 100 95 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 10 5 0 Unaffected individuals (n=81)

Adults (n=24)

Children (n=4)

Infants (n=46)

Figure 2: Ranges of acid α-glucosidase activity in fibroblasts of healthy individuals and patients of different ages Lengths of arrows show how much activity needs to be increased to reach lower limit of normal.

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biopsies. This assay also reveals the activity difference between affected infants and adults.36 Leucocytes cannot be used unless special precautions are taken to keep the interference of neutral α-glucosidases to a minimum. For this purpose, glycogen is used as a natural substrate and acarbose is added as an inhibitor of the neutral αglucosidases.39 Isolated lymphocytes are used as another diagnostic option, but this assay too requires the inclusion of acarbose, since lymphocyte preparations can be contaminated with granulocytes.40 Inclusion of isozymespecific antibodies for the assay of acid α-glucosidase activity in total leucocytes is another way to increase the specificity of the assay in blood cells.19 Only the assays in fibroblasts and skeletal muscle have proved sufficiently sensitive to correlate the clinical phenotype with the degree of enzyme deficiency (figure 2).36,38 Of late, several new methods used assays of the acid α-glucosidase activity in dried bloodspots.41–46 These methods are typically suitable for neonatal screening, but can in principle be used as a first-line diagnostic procedure in case obtaining or shipment of blood samples or other tissue specimens is difficult. Antibodies are needed to selectively capture acid α-glucosidase or inhibitors of neutral α-glucosidases to achieve specificity.41,43,45,47 The use of acarbose (3–10 μmol/L) rather than maltose for the specificity has been recommended.42,45 The application of multiplex systems that measure the activities of several lysosomal enzymes simultaneously either by immunofluorescent probing or by tandem mass spectroscopy, with novel substrates, are exciting new developments that make neonatal screening possible.43,46 The implementation of newborn screening for lysosomal diseases not only concerns the implementation of assay procedures, but also of ethical dilemmas. For example, how do we appreciate the consequences of a positive enzymatic or molecular diagnosis when we are uncertain whether disease-related symptoms will develop?48 Chorionic villi are the preferred material for enzymatic prenatal diagnosis of Pompe’s disease in 10–12 weeks of pregnancy.49 As opposed to amniotic fluid cells, the villi are obtained at an earlier stage of pregnancy, can be processed directly, and provide a diagnostic answer within days. Moreover, the acid α-glucosidase activity in the villi is substantially higher than in the amniocytes, which makes this assay more sensitive than the other. The absence of interfering neutral maltases allows for the application of the artificial substrate. The risk of maternal contamination is a disadvantage of chorionic villi sampling. In a doubtful situation, maternal contamination can be established or excluded by DNA fingerprinting.2 None of the enzymatic procedures reliably discriminates between unaffected carriers and non-carriers. In pregnancies at risk of late-onset forms of Pompe’s disease with residual activity, to distinguish between affected fetuses and carriers might be difficult. In these cases, www.thelancet.com Vol 372 October 11, 2008

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GAA genotype and clinical course Pompe’s disease is inherited in an autosomal recessive manner. No cases of affected carriers have been documented. Thus, both GAA alleles need to harbour a pathogenic mutation before the phenotype develops. Many of the reported mutations were characterised. We usually know precisely how they affect the splicing process, the GAA-mRNA stability, or the biosynthesis of acid α-glucosidase (including the various posttranslational modification steps, the intracellular transport, and finally the function). Approaches to obtain this type of information are a continuation of the pioneering work of Hasilik and Neufeld, who showed in 1980 the process of visualising the biosynthesis of lysosomal enzymes.63,64 Similar procedures are applied to analyse the effect of GAA gene mutations in transiently transfected cells. Therefore, the mutations are introduced into wild-type complementary DNA by in-vitro mutagenesis and expressed in a suitable cell type such as COS cells or enzyme-deficient human cells.61 Investigations have shown that the clinical course of Pompe’s disease is mainly established by the nature of the mutations in both GAA alleles, leading to different degrees of enzyme deficiency.65,66 Equally important, they www.thelancet.com Vol 372 October 11, 2008

100 α-glucocidase activity (%)

DNA analysis is a far better diagnostic procedure than are enzymatic procedures since it provides undisputable confirmation of the presence or absence of the familial mutations. The gene encoding acid α-glucosidase (GAA) is localised on chromosome 17q25.2-q25.3 and contains 19 coding exons.50,51 The locus is very heterogeneous. At present, nearly 180 different mutations have been reported, which are listed in the Pompe’s disease database. About 75% of these are pathogenic mutations. The development of enzyme replacement therapy has increased general awareness and demand for sophisticated diagnosis at both the enzymatic and molecular level. Consequently, we expect the number of pathogenic mutations to exceed 200 in 2008. If a mutation is not detected by genomic DNA analysis, mRNA analysis can be indicative of the occurrence of large deletions or insertions, or obscure mutations in the promoter region or in one of the introns decreasing the allele-specific amount of mRNA to a pathogenic level.52–55 In-depth discussion about the range of mutations in Pompe’s disease is beyond the scope of this review. We have restricted our discussion to mentioning frequently encountered mutations. c.-32-13T>G is the most common mutation in children and adults with a slowly progressive course of disease (75% of patients).55–58 c.1935C>A (p.Asp645Glu) is frequent in the Taiwanese population59 and c.del525, del exon18, and Arg309 are common in the Netherlands, but occur in other countries as well.54,56,60,61 c.2560C>T (p.Arg854Ter) is the most common mutation in American black population.2,62 The last five mutations result in total loss of acid α-glucosidase activity.

50 30 10 2 Adults Unaffected individuals

Infants Children

Disease phenotype

Figure 3: Model depicting that signs of Pompe’s disease emerge when the α-glucosidase activity drops below 30% of average normal activity White to purple zone: disease phenotype aggravates with increasing degree of enzyme deficiency, which is mainly dictated by the nature and combination of the mutations in the two GAA alleles. Within this zone, as yet to be identified, secondary factors modulate the clinical course such that patients with the same degree of enzyme deficiency might manifest symptoms at different ages and with different degrees of severity.

revealed the extent of clinical heterogeneity brought about by secondary genetic or non-genetic factors. A good example of secondary genetic factors is the analysis of a cohort of patients with a c.-32-13T>G/null genotype, in which null stands for any GAA mutation that leads to complete loss of acid α-glucosidase activity. Some of these patients manifested first symptoms in early childhood, whereas others remained presymptomatic until late adulthood.56–58 c.-32-13T>G reduces the fidelity of GAA-mRNA splicing such that exon 2 is spliced out in an estimated 90% of the splicing events.55 As a result, patients with the c.-32-13T>G/null genotype have in theory between 5% and 55% of GAA-mRNA (depending on the type of mutation in the null allele) and only 5% residual activity. In practice, the residual acid α-glucosidase activity in fibroblasts of such patients ranged from 3% to 20%.58 In this range of residual activities, the clinical course did not correlate with the degree of enzyme deficiency nor was it related to polymorphic diversity of the c.-32-13T>G allele. Thus, modulating factors seem to have a substantial effect on the clinical course of patients with the c.-32-13T>G/null genotype. These factors will equally modify the pathogenic effect of other GAA genotypes that are associated with some amount of residual activity, but have predictably little effect in case of complete acid α-glucosidase deficiency. Once the modulating factors have been identified, they can possibly be manipulated to improve the phenotype of a specific GAA genotype. For instance, positive effects have been reported with a combination of balanced nutrition and exercise.67,68 Physical therapy has an effect to a different degree and is part of standard care.16 Figure 3 depicts the correlation between residual acid α-glucosidase activity and phenotype, and the effect of modulating factors. Model depicting signs of Pompe’s

For Pompe’s disease database see http://www.pompecenter.nl

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disease emerge when the α-glucosidase activity drops below 30% of average normal activity. Enzyme and gene therapy aim to increase the acid α-glucosidase activity so as to exceed the critical threshold. Nutrition and exercise might reduce the critical threshold. Enzyme replacement therapy, gene therapy, and chaperone-based treatments aim to increase the amount of residual activity from the disease range to the normal range. The search for safe and efficient systems for in-vivo delivery of human GAA gene constructs is actively pursued, and promising results in animals have been reported.69–74 Targeting of muscle does not seem mandatory, since liver can serve as a depot from which the enzyme is delivered to other organs via circulation.69 The application of chaperones in Pompe’s disease to promote transport of mutant, misfolded, endogenous acid αglucosidase from the endoplasmic reticulum to the lysosomes is in very early stages of development, but might in future be of benefit to patients with specific types of GAA mutations.75,76 The therapeutic approaches we mention have in principle a complementary effect.

Pathophysiology Accumulation of lysosomal glycogen starts when the acid α-glucosidase activity decreases below critical.2 This threshold amount seems to vary depending on the organ. In knockout mouse models of Pompe’s disease with complete enzyme deficiency, storage was seen in almost every tissue and cell type—ie, liver, heart, and skeletal muscle, smooth-muscle cells of the gastrointestinal tract, bladder, blood-vessel walls, kidney, spleen, endothelial cells, and Schwann cells and in the perineurium of peripheral nerves.77,78 A similar widespread distribution of pathological changes in the tissues were previously noted in infants after post-mortem examination.2,79 Lysosomal glycogen storage was also identified in the organ of Corti, inner and outer hair cells, and spiral ganglia of knockout mice when investigating by analogy the cause of hearing deficit (30–90 dB) of some infants with Pompe’s disease. The mice, however, had normal audititory brainstem response by contrast with infants.15 Hypertrophic cardiomyopathy is a typical sign of classic infantile Pompe’s disease in which no residual acid α-glucosidase activity is present, but is rarely seen in attenuated forms with residual activity. Pathological changes in skeletal muscle, on the other hand, are prominent throughout the entire clinical spectrum.21,23,24 The different response of heart and skeletal muscle to the same enzyme deficiency can be attributed to the abundant glycogen in skeletal muscle fibres rather than in cardiomyocytes. Although most glycogen is turned over in the cytoplasm, in theory more cytoplasmic glycogen leads to more lysosomal storage through autophagy.80,81 The process by which skeletal muscle function is eventually lost is also intriguing. Additional insight is essential to improve understanding of the regenerative 1346

capacity of muscle in Pompe’s disease and increase the options for treatment. Many investigators have described the pathophysiology of skeletal muscle. They noted an order of events by comparing pathological changes in muscle in various stages of disease in knockout mice and patients.77–79,82–90 Initially, small vacuoles (being glycogenloaded lysosomes) staining positive with periodic acid Schiff reagent, are seen in the fibres (figure 4). These vacuoles can occur isolated or in linear arrays and are neither necessarily present in all fibres nor present along the entire length of the fibres. When the disease advances, the lysosomes expand, become many, and fuse to form larger structures that interfere with the architecture of the fibre. Additionally, regions develop with lipofuscin deposits, cellular debris surrounded by membranes (identified as autophagosomes) and freely dispersed cytoplasmic glycogen.79,81,82,85,87,88 With respect to loss of muscle function, both atrophy and reduced performance per unit of muscle mass have a role. In mice with Pompe’s disease, reduction of muscle mass accounted for a third of the loss, and decreased performance per unit of muscle mass for two-thirds.84 However, in man, the importance of both factors is unknown. A mathematical model predicted inadequate force transmission by the number and size of non-contractile inclusions, such as storage lysosomes and autophagosomes.91 The increase noted in the amount of titin and desmin in the mouse muscle points to the generation of mechanical stress by these inclusions.84,85 Titin and desmin are structural proteins that help to line up and hold together the sarcomers at the Z line. In work addressing pathological changes in muscles of a knockout mouse model of Pompe’s disease, both mobility of storage vesicles and communication between autophagosomes, endosomes, and lysosomes decreased with disease progression.81,87,88 Moreover, the endosomal and lysosomal acidification process stopped functioning normally when the autophagosomal and endosomal pathways became clogged with indigestible materials. The autophagic build-up was mainly seen in the fast-twitch type-2 fibres and much less in the slow-twitch type-1 fibres.88 These findings have led to a new view of the cascade of pathological events in type-2 muscle fibres. The authors suggested that the failure to digest glycogen results in local starvation, which induces autophagy while the autophagic pathway is blocked by the lysosomal dysfunction. They also proposed that the devastating pathological cycle might be interrupted by providing an alternative energy supply to the type-2 muscle fibres.88 In human beings, fibre-type specific involvement is less evident. Some investigators describe preferential involvement of type 1 whereas others that of type-2 fibres.79 Several other factors might contribute to the pathogenic process. Starvation increases proteolysis and autophagy as ways to supply energy to the body. In Pompe’s disease, a low caloric intake might enhance the loss of muscle www.thelancet.com Vol 372 October 11, 2008

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A

B

C

D

E

F

Figure 4: Histological changes in progressive muscle damage in infantile (A–C) and adolescent and adult (D–F) disease (A) 2·5-month-old infant. Most muscle fibres containing longitudinal arrays of small PAS-positive inclusions (glycogen), whereas muscle cell morphology is well preserved. Some fibres have areas with larger unstained spaces and loss of cross striation. (B) A more severely affected patient of about the same age. PAS-positive lysosomes are more numerous and larger than in (A). Most muscle fibres now contain lakes of glycogen. Morphology of only very few fibres is well preserved. (C) 8-month-old infant. Massive destruction of muscle tissue by the deposition of glycogen. In the most affected fibres, contractile filaments have been replaced by empty spaces. (D) Changes are mild with normal morphology in muscle fibres, and few and small PAS-positive lysosomes. (E and F) More severely affected adults show variable pathological changes. Some fibres have maintained their structure; others are severely damaged (E) and might be replaced in the long term by connective and adipose tissue, as in (F).

mass and function by these two processes, which emphasises the importance of adequate caloric intake. Ageing and immobilisation are two other factors that contribute to muscle atrophy, and physical exercise might therefore slow disease progression. A positive effect of nutrition and exercise therapy has been described in a report about two affected brothers who started this treatment in the first and second years of life, and in another report of 34 adults who were treated for 2–10 years.67,68 On the basis of our present knowledge about the pathophysiology of Pompe’s disease, the effectiveness of enzyme replacement therapy and other potential treatments will probably decrease with disease duration. Therefore, of utmost importance is that physicians diagnose patients early and start their treatment before serious tissue damage takes place.

Enzyme replacement therapy In the 1960s, Pompe’s disease was the first lysosomal storage disorder for which attempts at enzyme replacement therapy were undertaken in individual patients with enzyme preparations from Aspergillus niger and human placenta. However, these attempts were without clinical benefit. With experience, we clearly know that inappropriate enzyme source and insufficient dosing were the causes of failure.92,93 An important step forward was the knowledge that cell-surface receptors helped with uptake of extracellular glycoproteins via endocytosis. So was the finding that administration of missing lysosomal www.thelancet.com Vol 372 October 11, 2008

enzymes to the culture media of cells of patients led to clearance of storage products.94–96 The feasibility of enzyme replacement therapy for Pompe’s disease was shown in cultured skeletal muscle cells with mannose 6-phosphate acid α-glucosidase as a corrective enzyme from bovine testis and human urine. Efficient uptake and targeting to the lysosomes was followed by degradation of the lysosomal glycogen and was mediated by the mannose 6-phosphate or insulin-like growth factor II receptor.97–99 Uptake of intravenously administered acid α-glucosidase by muscle of healthy mice was also shown, but the 100-fold difference in uptake efficiency between enzyme with and without the mannose 6-phosphate recognition marker in vitro was only two-fold in vivo.100 These pilot experiments showed that skeletal muscle was not an easy target. Most of the intravenously given enzyme ended up in liver and spleen, and only a small fraction in heart and even less in skeletal muscle. The experiments predicted that doses in the order of tens of milligrams of enzyme per kilogram of bodyweight would be needed to correct the main target tissues.100 Similar conclusions were deduced from the treatment of quails and knockout mice with Pompe’s disease.78,101–105 Studies in mice with Fabry’s and Sly’s disease also pointed to the need for high doses to reach muscle.106–108 This fact and the preferred presence of mannose 6-phosphate groups on the enzyme excluded the use of enzyme from human placentas for treatment, as was previously introduced for 1347

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Gaucher’s disease.109–113 Cloning of the acid α-glucosidase gene provided the essential method to explore production of recombinant human enzyme in cell culture and in milk of transgenic animals. Last, this process led to large-scale production of recombinant human αglucosidase in milk of transgenic rabbits and in CHO cells.50,51,102,103,114–117 For the production in milk, the entire acid α-glucosidase gene was placed in an expression vector under the control of the bovine αS1-casein promoter.117 For production in CHO cells, GAA complementary DNA was used.103,116 Both products were tested in animals and showed similar uptake characteristics.101,117 Further, when both enzyme preparations were given in repeated high doses of more than 10 mg/kg, they diminished the lysosomal glycogen storage in heart, skeletal muscle, smooth muscle, and in several other organs.101–104,109,110 Brain, protected by the blood–brain barrier, remained devoid of enzyme. Studies in human beings started in January, 1999, with the application of recombinant human α-glucosidase from transgenic rabbit milk.86,118–120 Six patients with classic infantile Pompe’s disease, two teenagers, and one adult received this treatment for 3–5 years before they switched to the currently produced enzyme preparation from CHO cells (alglucosidase alfa), which has been approved by the European Medicine Agency

Dose (mg/kg per week)

Onset (month)

Patient 115,86,118,119

15 (23); 40

Birth

1

3

171

70

Walking

No

No

Abnormal

>4 years

Patient 215,86,118,119

15 (21); 40

3

4

7

208

160

No

Ventilator dependent

Ventilator dependent

Abnormal

>4 years

Patient 315,86,118,119

20 (14); 40

Birth

0·5

2·5

308

104

Sitting (U)

No

Ventilator dependent

Abnormal

3

6

8

599

115

No

Yes

Ventilator dependent

Abnormal

Patient 415,86, 118, 119 20 (14); 40

Diagnosis Start ERT LVMI (month) (month) (g/m2)

and US Food and Drug Administration.86,118,119,121,122 The first pilot study with recombinant human enzyme from CHO cells also started in 1999 and included three infants.123,124 In 2006, 1-year data for another group of eight infants, who received the CHO product, were reported. The children varied in age from 3·1 to 14·6 months at the start of treatment.17,90 Table 1 shows data obtained from the first 17 infants, who received experimental forms of recombinant human α-glucosidase. The studies showed a prominent effect on cardiac hypertrophy and function. Additionally, there was a substantial effect on survival. The longest survivors in these first trials are 8 years old (ATvdP, unpublished data), whereas untreated infants usually do not survive beyond 1 year of age. There were several patients who achieved milestones that are usually not reached—such as sitting, standing, and walking— showing that enzyme replacement therapy had an effect on muscle function. But, it also became evident that not all patients responded equally well. About half the patients died and most were dependent on ventilators. Five patients learned to walk and did not need supportive ventilation. The common denominator was that these patients started treatment early (before 5 months of age). All studies showed that the condition of the patient at the start of treatment was even more important for

LVMI (g/m2) LR

Milestones* achieved LR

Oxygen need Oxygen need LR (at start)

Hearing

Age LR

4 years 3 months† >4 years

Patient 5121,122

40

2·4

2·6

3·1

590

146

Sitting (U)

Yes

No

Normal

4 years 10 month

Patient 6121,122

40

Birth

3·1

5·9

490

96

Sitting (S)

Yes

Intermittent

Normal

4 years 7month

Patient 717,90

10

1·6

3·8

4·6

352

85·5

Walking

No

No

Normal

Patient 817,90

10

1·4

4·7

4·8

157·2

80·7

Transient gains

Yes

Ventilator dependent

Abnormal

1 years 3 months†

Patient 917,90

10 (90); 20 (2)

2·0

6·5

8·0

202·6

92·2

Sitting (U)

Yes

Ventilator dependent

Abnormal

2 years 10 months†

Patient 1017,90

10

4·8

5·4

8·4

320

87·5

Roll over

No

Ventilator dependent

Abnormal

Patient 1117,90

10

0·4

2·5

3·1

188·5

59·1

Walking

No

No

Normal

2 years 1 months† >3 years

Patient 1217,90

10 (70); 20 (20)

1·4

1·8

2·9

291·9

Walking

Yes

No

Normal

2 years 8 months†

Patient 1317,90

10/w

3·3

4·6

14·6

565·1

330

No

Yes

Ventilator dependent

Abnormal

1 year 6 months†

Patient 1417,90

10 (43); 20 (26)

Unknown Unknown

2·7

246·7

124

Transient gains

No

Ventilator dependent

Abnormal

1 years 6 months, end ERT 2 years†

Patient 15123 Patient 16123,124

Patient 17123

2×5 2×5 (15); 2×10 (9); 5×10 (80); none (3); 10 (18) 2×5

53·9

>3 years

2

4

250

180

No

No

Ventilator dependent

Unknown

1 years 10 months

Unknown Prenatal diagnosis

3

160

110

No

No

Ventilator dependent

Unknown

2 years 5 months

Unknown Prenatal diagnosis

2·5

64

40

Walking

No

No

Unknown

16 months

Data in parantheses=length of treatment in weeks. The first six patients were treated with enzyme from rabbit milk, the others were treated with enzyme produced in Chinese hamster ovary cells. All patients who are alive receive acid α-glucosidase from CHO cells (alglucosidase alfa). Some cases were published several times in follow-up reports, hence more than one reference. ERT=enzyme replacement therapy. LVMI=left ventricular mass index; upper limit of normal is 65 g/m2. (S)=supported. (U)=unsupported. LR=last reported data in peer-reviewed publication. *Major milestones: rolling over, sitting, standing, walking. †Patient died.

Table 1: Results of long-term enzyme replacement therapy for infantile Pompe’s disease with first experimental products

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outcome than was the age.17,118,119,123 Additionally, good responders were reported to have a high proportion of type-1 fibres and to show a milder ultrastructural damage of skeletal muscle fibres and decreased glycogen concentrations at baseline than those who responded poorly.90 Post-mortem data were reported for one patient who had a poor response and had died 40 weeks after start of therapy. Cardiac size had remained twice normal and glycogen storage was still present in cardiomyocytes of the intraventricular septum and left and right ventricles. Pathological changes in skeletal muscle were severe; the muscles studied (quadriceps muscle, deltoid muscle, and diaphragm) had lost their structure. This loss was in accordance with the poor motor and respiratory conditions of the patient at time of death. Glycogen storage was also present in smooth-muscle cells of the bladder and vascular media of a large artery. Additionally, glycogen accumulated in Purkinje cells of the cerebellum, cortical neurons, and most notably motor neurons of the ventral horns in the spinal cord.90 Two large studies with a new CHO product were started in 2003 to obtain data for registration: one with infants younger than 6 months of age125 and another with infants older than 6 but younger than 36 months. Doses of 20 mg/kg and 40 mg/kg were given once every 2 weeks. Results from these studies have led to the approval of alglucosidase alfa. The results corroborate the conclusions of the initial trials that early start of therapy leads to the best outcome. Data were reported for 18 patients younger than 6 months of age who received therapy (table 2).125 At the time of publication, the study duration ranged from 52 to 106 weeks per patient. During this period, 15 of the 18 patients had reached age of 18 months. The other three patients were 14·4, 15·9, and 17·9 months old by the end of the study. One patient died at the age of 19·8 months. Six patients became ventilator dependent, of whom three needed invasive ventilation. Ten patients learned to stand (n=3) or to walk (n=7), three others learned to sit or roll over, and five did not show any improvement. Antibody formation was discussed as a potentially counteractive event. No difference in response was reported between patients who received 20 mg/kg or 40 mg/kg every other week during the study period.125 Major beneficial effects of enzyme therapy in infants are very encouraging, but leave no doubt that the treatment of patients with classic infantile Pompe’s disease is very challenging because of the combination of profound deficiency of acid α-glucosidase, the difficulty of targeting muscle, and the time needed to remodel the muscle fibres and restore the muscle function. The results obtained in infants hold promise for patients with residual acid α-glucosidase activity and a less progressive clinical course (figure 2). Few results are presently available about the effect of enzyme therapy in older children and adults. The longest follow-up study was of three patients who received recombinant human α-glucosidase from rabbit milk www.thelancet.com Vol 372 October 11, 2008

Number of patients

Treatment duration (weeks)

Start of treatment (<6 months)

18

52–106

Survival (>18 months)

15

52

Survival (14–18 months)

3

52

Survival (14–30 months)

17

106

Death (19·8 months)

1

56

Walk

7

..

Stand

3

..

Sitting or rolling

3

..

12

..

Ventilator free

Data from reference 125. Age shown in parentheses.

Table 2: Enzyme replacement therapy with alglucosidase alfa in infants

in 1999 when they were 11, 16, and 32 years old. The youngest had normal respiratory function; the two older patients had severe loss of respiratory capacity (forced vital capacity of 17% and 13%, respectively) and were ventilator dependent. All three patients were in wheelchairs. The youngest patient was able to gain some support of his legs. Long-term treatment with enzyme replacement therapy resulted in stabilisation of respiratory function in all three patients and substantial improvement in their quality of life. The youngest patient gained sufficient muscle strength and function to walk after 72 weeks of treatment.120

Conclusion Several important lessons have been learned from the studies in mice and man, which showed that the acid α-glucosidase activity in blood needs to surpass a specific threshold to elicit a therapeutic response in skeletal muscles. Studies of mice and quail showed that this threshold was achieved at a dose of about 20 mg/kg.101,103–105,109,110,126 Further, studies showed that young mice with mild pathological changes in the tissue responded better to therapy than old mice with advanced stage of disease.104,105,126 However, complete correction of the enzyme deficiency might not be necessary. Heterozygote patients with 50% of average normal activity are unaffected and patients with more than 30% of residual activity are very rare, suggesting that an activity of slightly more than 30% of average normal activity is sufficient to prevent and possibly reverse disease manifestations (figures 2 and 3).38 On the basis of present knowledge, enzyme replacement therapy will theoretically lead to a shift in the clinical range whereby patients with classic infantile Pompe’s disease might retain a form of residual disease. Increased risk of motor and respiratory problems, cardiac arrhythmias during anaesthesia, osteoporosis, and hearing deficits have been mentioned as potential problems that should be given proper attention.15,16,18,127,128 Biopsy samples of skeletal muscle taken from infants and adults before and during treatment showed that enzyme replacement 1349

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therapy first clears the glycogen in endothelial cells and thereafter in smooth-muscle layers of blood vessels, and perineurium and Schwann cells of peripheral nerves.86 Many months were needed to convincingly show substantial degradation of glycogen in skeletal muscle, indicating that clinical effects of enzyme therapy should not be expected to show within weeks. Furthermore, we have learned that the best response is obtained when the architecture of the skeletal muscle fibres is well preserved at the start of treatment. Muscle fibres with excessive glycogen storage, autophagic debris, and loss of cross striation do not seem to recover. Accordingly, the best clinical response with improved motor and respiratory function was obtained in those patients who were in the best state at start of treatment. Enzyme replacement therapy in Pompe’s disease is tolerated well despite the very high dosing. Infusion associated reactions such as chills, rashes, and fever might occur, but are usually manageable as in Gaucher’s, mucopolysaccharide (I, II, VI), and Fabry’s diseases.112,129–137 A serious adverse event occurred in the initial phase of product development: an infant who received enzyme therapy five times every week for 80 consecutive weeks developed immune nephritis (patient 16 in table 1), but the kidney problem resolved after lowering of the dose.124 As of now, more than 300 patients worldwide receive recombinant human α-glucosidase. The recommended dose is 20 mg/kg every other week, but patients also receive higher doses than recommended. Two large trials with infants and children younger than 3 years of age have been completed, as has an open-label study of five children aged 5–15 years. An open-label study of five children aged 5–15 years and a double-blind placebo-controlled trial in adults and children older than 8 years have been completed as well and study results are expected shortly. On the basis of available data, recombinant human αglucosidase from CHO cells (alglucosidase alfa) obtained broad label registration. Long-term follow-up data are needed to fully understand the potential of enzyme replacement therapy and to formulate guidelines for treatment. Conflict of interest statement As of August, 2004, ATVP and AJJR provide consulting services for Genzyme Corp, Cambridge, MA, USA, under an agreement between Genzyme Corp and Erasmus MC, Rotterdam, the Netherlands. This agreement also caters to financial support for Erasmus MC for research in Pompe’s disease. Employees of Erasmus MC working in this specialty might benefit by receiving support for their research activities. If enzyme replacement therapy proves successful commercially, Erasmus MC and inventors for some methods of treatment could benefit financially subject to Erasmus MC’s policy on technology transfer. References 1 Ausems MG, Verbiest J, Hermans MP, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Europ J Hum Genet 1999; 7: 713–16. 2 Hirschhorn R, Reuser AJJ. Glycogen Storage Disease Type II (GSDII). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th edn. NY: McGraw-Hill, 2001: 3389–420.

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6 7 8

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72

73

74

75

76

77

78

79 80 81 82

83

84

85

86

87

88

89

90

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92

1352

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112 113

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