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Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)

Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)
Author:
Sihoun Hahn, MD, PhD
Section Editor:
Helen V Firth, DM, FRCP, FMedSci
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Nov 10, 2021.

INTRODUCTION — Acid alpha-glucosidase (GAA, also called acid maltase) deficiency (Pompe disease, MIM #232300) was the first identified lysosomal storage disease. It is also classified as glycogen storage disease type II (GSD II) (table 1) [1]. GAA deficiency leads to accumulation of glycogen within the lysosome in all tissues (figure 1). The defect in the lysosomal GAA enzyme affects lysosomal-mediated degradation of glycogenesis, unlike the defects in most other GSDs that affect glycogen synthesis or regulation of energy production. Therapies developed for GAA deficiency resemble those used for other lysosomal storage diseases since they share similar disease mechanisms. (See "Inborn errors of metabolism: Classification", section on 'Lysosomal storage disorders'.)

This topic reviews Pompe disease due to GAA deficiency. An overview of GSDs due to defects in glycogen synthesis and energy production is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)

EPIDEMIOLOGY — The estimated incidence of GAA deficiency was 1 in 40,000 in a study in the Netherlands that screened newborn blood spots for the three common variant alleles in that population [2]. The predicted incidence based upon carrier frequencies was 1 in 138,000 for classic infantile disease and 1 in 57,000 for late-onset disease. Studies investigating strategies for newborn screening (NBS) in Austrian and United States populations found a higher incidence (1 in 8686 and 1 in 21,979, respectively) for the early- and late-onset forms combined [3,4].

PATHOGENESIS — Lysosomal GAA is needed to hydrolyze both alpha-1,4- and alpha-1,6-glucosidic linkages in the low pH environment of the lysosome. Deficiency of the enzyme leads to accumulation of glycogen in lysosomes and in the cytoplasm, resulting in tissue destruction [5]. The effect of the enzyme deficiency may extend to vesicle systems that are linked to lysosomes and may also affect receptors, such as glucose transporter 4, that cycle through these organelles [6]. Enzyme activity correlates with genotype and is absent or minimal in patients with infantile-onset phenotype and variably reduced in those with late-onset phenotype [7].

GENETICS — GAA deficiency is an autosomal-recessive disorder with considerable allelic heterogeneity. It is caused by pathogenic variants in the gene encoding lysosomal acid alpha-1,4-glucosidase (GAA), located at 17q25.2-q25.3. More than 634 variants causing the disorder have been reported [8]. Common variants have been described in a number of populations with a higher incidence (such as Israel, Taiwan, and the Maroon population of French Guiana) [9,10], including pseudodeficiency alleles (a variant that reduces GAA enzyme activity but does not cause disease, two common alleles being c.1726G>A,p.G576S and c.2065G>A, p.E689K) [11] that can lower GAA activity to levels leading to a false-positive diagnosis.

CLINICAL FEATURES — GAA deficiency has an infantile-onset ("classic") form presenting with hypertrophic cardiomyopathy, as well as a late-onset (including juvenile and adult presentations) form that typically presents without cardiac manifestations. Serum creatine kinase (CK) is typically elevated in GAA deficiency, and leukocyte GAA activity is usually decreased [12,13]. GAA activity is also decreased to less than 10 percent of normal in other tissues, such as fibroblasts and muscle. (See 'Diagnosis' below.)

Muscle biopsy reveals vacuolar myopathy with glycogen storage within lysosomes and free glycogen in the cytoplasm by electron microscopy. The vacuoles are periodic acid-Schiff (PAS) positive, digestible by diastase, and positive for acid phosphatase. Similar lysosomal inclusions are found in a variety of other tissues in infantile disease.

Infantile-onset form — Infants with infantile-onset GAA deficiency typically present during the first few months of life [14]. The classic infantile form is characterized by cardiomyopathy and severe, generalized muscular hypotonia [15]. Clinical findings present at a median age of approximately four months, including cardiomegaly (92 percent), respiratory distress (78 percent), muscle weakness (63 percent), feeding difficulties (57 percent), and failure to thrive (53 percent) in one series [16]. The tongue may be enlarged. Hepatomegaly also may be present and is usually due to heart failure. There is no metabolic derangement. An early-onset "nonclassic" phenotype is probably just an earlier presentation of the late-onset form of GAA deficiency, presenting with hypotonia without cardiomyopathy during the first one to two years of life. (See "Overview of peripheral nerve and muscle disorders causing hypotonia in the newborn".)

Late-onset form — Patients with late-onset GAA deficiency do not develop cardiomyopathy and may present at any age. Age of onset is variable even in patients with identical variants (commonly heterozygous for the c.-32-13T>G splice-site variant), suggesting that secondary factors influence the clinical course [17-20]. In a multinational survey of 255 children and adults (aged 2.6 to 81 years) with late-onset GAA deficiency, the age at first complaint ranged from 0 to 62 years and the age at diagnosis from 0 to 66 years [18]. In a survey of 54 Dutch patients, the mean age of onset of symptoms was 28 years, but 18 percent of patients had symptoms before 12 years of age [19].

Clinical and histologic features are also variable and can range from asymptomatic to severe, progressive myopathy with typical histologic features. In late-onset GAA deficiency, the primary clinical finding is skeletal myopathy, with a more protracted course leading to respiratory failure [21]. Affected children usually present with delayed gross-motor development and progressive weakness in a limb-girdle distribution [17]. Early involvement of the diaphragm is a common feature, and sleep-disordered breathing may occur [22]. This usually leads to respiratory failure and death in the second or third decade of life.

Affected adults with late-onset GAA deficiency also present with progressive, proximal weakness in a limb-girdle distribution, particularly the hip flexors in the earliest stages of the disease [23]. The weakness is accompanied by diaphragmatic involvement, leading to respiratory insufficiency early in the course of the disease [24]. As an example, three patients over the age of 50 years were diagnosed when they presented with camptocormia (severe anterior flexion of the spine, also called bent spine syndrome) despite initial development of symptoms prior to 21 years of age [25]. These patients were found to be compound heterozygous for the c.-32-13T>G variant and another GAA variant. Dilative arteriopathy, carotid artery dissection, and basilar artery dolichoectasia have been reported in a small number of patients with late-onset GAA deficiency; however, the real incidence of these vascular complications is unknown [26]. Both upper gastrointestinal and, less commonly, lower gastrointestinal symptoms have been reported, including swallowing difficulties, gastroesophageal reflux, diarrhea, and constipation [27-31].

In a review that included 74 patients with "nonclassic" GAA deficiency who had a muscle biopsy, 97 percent reported lysosomal pathology, although 15 had normal glycogen content (including 13 who were over 18 years old) [17].

DIAGNOSIS — The diagnosis of infantile-onset GAA deficiency should be suspected in an infant with profound hypotonia and cardiac insufficiency. Elevations of creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) are commonly seen. The electrocardiogram reveals a short PR interval with giant QRS complexes in all leads, suggesting biventricular hypertrophy, although this is not unique to GAA deficiency.

The late-onset form of GAA deficiency should be suspected in children and adults with progressive proximal weakness in a limb-girdle distribution. The electromyogram is characteristic, with evidence of myopathic discharges that are sometimes associated with abundant myotonic and complex repetitive discharges, most prominently in the paraspinal muscles [32]. The forced vital capacity (FVC) on pulmonary function testing typically is reduced substantially in adults. The forearm ischemic lactate test is normal in patients with GAA deficiency [33]. (See "Approach to the metabolic myopathies", section on 'Semi-ischemic exercise test'.)

GAA enzyme activity can be measured in white blood cells or dried blood spots. This assay is available through clinical biochemical/genetics diagnostic laboratories. The addition of acarbose, an inhibitor that blocks interfering alpha-glucosidase present in granulocytes, to enzyme assays performed with blood samples is recommended because it improves the sensitivity of the assays [13]. The assay of GAA enzyme activity is a reliable detection tool for the diagnosis of all forms of GAA deficiency [13,34]. Measurement of GAA activity in another tissue (skin fibroblast or muscle) is useful when results of the assay performed on a blood sample are ambiguous or in the indeterminate range.

Gene sequencing is the preferred test to confirm the diagnosis since it is routinely available, is less invasive, may provide genotype-phenotype information, and may help predict cross-reactive immunologic material (CRIM) status (amount of residual endogenous GAA production) in some cases [13] (see 'CRIM status, anti-GAA antibodies, and immune tolerance induction' below). The finding of two pathogenic variants in trans in the GAA gene is considered confirmatory. C.-13-13T.G splice mutation is the most common variant in patients with late-onset GAA deficiency, with an allele frequency ranging from 40 to 70 percent [35]. Assay of GAA enzyme activity in fibroblasts can be performed as the confirmatory test in patients that require skin biopsy for antibody-based analysis to determine CRIM status. Measurement of GAA activity in muscle obtained by biopsy is another option for confirming the diagnosis, but this approach is complicated by increased invasiveness, anesthesia, and the potential for false positives due to poor sample processing.

Newborn screening — Many countries around the world and states within the United States are implementing NBS for GAA deficiency. In 2013, the US Advisory Committee on Heritable Disorders in Newborns and Children recommended inclusion of GAA deficiency in the Recommended Uniform Screening Panel (RUSP), and, in March 2015, the US Secretary of Health and Human Services approved this recommendation. More states continue to add GAA deficiency to NBS panels, but whether this recommendation is implemented is up to each state.

NBS for GAA deficiency is most often performed in a tiered algorithm, typically with a first-tier enzymatic assay and second-tier molecular genetic testing. The first tier involves multiplexed assays (either via fluorometric, digital microfluidics, or tandem mass spectrometry-based technologies) with other lysosomal storage disease due to the availability of enzyme therapy for these disorders [3,36-38]. Earlier diagnosis and resultant early treatment improve morbidity and mortality. Recommendations for initial follow-up and management of these NBS screen-positive infants are available [39-41]. Screen-positive infants may ultimately be found to be false positives (are normal, carriers, or have pseudodeficiency alleles), have unknown variants, or be affected with either infantile-onset or late-onset GAA deficiency. (See 'Treatment' below and 'Prognosis' below.)

The feasibility and impact of NBS based upon enzyme analysis in dried blood spots were demonstrated in a nationwide pilot study in Taiwan from October 2005 through March 2007 [9,42]. More than 206,000 newborns (approximately 45 percent) were screened. Repeat samples and additional evaluation were required for less than 1 percent of infants. Six infants were detected through screening. The number of infants with confirmed GAA deficiency was similar in the screened and unscreened populations, but the infants who were screened were diagnosed earlier (less than one month versus three to six months of age). In a follow-up analysis from January 2008 to January 2014, 47 of 669,797 infants screened were referred for evaluation, and 14 were diagnosed with infantile-onset GAA deficiency [43].

In a statewide pilot study in Illinois in the United States from November 2014 through August 2016, there were 139 positive or borderline tests for GAA deficiency with 10 cases confirmed (two with the infantile form and the rest with late-onset disease) out of 219,793 infants screened [4]. The two cases with early-onset disease had evidence of cardiomyopathy and were started on enzyme replacement therapy (ERT), whereas the eight infants diagnosed with late-onset disease were asymptomatic and will be followed over time (therapy will commence once active disease is noted). Of the remainder of the initial positive tests, 87 were determined to be normal with further testing (just under half were born at <37 weeks gestation), 15 were carriers, 15 had a pseudodeficiency, 4 were undetermined, and 8 were unresolved. The last two groups of patients will also require ongoing monitoring for disease manifestations. No false-negative tests have been identified.

Second-tier testing most commonly involves next-generation sequencing, which can be done within the NBS laboratory as a reflex or by the infant's clinical provider or clinical geneticist through clinical laboratory testing [44]. Genetic sequencing is required due to the presence of homozygosity for the pseudodeficiency allele, which results in low GAA activity detected on NBS that can lead to false-positive results [45]. Alternative strategies such as a creatine/creatinine-to-GAA activity ratio are under evaluation [46].

Any infant with a low GAA enzyme activity from NBS should receive genetic sequencing of the GAA gene to help determine their risk for GAA deficiency. Initial evaluation of infants with suspected GAA deficiency may include a clinical evaluation and CK levels, electrocardiogram, chest radiograph, echocardiogram, pro-B-type natriuretic peptide (BNP), and urine Glc(4) levels.

Prenatal diagnosis — Prenatal diagnosis is possible by DNA analysis if the pathogenic variant in the family is known. If the genetic defect is not known, alpha-glucosidase activity can be measured in cultured amniocytes or chorionic villus samples.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of GAA deficiency is based largely upon the age of onset of symptoms. GAA deficiency is usually distinguished from the other disorders in the differential diagnosis by the presence of elevated creatine kinase (CK) and absence of other metabolic abnormalities such as hypoglycemia, lactic acidosis, and metabolic acidosis.

The differential diagnosis for classic infantile disease with hypertrophic cardiomyopathy includes:

Lysosome-associated membrane protein 2 deficiency, which presents with hypertrophic cardiomyopathy, muscle weakness, and hypotonia (see "Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)")

Fatty acid oxidation disorders, including very-long-chain acyl-CoA dehydrogenase deficiency, long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency, carnitine transporter deficiency, carnitine-acylcarnitine translocase deficiency, and carnitine palmitoyltransferase deficiency type 2, which may present in infancy with hypertrophic cardiomyopathy with nonketotic hypoglycemia (see "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders")

Mitochondrial and respiratory chain disorders, which may present with hypotonia, cardiomyopathy, hepatomegaly, and seizures (see "Mitochondrial myopathies: Clinical features and diagnosis")

Other infantile-onset hypotonia without cardiomyopathy, including spinal muscular atrophy type 1 and GSD type IIIa (see "Spinal muscular atrophy" and "Glycogen debrancher deficiency (glycogen storage disease III)")

Other congenital myopathies may lack cardiac involvement and therefore are not as commonly considered in the differential diagnosis of classic infantile GAA deficiency. (See "Congenital myopathies".)

The differential diagnosis for late-onset disease includes disorders presenting with hypotonia or muscle weakness:

GSD type V (McArdle disease) and GSD type VI (see "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)" and "Liver phosphorylase deficiency (glycogen storage disease VI, Hers disease)")

Muscular dystrophies including Duchenne-Becker muscular dystrophy and limb-girdle muscular dystrophy (see "Duchenne and Becker muscular dystrophy: Clinical features and diagnosis" and "Limb-girdle muscular dystrophy")

The approach to metabolic myopathies is reviewed in greater detail separately. (See "Approach to the metabolic myopathies" and "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Mitochondrial myopathies: Clinical features and diagnosis".)

NATURAL HISTORY — Without treatment, most patients with the classic infantile form have unremitting deterioration, with death during the first one to two years of age from cardiac insufficiency [16,47]. However, prolonged survival has been reported in infants with less severe cardiomyopathy [17,48]. The rate of progression is much more variable in late-onset disease.

The course of disease was illustrated in a review of 168 patients who presented by 12 months of age [16]:

The median age at symptom onset was two months and at diagnosis was 4.7 months.

The median age at first ventilator support was 5.9 months (range 0.1 to 31 months); ventilator-free survival rates at 12 and 18 months were 16.9 and 6.7 percent, respectively.

The median age at death was 8.7 months (range 0.3 to 73 months); survival rates at 12 and 18 months were 26 and 12 percent, respectively.

These findings highlight the need for early diagnosis and prompt initiation of enzyme replacement therapy (ERT). (See 'Treatment' below.)

The rate of progression and sequence of respiratory and skeletal involvement vary substantially between patients with late-onset disease [17-19,49]. In the multinational survey described previously, disease severity was related to disease duration rather than age [18], with the odds for wheelchair use and respiratory support increasing by 13 and 8 percent, respectively, for every additional year since diagnosis. Two-year follow-up of 52 Dutch patients with untreated late-onset GAA deficiency indicated progressive decline at the group level in functional activities, respiratory function, handicap, and survival [49].

TREATMENT — The primary treatment for GAA deficiency is enzyme replacement therapy (ERT) with alglucosidase alfa. Standard dosing is 20 mg/kg given intravenously every two weeks. Dosing may be increased twofold to 20 mg/kg once a week or 40 mg/kg every two weeks in those with a poor response to initial therapy. One study provides support for initiation of the twofold-higher dosing at initiation of therapy for infantile-onset GAA deficiency [41]. In another study of 18 patients in the Netherlands comparing a fourfold-higher-dose (40 mg/kg/week) versus lower-dose (20 mg/kg/every other week) ERT with or without immunomodulation, fourfold-higher-dose ERT led to improved survival, ventilator-free survival, and motor outcome irrespective of immunomodulation [50]. Avalglucosidase alfa was approved by the US Food and Drug Administration (FDA) in 2021 to treat patients ≥1 year of age with late-onset GAA deficiency. Recommended intravenous infusion dosing is 20 mg/kg for patients weighing more than 30 kg and 40 mg/kg for patients less than 30 kg.

A multidisciplinary care team is often helpful for coordination of care, often led by a clinical biochemical geneticist, with support from physical medicine and rehabilitation; cardiology; pulmonology; orthopedics; nutrition; and physical, occupational, and speech therapy. Many patients require some level of respiratory support. Noninvasive ventilation during sleep may improve nighttime hypoxemia and daytime hypercapnia in some patients with late-onset disease [22,51]. Some patients may require increased levels of noninvasive respiratory support and may progress to require mechanical ventilation [49]. (See "Respiratory muscle weakness due to neuromuscular disease: Clinical manifestations and evaluation".)

ERT with alglucosidase alfa (also called recombinant human acid alfa-glucosidase [rhGAA]) derived from Chinese hamster ovary cells was approved by the US Food and Drug Administration (FDA) in 2006 for use in patients with infantile-onset GAA deficiency (this form is no longer available in the US but is available in other countries) [52]. A second recombinant alglucosidase alfa, produced from the same cell line but with a larger-volume bioreactor to scale-up production, was approved by the US FDA for late-onset disease in 2010, and approval was expanded to all ages, including early-onset disease, in 2014 [53]. This new, larger 4000 liter scale alglucosidase alfa was found to result in similar clinical stability and safety [54].

Infantile-onset disease

Efficacy of enzyme replacement therapy — Several small studies in patients with infantile GAA deficiency have found short- and long-term improvements in cardiac and skeletal muscle function, need for ventilatory support, and survival, as is illustrated below:

In a pre-licensure trial of 18 patients with infantile-onset disease who were treated with 20 or 40 mg/kg of alglucosidase alfa given intravenously every two weeks, all 18 of the patients survived to age 18 months (compared with only 1 of 61 historic controls), and 13 had improved motor function [55,56]. Seven of the treated patients required ventilatory support, and there were two deaths, one after 14 months of treatment and one after 25 months. In an extension of the trial, the 16 surviving patients continued therapy for up to three years [57]. Over the entire study period, alglucosidase alfa therapy was associated with a 95 percent reduction in the risk of death, a 91 percent reduction in the risk of invasive ventilation, and continued improvement in cardiomyopathy and motor skills.

In a second trial, 21 patients (three months to 3.5 years at initiation) were treated with 20 mg/kg alglucosidase alfa every other week for up to 168 weeks (median 120 weeks) [58]. Treatment was associated with a 79 percent reduction in the risk of death, a 58 percent reduction in the risk of invasive ventilation, improvement or stabilization of left ventricular mass, and improved motor milestones.

An observational study examined outcomes in four patients started on 20 mg/kg alglucosidase alfa every two weeks prior to 2009 and four patients started on ERT in 2009 or later and treated with a dose of 40 mg/kg every week [59]. Patients in both groups were treated for at least three years. Three of four patients in the 20 mg/kg group had multiple hospitalizations for respiratory infections or aspiration pneumonias, and one required ventilator support beginning at 2.7 years of age. None of four in the 40 mg/kg/week group was hospitalized for respiratory problems, and none became ventilator dependent. Out of the eight patients, all but one (in the 20 mg/kg group) learned how to walk, although the one patient who became ventilator dependent lost this ability. There were equal effects in cardiac hypertrophy responses, but skeletal muscular problems were still seen in both groups, and no differences were seen in infusion-related reactions and immunologic responses [43].

Institution of ERT has been reported as early as 18 hours of age with resolved hypertrophic cardiomyopathy and normal neurodevelopment at 46 weeks [60].

Results from one series suggest that very early treatment improves outcomes. In this study, 13 infants born in Taipei from 2010 through 2015 were diagnosed with infantile GAA by a nationwide newborn screening (NBS) program [43]. The mean age at start of ERT was 12 days. Left ventricular function improved after three to four months of therapy. All patients had normal cognitive and motor function one year after the start of ERT. Age at start of independent walking was normal at a mean of 11.9 months.

A long-term follow-up study of 17 patients with infantile-onset GAA deficiency (up to 5.4 to 12 years of age) on ERT demonstrated improvements in cardiac measures of left ventricular mass index within five months of initiation of ERT, but did not report prevention of arrhythmia such as Wolff-Parkinson-White [61]. This study also reported improvements in gross motor function, although residual muscle weakness with contractures, dysphagia with aspiration risk, hypernasal speech, and osteopenia were still present.

Glc(4) measurement — Urine glucose tetrasaccharide (Glc(4)) is elevated in patients with infantile-onset, but not late-onset, GAA deficiency [62]. It is a primary screening and clinical monitoring biomarker for monitoring treatment and efficacy with ERT [63,64]. A follow-up NBS study in Taiwan found a correlation between lower initial elevations of urine Glc(4) and a positive response to ERT in patient with infantile-onset GAA deficiency [41].

CRIM status, anti-GAA antibodies, and immune tolerance induction — Treatment outcome in infantile-onset, but not late-onset, GAA deficiency is affected by cross-reactive immunologic material (CRIM) status, with negative CRIM status associated with a poorer response to ERT and worse prognosis. Databases of previously identified CRIM-negative status are available. Use of these databases is the most effective way of determining CRIM status [39]. Most patients with GAA deficiency have some residual GAA production. Endogenous GAA protein is considered CRIM because it is recognized by anti-GAA antibodies on an assay.

In a retrospective analysis of 32 patients who were treated with alglucosidase alfa, CRIM-negative status (lacking any residual GAA expression) was associated with an increased risk of death or invasive ventilation after 52 weeks of therapy (54.5 versus 4.8 percent in CRIM-positive patients) [65]. In another study of 11 infants, higher antibody titer >1:31,250 was associated with poorer response to ERT [66].

Antibodies to alglucosidase alfa develop earlier, and antibody titers are higher and more sustained in CRIM-negative patients compared with CRIM-positive patients, suggesting that antibody interference may attenuate the treatment response [67]. This hypothesis is supported by studies demonstrating enhanced response to ERT following induction of immune tolerance in animals [68-70] and a CRIM-negative infant [71]. The antibodies are also frequently found in late-onset GAA deficiency and persist over time but at low-to-intermediate levels that may not effect clinical response to alglucosidase alfa [72].

Immune tolerance induction (ITI) using combinations of rituximab and low- or high-dose methotrexate with or without intravenous immune globulin (IVIG) was reported in one study of four CRIM-negative patients, two with preexisting anti-GAA antibodies and two treated prophylactically at the onset of alglucosidase alfa therapy [73]. Both patients treated therapeutically demonstrated elimination of anti-rhGAA antibodies, and all tolerated alglucosidase and showed clinical response to ERT, even off immune therapy. However, in another series of three patients who received similar treatment, all three patients had induced B cell depletion; only two of three patients developed high sustained antibody titers after discontinuation of rituximab [74]. Transient low-dose methotrexate used at initiation of therapy has also shown encouraging results [75].

ITI methods are increasingly used at initiation of therapy in not only CRIM-negative patients, but also in CRIM-positive patients, including NBS-positive patients with early-onset GAA deficiency [41]. The effects of ITI are still under investigation and do not always lead to improved outcomes [50].

Late-onset disease — Two intravenous ERTs are US FDA approved for late-onset GAA deficiency: alglucosidase alfa (approved in 2006 and 2010) [27-31,76-85] and avalglucosidase alfa (approved in 2021) [86,87]. Both demonstrated improved lung function on pulmonary function testing and six-minute walk test (6MWT) in randomized trials [88].

In a multicenter trial, 90 patients aged 10 to 70 years were randomly assigned 2:1 to intravenous alglucosidase alfa (20 mg/kg every two weeks) or placebo every two weeks for 78 weeks [81]. Treatment with alglucosidase alfa led to improved walking distance and pulmonary function, whereas these measures declined in the placebo group. The estimated differential treatment effect was 28.1 m for the 6MWT and 3.4 percent for the change in forced vital capacity (FVC). In this same study, no significant change in cardiovascular status related to ERT was seen [82]. Treatment with alglucosidase alfa was also associated with improvement in survival, fatigue, quality of life, participation in activities of daily living [84,85], and gastrointestinal symptoms [27-31] in observational studies. In data supplied from drug manufacturers to the US FDA, intravenous avalglucosidase alfa (20 mg/kg every two weeks) showed similar efficacy to alglucosidase alfa in a randomized trial of 100 treatment-naïve patients aged 16 to 78 years [86,87]. At 49 weeks, the mean change in FVC (percent predicted) was 2.9 and 0.5 percent for avalglucosidase alfa and alglucosidase alfa, respectively (estimated treatment difference 2.4 percent), and the mean change in 6MWT was 32.2 and 2.2 meters, respectively (estimated treatment difference 30 meters).

While there is a paucity of good-quality evidence, data from a systematic search of juvenile-onset GAA deficiency (2 to 18 years at symptom onset, a subset of late-onset GAA deficiency) suggest that some patients with juvenile-onset disease may benefit from ERT, with improved muscle strength and reduced need for assisted ventilation [83].

A study from the Pompe Registry of 396 patients demonstrated that respiratory function as determined by FVC was more impaired in patients with late-onset GAA deficiency who were older at ERT initiation or in those with a longer time from onset of symptoms or diagnosis to time of ERT initiation. Respiratory function typically remains stable while on ERT, so earlier initiation of ERT is clinically meaningful [89].

Adverse effects of enzyme replacement therapy — Adverse effects of alglucosidase alfa or avalglucosidase alfa infusion are similar and include severe hypersensitivity reactions, acute cardiorespiratory failure, and infusion reactions [55,57,58]. These adverse effects can be managed through standard use of premedications including but not limited to acetaminophen, loratadine, and/or famotidine; anaphylaxis protocols including epinephrine, H1- and H2-blockers, glucocorticoids, albuterol, and/or saline infusions; and adjustment of infusions such as slowing infusion rates and increased dilution of alglucosidase alfa. The majority of patients in the clinical trials discussed above developed antibodies to alglucosidase alfa or avalglucosidase alfa [55,57,58,86,87]. (See 'CRIM status, anti-GAA antibodies, and immune tolerance induction' above.)

Experimental therapies — Experimental therapies include gene therapy, alternative forms of ERT, exercise therapy, and high-protein diet.

Gene therapy strategies are under investigation, with numerous preclinical and phase-I clinical trials underway [90]. Research also continues into alternative forms of ERT with improved cellular mannose-6-phosphate uptake and lysosomal trafficking [91].

Exercise therapy is under investigation. A case series of three patients (two adults and one child) reported a positive response to diaphragm pacing following a period of inspiratory muscle-strengthening exercises, with a reduction in daytime ventilator dependence [92].

A study of moderate-intensity aerobic exercise therapy with or without a high-protein diet in patients with late-onset disease receiving ERT showed increases in VO2 maximal aerobic power after exercise and more significant increases after exercise plus diet [93]. Lactate dehydrogenase and CK were also reduced to a greater degree with exercise plus diet compared with exercise alone. Changes were also seen in exercise tolerance, pulmonary function, and quality of life.

PROGNOSIS — The advent of enzyme replacement therapy (ERT) has improved clinical outcomes and survival for both early- and late-onset GAA deficiency. (See 'Treatment' above.)

Early treatment of five infants detected through newborn screening (NBS) was associated with normalization or improvement in cardiac size, muscle pathology, growth, and motor development [9]. Survival was significantly improved compared with untreated historical controls but not compared with treated patients who were diagnosed clinically. All of the patients were alive at the time of the report (age range 14 to 40 months), and none had required mechanical ventilation. A continuation of this study that included five additional patients found that all patients could walk independently and none needed mechanical ventilation (age range 28 to 90 months), but gradually progressive pelvic girdle muscle weakness began after two years of age [94].

A long-term follow-up study of infantile-onset Pompe patients revealed that, while ERT improves survival, cardiac, and motor function, there is evidence of brain involvement with progressive periventricular white-matter abnormalities in all age groups and a disharmonic intelligence profile with lower processing speed and problems with social interaction, working memory, and attention [95,96].

In untreated patients with late-onset disease, the estimated five-year survival rate from the time of diagnosis was 95 percent and dropped to 40 percent at 30 years postdiagnosis [85]. The effect of ERT was a 59 percent smaller chance of dying at any time point or a gain of approximately one year of life for eight years of treatment. The mean age at death was just under 60 years. Additional evidence of the benefit of ERT includes positive effects and stabilization in areas of ambulation, ventilator support with improvements in creatine kinase (CK) levels, motor performance, and respiratory function in two-thirds of patients on ERT [97]. Serial monitoring of pulmonary function tests, particularly for declines in maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), and upright vital capacity (VC-U), may help predict the need for daytime and nighttime ventilation and wheelchair use [98]. Following respiratory muscular strength training done in combination with ERT, eight late-onset patients demonstrated improvements in MIP and MEP during the first year, with stability in the second year [99]. Children who were diagnosed by NBS, have late-onset GAA deficiency, and are heterozygous for the common c.-32-13T>G variant require regular cardiac follow-up with electrocardiography for arrhythmias, but they have a lower risk of hypertrophic cardiomyopathy [100].

COMPLICATIONS — Enzyme replacement therapy (ERT) enhances survival in GAA deficiency, which has revealed long-term, progressive complications of the disease, one of which appears to be fractures [101]. In a series of 10 infants with 15 fractures receiving ERT, the median age at the time of the first fracture was 22.7 months (range 13 months to eight years) [101]. A high prevalence of asymptomatic and atraumatic of mostly thoracic vertebral fractures was found in 17 of 22 late-onset GAA deficiency patients that did not correlate with ERT, no ERT, vitamin D levels (although nearly all patients had low levels), or genotype [102].

Other complications seen in patients treated with ERT include facial muscle weakness, speech disorders, and dysphagia [103]; obstructive sleep apnea and central hypoventilation [104]; and premature pubarche [105]. Cognitive outcome is good, with normal to only mildly delayed development seen in one small series [106]. The ability to accurately assess cognitive development in children less than five years of age was affected by their degree of motor problems in this series.

Complications seen in late-onset disease are largely minor to moderate and typically related to infusion-related reactions (see 'Adverse effects of enzyme replacement therapy' above), including rash, erythema, tachycardia, facial erythema, globus pharynges, itching, vomiting, and hypertension [97]. Individual cases of significant complications have been reported, including pneumothorax, severe emphysema, and tracheal hemorrhage resulting in death [107-109].

RESOURCES — A list of websites for organizations and support groups for patients with GAA deficiency and their caregivers/families is provided in the table (table 2).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glycogen storage disease types I and II".)

SUMMARY

Lysosomal acid alpha-glucosidase (GAA, also called acid maltase) deficiency (Pompe disease, formerly classified as glycogen storage disease type II [GSD II]) is an autosomal-recessive disorder with considerable allelic heterogeneity. It is caused by pathogenic variants in the gene for lysosomal acid alpha-1,4-glucosidase. Deficiency of lysosomal GAA leads to accumulation of glycogen in lysosomes and cytoplasm (figure 1), which results in tissue destruction. (See 'Pathogenesis' above and 'Genetics' above.)

Infantile-onset GAA deficiency is characterized by cardiomyopathy and severe, generalized hypotonia. Most patients with this form die within the first year or two of life without treatment. (See 'Infantile-onset form' above and 'Natural history' above.)

Late-onset disease (juvenile and adult presentations) is characterized by skeletal myopathy (usually in a limb-girdle distribution) and a protracted course leading to respiratory failure without cardiomyopathy. (See 'Late-onset form' above and 'Natural history' above.)

Infantile-onset GAA deficiency should be suspected in infants with profound hypotonia and cardiac insufficiency. Juvenile or adult-onset GAA deficiency should be considered in patients with progressive weakness in a limb-girdle distribution.

Supportive findings may include:

Electrocardiogram demonstrating short PR interval and giant QRS complexes in all leads, suggesting biventricular hypertrophy, although this is a nonspecific finding (infantile-onset form).

Electromyogram demonstrating myopathic discharges, sometimes associated with abundant myotonic and complex repetitive discharges, most prominent in the paraspinal muscles (late-onset form).

Elevated serum creatine kinase (CK; all forms).

Demonstration of reduced GAA activity in a dried blood spot or leukocytes, followed by sequencing of the GAA gene, confirms the disease. Enzyme activity assays using skin fibroblasts or muscle tissue are alternatives to genetic testing to confirm the diagnosis. (See 'Diagnosis' above.)

GAA deficiency is treated with enzyme replacement therapy (ERT), physical and occupational therapy, and supportive care (eg, mechanical ventilation for respiratory failure). (See 'Treatment' above.)

The advent of ERT has improved clinical outcomes and survival for both early- and late-onset GAA deficiency. However, patients on ERT may still develop gradual pelvic girdle muscle weakness. Additional complications may include fractures and sleep-disordered breathing. (See 'Prognosis' above and 'Complications' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Basil T Darras, MD; William J Craigen, MD, PhD; and J Lawrence Merritt II, MD, who contributed to an earlier version of this topic review.

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Topic 2905 Version 21.0

References