Glycogen storage disease II, an autosomal recessive disorder, is the prototypic lysosomal storage disease. In the classic infantile form (Pompe disease), cardiomyopathy and muscular hypotonia are the cardinal features; in the juvenile and adult forms, involvement of skeletal ... Glycogen storage disease II, an autosomal recessive disorder, is the prototypic lysosomal storage disease. In the classic infantile form (Pompe disease), cardiomyopathy and muscular hypotonia are the cardinal features; in the juvenile and adult forms, involvement of skeletal muscles dominates the clinical picture Matsuishi et al. (1984).
Angelini et al. (1972) showed that the adult form of the disease can be diagnosed in cultured skin fibroblasts. Askanas et al. (1976) established muscle tissue cultures from a 34-year-old patient with the adult-onset myopathy. Morphologically and biochemically, ... Angelini et al. (1972) showed that the adult form of the disease can be diagnosed in cultured skin fibroblasts. Askanas et al. (1976) established muscle tissue cultures from a 34-year-old patient with the adult-onset myopathy. Morphologically and biochemically, the newly grown fibers of cultured muscle showed the same changes as did biopsied muscle. Ausems et al. (1999) found that creatine kinase (CK) elevation is a sensitive marker of GSD II. CK levels were elevated in all 18 patients in their cohort and in 94.3% of GSD II patients reported in the literature. They proposed a diagnostic protocol for adult-onset GSD II. In patients presenting with a slowly progressive proximal muscle weakness or with respiratory insufficiency, they recommended measurement of serum levels of CK, followed by measurement of acid alpha-glucosidase activity in leukocytes, using glycogen as a substrate. To rule out the pseudodeficiency state seen in carriers of the GAA2 allele, they recommended that patients with depressed leukocyte activity have a repeat assay in cultured fibroblasts using artificial substrate. Kallwass et al. (2007) reported a simple and reliable method to measure alpha-glucosidase activity in dried blood spots using Acarbose, a highly selective alpha-glucosidase inhibitor, to eliminate isoenzyme interference. The authors demonstrated that this method efficiently detected late-onset Pompe patients who were frequently misdiagnosed by conventional methods due to residual GAA activity in other tissue types. Bembi et al. (2008) provided a detailed guide to the diagnosis of GSD II, with emphasis on the importance of early recognition of clinical manifestations. Diagnosis is confirmed by biochemical assays showing absent or decreased GAA enzyme and enzyme activity in peripheral blood cells, skin fibroblasts, or muscle biopsy. Affected adults usually present with skeletal muscle weakness and cramps and may often have respiratory failure. Progression is usually slow. Muscle imaging may be useful to assess the extent of involvement in older patients. Affected infants can present with hypertrophic cardiomyopathy in the first months of life and show rapid progression, often leading to death within the first 2 years. Patients with juvenile onset have a more attenuated course compared to infantile onset, and do not have cardiomyopathy. Other features include generalized hypotonia and hepatomegaly.
In classic cases of Pompe disease, affected children are prostrate and markedly hypotonic with large hearts. The tongue may be enlarged. Although the enzyme is deficient in all tissues, muscle weakness ... - Infantile Onset (Pompe Disease) In classic cases of Pompe disease, affected children are prostrate and markedly hypotonic with large hearts. The tongue may be enlarged. Although the enzyme is deficient in all tissues, muscle weakness and heart involvement are the most common features. The liver is rarely enlarged, except as a result of heart failure, and hypoglycemia and acidosis do not occur as they do in glycogen storage disease I (232200). Death usually occurs in the first year of life in the classic form of the disorder and cardiac involvement is striking. Indeed, Pompe (1932) reported this condition as 'idiopathic hypertrophy of the heart,' and 'cardiomegalia glycogenica' is a synonym. Slonim et al. (2000) proposed a second, milder subtype of the infantile form. They reported 12 infants who showed less severe cardiomyopathy, absence of left ventricular outflow obstruction, and traces (less than 5%) of residual acid maltase activity; 9 of the 12 had longer survival with assisted ventilation and intubation. Smith et al. (1967) reported a boy with a myotonic form of disease and survival to the age of almost 11 years. The heart was not significantly involved. Alpha-1,4-glucosidase was absent from liver and muscle. There were heavy glycogen deposits and an anomalous polysaccharide with short outer chains was identified. Smith et al. (1966) reported a similar case in a boy who survived to the age of 4.5 years. Zellweger et al. (1965) described brothers, aged 15 and 4.5 years, with minimal manifestations limited to skeletal muscle. A deficiency of muscle alpha-1,4-glucosidase was demonstrated. Muscle showed abnormal accumulations of glycogen. A maternal uncle may have also been affected. On analysis of questionnaire data from 255 children and adults with Pompe disease, Hagemans et al. (2005) found that disease severity, including wheelchair use and use of respiratory support, increased with disease duration, but was not related to the age of the patients. However, there was a subset of patients under age 15 years with a more severe disease, requiring increased use of ventilatory support, wheelchair support, and nutritional support. All within this patient subgroup had onset of symptoms within the first 2 years of life. Forsha et al. (2011) studied the prevalence of cardiovascular abnormalities and the efficacy and safety of enzyme replacement therapy in patients with late-onset Pompe disease. Ninety patients were randomized 2:1 to enzyme replacement therapy or placebo in a double-blinded protocol. ECGs and echocardiograms were obtained at baseline and scheduled intervals during the 78-week study period. Eighty-seven patients were included. Median age was 44 years, and half were men. At baseline, a short PR interval was present in 10%, 7% had decreased left ventricular systolic function, and 5% had elevated left ventricular mass on echocardiogram (all in the mild range). There was no change in cardiovascular status associated with enzyme replacement therapy. No significant safety concerns were identified. Although some patients with late-onset Pompe disease had abnormalities on ECG or echocardiogram, those classically seen in infantile Pompe disease, such as significant ventricular hypertrophy, were not noted. Banugaria et al. (2011) retrospectively analyzed 34 infants with Pompe disease; 11 were cross-reactive immunologic material (CRIM)-negative patients; 9 were high-titer CRIM-positive patients; and 14 were low-titer CRIM-positive patients. Clinical outcome measures included survival, ventilator-free survival, left ventricular mass index, the Alberta Infant Motor Scale score, and urine Glc4 levels. Clinical outcomes in the high-titer CRIM-positive group were poor across all areas evaluated relative to the low-titer CRIM-positive group. For the CRIM-negative and high-titer CRIM-positive groups, no statistically significant differences were observed for any outcome measures, and both patient groups did poorly. Banugaria et al. (2011) concluded that, irrespective of CRIM material status, patients with infantile Pompe disease and high sustained antibody titer have an attenuated therapeutic response to enzyme replacement therapy. Banugaria et al. (2011) concluded that with the advent of immunomodulation therapies, identification of patients at risk for developing high sustained antibody titer is critical. Prater et al. (2012) described the phenotype of long-term survivors with infantile Pompe disease. Inclusion criteria included ventilator-free status and age less than 6 months at treatment initiation, as well as survival to age greater than 5 years. Eleven of 17 patients met these study criteria; all were CRIM-positive, alive, and invasive ventilator-free at most recent assessment, with a median age of 8.0 years (range 5.4-12.0 years). All had marked improvements in cardiac parameters. Commonly present were gross motor weakness, motor speech deficits, sensorineural and/or conductive hearing loss, osteopenia, gastroesophageal reflux, and dysphagia with aspiration risk. Seven of 11 patients were independently ambulatory and 4 required the use of assistive ambulatory devices. All long-term survivors had low or undetectable anti-alglucosidase alfa antibody titers. Prater et al. (2012) concluded that long-term survivors exhibited sustained improvements in cardiac parameters and gross motor function. Residual muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, dysphagia with risk for aspiration, and osteopenia were commonly observed findings. - Adult Onset Hudgson et al. (1968) reported the case of a Portuguese girl who died at age 19 and that of a living 44-year-old housewife. Other experiences suggesting the existence of more than one type of glycogenosis II were reported by Swaiman et al. (1968). Adult-onset acid maltase deficiency may simulate limb-girdle dystrophy and the only clinical clue may be early involvement of the diaphragm (Engel, 1970; Newsom-Davis et al., 1976; Sivak et al., 1981). Trend et al. (1985) reported 4 of 5 patients who presented with acute respiratory insufficiency or chronic nocturnal ventilatory insufficiency. They reported that long-term domiciliary ventilatory support using a rocking bed or intermittent positive pressure respirations with a tracheostomy permitted patients to return to work. Molho et al. (1987) reported the cases of monozygotic twin brothers who at age 50 developed bilateral paralysis of the diaphragm. Severe dyspnea in the supine position necessitated mechanical ventilation by pneumobelts during the night. The possibility of adult acid maltase deficiency should be considered in these cases. Francesconi and Auff (1982) described Wolff-Parkinson-White syndrome (194200) and second-degree atrioventricular block in a patient with the adult form of glycogenosis II. Byrne et al. (1986) stated that 'cardiac involvement has only been reported in 1 patient with noninfantile acid maltase deficiency.' Makos et al. (1987) described 3 brothers with alpha-glucosidase deficiency, each of whom developed a fusiform basilar artery aneurysm as young adults, which was complicated by fatal rupture in 2 of them and by a cerebellar infarction in the third. Postmortem examination demonstrated severe vacuolization of skeletal muscle, liver, and vascular smooth muscle with accumulation of glycogen. In the surviving brother, similar glycogen deposition was demonstrated in the smooth muscle of the superficial temporal artery. Glycogen deposition in vascular smooth muscle had been demonstrated previously in this disorder but had not been considered clinically significant. One of the brothers had onset of weakness at age 19, demonstration at age 27 of basilar artery aneurysm by cerebral angiography, which was performed because of throbbing, occipital headaches, and, at age 32, cerebellar infarction. He had 2 sons who were normal. The patients in this family had normal alpha-glucosidase activity in leukocytes but barely detectable alpha-glucosidase in muscle homogenates at acid pH. Kretzschmar et al. (1990) described a 40-year-old male with adult acid maltase deficiency who, in addition to involvement of the liver and skeletal muscles, had extensive involvement of large and small cerebral arteries with aneurysm formation. Chancellor et al. (1991) described the case of a 68-year-old man who first developed difficulty walking at the age of 65 and for several months had experienced urinary incontinence with exercise. Chancellor et al. (1991) pointed out that many patients with detrusor instability remain asymptomatic, probably because they augment urethral closure pressure by increasing striatal muscle activity in the sphincter mechanism. They postulated that the inability to withstand increases in detrusor pressure only occurred because of striated pelvic floor muscle fatigue associated with exercise. Alternatively, there may have been a neurogenic component in the muscle weakness because of involvement of spinal motor neurons. Laforet et al. (2000) reported the clinical features of 21 unrelated patients with juvenile- or adult-onset GAA deficiency. The mean age at onset of obvious muscle complaints was 36 years, although most patients (16 of 21) reported mild muscular symptoms since childhood, including scapular winging, scoliosis, and difficulty running. Most patients had predominant involvement of pelvic girdle muscles without significant distal leg involvement. Eight (40%) patients had severe respiratory muscle involvement, which was not correlated with the severity of limb muscle weakness. Biochemical studies showed residual GAA activity in leukocytes ranging from 0 to 17% of normal values; there was no correlation between leukocyte GAA activity and clinical severity. Genetic analysis identified the common -13T-G transversion in the GAA gene (606800.0006) in 17 patients (16 compound heterozygotes and 1 homozygote). There were no genotype/phenotype correlations. Anneser et al. (2005) reported a 30-year-old woman with alpha-glucosidase deficiency confirmed by mutation in the GAA gene (606800.0016; 606800.0017). She presented with a 4-year history of progressive proximal muscle weakness, and examination showed marked vacuolar myopathy, marked reduction in GAA enzyme activity, increased serum creatine kinase, and increased transaminase levels. After diagnosis, she experienced 3 stroke-like episodes within 3 months. Brain CT showed dilatative angiopathy of the intracerebral vessels, especially of the basilar artery, with calcifications of the carotid and medial cerebral arteries. MRI showed several white matter lesions. She had no other additional risk factors for atherosclerosis. Anneser et al. (2005) suggested that similar extramuscular vascular changes may be the most relevant prognostic factor for adult patients with slowly progressive Pompe disease. Groen et al. (2006) found that 4 (33%) of 12 patients with adult-onset GSD II had ptosis, which was the presenting feature in 3 patients. Six (50%) of the 12 had measurable evidence of decreased levator palpebral muscle function. The prevalence of ptosis was significantly higher in patients compared to the general population, suggesting that it may be considered a clinical feature of adult-onset GSD II. GENOTYPE/PHENOTYPE CORRELATIONS Koster et al. (1978) and Loonen et al. (1981) described a grandfather with acid maltase deficiency leading to difficulty climbing stairs after age 52, and a granddaughter with typical Pompe disease leading to death at 16 weeks. The muscle of both subjects showed residual activity. It seems likely that the grandfather was a genetic compound. In this same family, Hoefsloot et al. (1990) showed that 3 sibs were homozygous for an allele that caused complete deficiency of acid alpha-glucosidase; these patients had a severe infantile form of the disease. The eldest patient in the family, with very mild clinical symptoms, was shown to be a compound heterozygote for this allele and for a second allele characterized by a reduced net production of catalytically active acid alpha-glucosidase, resulting in partial enzyme deficiency. The mutant alleles were segregated in human-mouse somatic cell hybrids to investigate their individual function. Danon et al. (1986) also reported instances of the probable genetic compound state. Nishimoto et al. (1988) described a family in which the proband, aged 15, had the juvenile muscular dystrophy form of glycogenosis type II, whereas both parents and 2 sisters had pseudodeficiency of acid alpha-glucosidase. It was almost impossible to distinguish the homozygote from the heterozygous members by lymphocyte assays alone. Both parents may have been compound heterozygotes for the pseudodeficiency allele and the allele for the juvenile form. Allelic heterogeneity was demonstrated further by the patient reported by Suzuki et al. (1988): a male developed cardiomyopathy at 12 years of age and died of heart failure at age 15 years without any sign of skeletal muscle involvement, either clinically or histologically. A Km mutant of acid alpha-glucosidase was demonstrated. Iancu et al. (1988) described an affected 12-year-old boy who presented with a right lumbar mass which appeared to represent local pseudohypertrophy.
Multiple mutations in the acid maltase gene have been shown to cause glycogen storage disease II. Martiniuk et al. (1990) demonstrated a single basepair substitution of G to A at position 271 (606800.0001). Wokke et al. (1995) found ... Multiple mutations in the acid maltase gene have been shown to cause glycogen storage disease II. Martiniuk et al. (1990) demonstrated a single basepair substitution of G to A at position 271 (606800.0001). Wokke et al. (1995) found a single mutation in intron 1 of the acid maltase (606800.0006) in 16 patients with adult-onset acid maltase deficiency. Lam et al. (2003) reported compound heterozygosity for mutations in the GAA gene in a 16-year-old Chinese boy with juvenile-onset GSD II. The patient had mild symptoms in early childhood, but his condition worsened at age 12 years, with severe weakness, sleep-disordered breathing, and respiratory difficulties. His asymptomatic 13-year-old brother, who had the same mutations, had only biochemical abnormalities suggestive of disease (elevated CK, lack of GAA activity in leukocytes). The authors commented on the intrafamilial variability. Amartino et al. (2006) reported severe infantile and asymptomatic adult forms of GSD II in 2 generations of the same family. The proband was a 2-month-old male infant of nonconsanguineous Argentinian parents who was admitted to the hospital at 5 days with cyanosis and found to have cardiomegaly, an elevated CK level, high-voltage QRS complexes on ECG, and a thick interventricular septum and hypertrophic ventricular walls on echocardiogram. Pompe disease was suspected and confirmed by measuring GAA activity in leukocytes, and Amartino et al. (2006) identified homozygosity for mutations in the GAA gene, inherited from the parents, respectively. The asymptomatic father was found to have a second mutation on his other allele, the common adult-onset IVS1 splice site mutation (606800.0006). Subsequent evaluation revealed a normal physical examination with no neuromuscular complaints and normal ECG and echocardiogram, but he had elevated CK, short duration potentials on electromyography, and reductions in maximal expiratory and inspiratory pressures on spirometry. Among 40 Italian patients with late-onset GSD II, Montalvo et al. (2006) identified 26 different mutations, including 12 novel mutations, in the GAA gene. The most common mutation was a splice site mutation in intron 1 (606800.0006), present in heterozygosity in 34 (85%) of 40 patients (allele frequency 42.3%). - Modifier Genes De Filippi et al. (2010) studied 38 patients with late-onset Pompe disease, aged 44.6 +/- 19.8 years, and compared the distribution of angiotensin I-converting enzyme (ACE) polymorphism (106180.0001) according to demographic and disease parameters. The distribution of ACE polymorphism was in line with the general population, with 16% of patients carrying the II genotype, 37% carrying the DD genotype, and the remaining patients with the ID genotype. The 3 groups did not differ in mean age, disease duration, Walton score, and other scores used to measure disease severity. The DD polymorphism was associated with earlier onset of disease (P = 0.041), higher creatine kinase levels at diagnosis (P = 0.024), presence of muscle pain (P = 0.014), and more severe rate of disease progression (P = 0.037, analysis of variance test for interaction).
In Israel, almost all cases of Pompe disease have occurred in Palestinian Arabs (Bashan et al., 1988).
On the basis of Hardy-Weinberg equilibrium and the fact that 7 mutations they tested represented only 29% of the ... In Israel, almost all cases of Pompe disease have occurred in Palestinian Arabs (Bashan et al., 1988). On the basis of Hardy-Weinberg equilibrium and the fact that 7 mutations they tested represented only 29% of the total, Martiniuk et al. (1998) estimated the actual carrier frequency to be about 1 in 100. Mutant gene frequency, q, was calculated to be 0.005. The expected number of individuals born with GSD II was estimated to be 1 in 40,000 births. Three mutations in the GAA gene are common in the Dutch patient population: IVS1, T-G,-13 (606800.0006), 525delT (606800.0014), and EX18DEL (606800.0012). Sixty-three percent of Dutch GSD II patients carry 1 or 2 of these mutations, and the genotype-phenotype correlation is known (Kroos et al., 1995). To determine the frequency of GSD II, Ausems et al. (1999) screened an unselected sample of neonates for these 3 mutations. Based on the calculated carrier frequencies so derived, the predicted frequency of the disease was 1 in 40,000, divided into 1 in 138,000 for infantile GSD II and 1 in 57,000 for adult GSD II. This was about 2 to 4 times higher than previously suggested.
The two general subtypes of glycogen storage disease type II (GSD II), also known as Pompe disease, differ by age of onset and clinical findings....
Diagnosis
Clinical DiagnosisThe two general subtypes of glycogen storage disease type II (GSD II), also known as Pompe disease, differ by age of onset and clinical findings.Infantile-onset Pompe disease is suspected in infants with the following [van den Hout et al 2003, Kishnani et al 2006a]:Poor feeding/failure to thrive (44%-97% of cases)Motor delay/muscle weakness (20%-63%)Respiratory concerns (infections/difficulty) (27%-78%)Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy) (50%-92%)Late-onset (i.e., childhood, juvenile, and adult-onset) Pompe disease is suspected in individuals with proximal muscular weakness and respiratory insufficiency without clinically apparent cardiac involvement.TestingNonspecific tests used to support the diagnosis of Pompe diseaseSerum creatine kinase (CK) concentration is uniformly elevated (as high as 2000 IU/L; normal: 60-305 IU/L) in classic infantile-onset Pompe disease and in the childhood and juvenile variants, but may be normal in adult-onset disease [Laforêt et al 2000, Kishnani et al 2006b]. However, serum CK concentration is elevated in many conditions and must be considered nonspecific.Urinary oligosaccharides. Elevation of a specific urinary glucose tetrasaccharide is highly sensitive in Pompe disease but is also seen in other glycogen storage diseases [An et al 2000, Kallwass et al 2007, Young et al 2012].Testing used to establish the diagnosis of Pompe diseaseAcid alpha-glucosidase (GAA) enzyme activity. GAA enzyme activity analysis can be performed on dried blood spots [Chamoles et al 2004, Zhang et al 2006, Pompe Disease Diagnostic Working Group 2008], thus permitting rapid and sensitive analysis. Standard conditions for assay of GAA in blood samples have been proposed by a Pompe Disease Diagnostic Working Group. Confirmation by measurement of GAA activity in another tissue (e.g., culture skin fibroblasts) or molecular analysis is recommended [Pompe Disease Diagnostic Working Group 2008]. Historically, measurement of GAA enzyme activity has been performed using cultured skin fibroblasts, but it may take four to six weeks to obtain results, and delayed diagnosis and initiation of treatment, particularly in infants, may affect outcome.Complete deficiency (activity <1% of normal controls) of GAA enzyme activity is associated with classic infantile-onset Pompe disease.Partial deficiency (activity 2%-40% of normal controls) of GAA enzyme activity is associated with the non-classic infantile-onset and the late-onset forms [Hirschhorn & Reuser 2001]. Note: (1) As a general rule, the lower the GAA enzyme activity the earlier the age of onset of disease. (2) GAA enzyme activity can be assayed in muscle; however, this invasive procedure usually requires anesthesia, which may not be tolerated in those who have infantile Pompe disease and cardiopulmonary compromise. (3) Peripheral leukocytes have been used to measure GAA enzyme activity but alternate isoenzymes such as maltase-glucoamylase may interfere with the assay. (4) GAA enzyme activity analysis can be performed on dried blood spots [Chamoles et al 2004, Zhang et al 2006], thus permitting rapid and sensitive analysis that is potentially useful for newborn screening [Kishnani et al 2006b].Acid alpha-glucosidase protein quantitation can be performed by an antibody-based method in cultured fibroblasts. Such testing may be important in determining if an affected individual produces cross-reactive immunologic material (CRIM). CRIM status affects response to ERT and CRIM-negative individuals need an altered plan for enzyme therapy [Pompe Disease Diagnostic Working Group 2008, Kishnani et al 2010, Messinger et al 2012]. Muscle biopsy. In contrast to the other glycogen storage disorders, GSD II is also a lysosomal storage disease. In GSD II glycogen storage may be observed in the lysosomes of muscle cells as vacuoles of varying severity that stain positively with periodic acid-Schiff. However, 20%-30% of individuals with late-onset Pompe disease with documented partial enzyme deficiency may not show these muscle-specific changes [Laforêt et al 2000, Winkel et al 2005].Newborn screening. Newborn screening for GSD II, using GAA enzyme activity in dried blood spots as a primary screening tool, has been under study in Taiwan. Variants associated with infantile-onset and late-onset disease have been identified in the Taiwanese population. A nationwide study in Austria using enzymatic activity followed by mutation analysis identified one newborn among 34,736 samples [Mechtler et al 2012]. Similar feasibility studies have occurred in Japan [Oda et al 2011]. Pilot trials in the US are planned in several states.The rationale for newborn screening is that infants with confirmed infantile-onset GSD II (Pompe disease) who are treated early with ERT have demonstrated improved cardiac status and motor gains, when compared to controls [Chien et al 2009]. Cautions: (1) The pseudodeficiency allele c.1726 G>A (p.Gly576Ser), which is relatively common in Asian populations, complicates the assessment and diagnostic confirmation in these populations. It remains to be seen whether pseudodeficiency is common in other populations [Labrousse et al 2010]. (2) In areas in which mutations that result in CRIM-negative proteins are more common (e.g., the US, the Middle East), newborn screening to facilitate early diagnosis and hence initiation of ERT may not provide much improvement unless alternative therapy protocols using immunomodulation are considered [Messinger et al 2012].Molecular Genetic TestingGene. GAA is the only gene in which mutations are known to cause GSD II.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Glycogen Storage Disease Type II (Pompe Disease)View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityGAASequence analysis
p.Arg854*~50%-60% 2Clinicalp.Asp645Glu~40%-80% 3c.336-13T>G~50%-85% 4Other sequence variants in the gene 583%-93% 6Sequence analysis of select exonsSequence variants in the select exons 783%-93% 6 Targeted mutation analysisSequence variants in targeted sites 7100% of for variants among the targeted mutationsDeletion/duplication analysis 8Exonic and whole-gene deletions/duplications5%-13% 91. The ability of the test method used to detect a mutation that is present in the indicated gene2. In African Americans with infantile-onset Pompe disease [Becker et al 1998, Hirschhorn & Reuser 2001]3. In individuals of Chinese ancestry with infantile Pompe disease [Shieh & Lin 1998, Ko et al 1999, Hirschhorn & Reuser 2001]4. In adults with late-onset disease; typically this mutation occurs in the compound heterozygous state [Laforêt et al 2000, Hirschhorn & Reuser 2001, Winkel et al 2005, Montalvo et al 2006].5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected.6. Detection rate of two mutations in sequencing of the genomic DNA in patients with confirmed reduced or absent GAA enzyme activity [Hermans et al 2004, Montalvo et al 2006]8. Targeted mutations and select exons may vary by laboratory7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.9. Deletion/duplication analysis. One of the more common pathogenic alleles involves the deletion of exon 18, seen in approximately 5%-7% of alleles [Van der Kraan et al 1994]. Exonic and multiexonic deletions have been seen. With the exception of deletion of exon 18, such deletions are rare except in consanguineous unions [McCready et al 2007, Pittis et al 2008, Bali et al 2012]. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. Guidelines for the diagnosis of Pompe disease have been put forth by an expert panel from the American College of Medical Genetics [Kishnani et al 2006b] (see ).Clinical evaluation alone is not sufficient to establish the diagnosis of any of the forms of Pompe disease:Assay of acid alpha-glucosidase (GAA) enzyme activity in cultured skin fibroblasts or muscle, considered the gold standard for diagnosis, is the diagnostic test of choice if feasible, but it may take weeks to obtain results.Assay of GAA enzyme activity in whole blood or dried bloodspot reliably detects GAA enzyme deficiency; confirmation by a second method is preferred prior to initiation of therapy [Kallwass et al 2007, Pompe Disease Diagnostic Working Group 2008].Urinary tetrasaccharide levels are elevated in nearly 100% of individuals with infantile Pompe disease, but may be normal in late-onset disease [Young et al 2009]. Note: Histochemical evidence of glycogen storage in muscle is supportive of a glycogen storage disorder but not specific for Pompe disease.Identification of two disease-causing GAA alleles using molecular genetic testing provides additional confirmation of the diagnosis. Depending on ethnicity and phenotype, an individual could be tested first for one of the three common mutations — p.Asp645Glu, p.Arg854*, and c.336-13T>G — before proceeding to full gene sequence analysis. Molecular analysis is an important element in the rapid assessment of cross-reactive immunologic material (CRIM) status in infantile Pompe [Bali et al 2012]. Experience with molecular analysis as the sole diagnostic test is limited, particularly in individuals who are asymptomatic or lacking sentinel clinical findings. Carrier testing for at-risk relatives using molecular genetic testing requires prior identification of the disease-causing GAA mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Predictive testing for at-risk asymptomatic family members using molecular genetic testing requires prior identification of the GAA disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with mutations in GAA.
Glycogen storage disease type II (GSD II; Pompe disease) has been classified based on age of onset, organ involvement, severity, and rate of progression. As a general rule, the earlier the onset of symptoms, the faster the rate of progression....
Natural History
Glycogen storage disease type II (GSD II; Pompe disease) has been classified based on age of onset, organ involvement, severity, and rate of progression. As a general rule, the earlier the onset of symptoms, the faster the rate of progression.Although "late-onset" Pompe disease has been divided into childhood, juvenile, and adult-onset forms, many persons with the adult-onset type recall symptoms beginning in childhood and thus, "late-onset" is often the preferred term for those presenting after the first few years of life [Laforêt et al 2000]. Most likely, late-onset Pompe disease represents a clinical continuum in which subtypes cannot be reliably distinguished by age of onset.Classic infantile-onset Pompe disease may be apparent in utero but more often presents in the first two months of life as hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, and respiratory distress (see Table 2).Feeding difficulties may result from facial hypotonia, macroglossia, tongue weakness, and/or poor oromotor skills [van Gelder et al 2012].Hearing abnormalities are common, possibly reflecting a cochlear or conductive pathology or both [Kamphoven et al 2004, van Capelle et al 2010].Without treatment by enzyme replacement therapy (ERT), the cardiomegaly and hypertrophic cardiomyopathy that are often identified at birth by echocardiography progress to left ventricular outflow obstruction. Enlargement of the heart can also result in diminished lung volumes, atelectasis, and sometimes bronchial compression. Progressive deposition of glycogen results in conduction defects as seen by shortening of the PR interval on ECG.In untreated infants, death commonly occurs in the first year of life from cardiopulmonary insufficiency [van den Hout et al 2003, Kishnani et al 2006a].Table 2. Common Findings at Presentation of Infantile Pompe DiseaseView in own windowPhysical SignsProportion of Cases 1Hypotonia/muscle weakness
52%-96%Cardiomegaly92%-100%Hepatomegaly29%-90%Left ventricular hypertrophy83%-100%Cardiomyopathy88%Respiratory distress41%-78%Murmur46%-75%Enlarged tongue (macroglossia)29%-62%Feeding difficulties57%Failure to thrive53%Absent deep tendon reflexes33%-35%Normal cognition95%1. Hirschhorn & Reuser [2001], van den Hout et al [2003]The non-classic variant of infantile-onset Pompe disease usually presents within the first year of life predominantly with motor delays and/or muscle weakness. Muscles are firm and rubbery as a result of glycogen deposition. Pseudohypertrophy of the calf muscles and a Gower sign simulate Duchenne muscular dystrophy (DMD), but these findings typically occur at an earlier age in Pompe disease than in DMD. Muscular weakness progresses more slowly than in classic infantile-onset Pompe disease.Cardiomegaly can be seen with or without left ventricular outflow obstruction; it is not a major source of clinical morbidity [Slonim et al 2000].Death from ventilatory failure typically occurs in early childhood.Late-onset Pompe disease can present at various ages with muscle weakness and respiratory insufficiency. Progression of the disease is often predicted by the age of onset, as progression is more rapid if symptoms present in childhood.Late-onset Pompe disease presenting in infancy or early childhood may be difficult to differentiate from the non-classic infantile form. Cardiomegaly is not typically seen but progressive muscle weakness resulting in motor delays, swallowing difficulties, and respiratory insufficiency usually occurs as in the infantile form, but at a slower rate.While initial symptom presentation in late childhood to adolescence is typically not associated with heart complications, some adults with late onset disease have been found to have arteriopathy [El-Gharbawy et al 2011]. Ectasia of the basilar and internal carotid arteries has been noted, and may be associated with clinical signs, such as transient ischemic attacks and 3rd nerve paralysis [Sacconi et al 2010]. In addition, dilation of the ascending thoracic aorta has been noted. Echocardiography may not always be sufficient to visualize this complication [El-Gharbawy et al 2011].Progression of skeletal muscle involvement is slower than in the infantile forms and eventually involves the diaphragm and accessory respiratory muscles [Winkel et al 2005]. Affected individuals often become wheelchair dependent because of lower limb weakness. Respiratory failure causes the major morbidity and mortality of this form of the disease [Gungor et al 2011].Late-onset Pompe disease may present from the second to as late as the seventh decade of life with progressive proximal muscle weakness primarily affecting the lower limbs, as in a limb-girdle muscular dystrophy or polymyositis. Affected adults often describe symptoms beginning in childhood with difficulty participating in sports. Later, fatigue and difficulty with rising from a sitting position, climbing stairs, and walking prompt medical attention. In an untreated cohort of affected individuals with late-onset Pompe, the median age at diagnosis was 38 years, the median survival after diagnosis was 27 years, and the median age at death was 55 years (range 23-77 years) [Gungor et al 2011] Evidence of advanced osteoporosis in adults with Pompe disease is accumulating; while this is likely in large part secondary to decreased ambulation, other pathologic processes cannot be overlooked [Oktenli 2000, Case et al 2007].Respiratory failure causes the major morbidity and mortality in this form of the disease [Hagemans et al 2005]. Male gender, severity of skeletal muscle weakness, and duration of disease are all risk factors for severe respiratory insufficiency [van der Beek et al 2011]. Clinical manifestations of late-onset Pompe disease [Hirschhorn & Reuser 2001]Progressive proximal muscle weakness (95%) [Winkel et al 2005]Respiratory insufficiencyExercise intoleranceExertional dyspneaOrthopneaSleep apneaHyperlordosis and/or scoliosis (childhood and juvenile onset)Hepatomegaly (childhood and juvenile onset)Macroglossia (childhood onset)Difficulty chewing and swallowingIncreased respiratory infectionsDecreased deep tendon reflexesGower signJoint contracturesCardiac hypertrophy (childhood onset)Electrophysiologic studies. Myopathy can be documented by electromyography (EMG) in all forms of Pompe disease although some muscles may appear normal. In adults, needle EMG of the paraspinal muscles may be required to demonstrate abnormalities [Hobson-Webb et al 2011]. Nerve conduction velocity (NCV) studies are normal for both motor and sensory nerves, particularly at the time of diagnosis in infantile-onset disease and in late-onset disease. However, an evolving motor axonal neuropathy has been demonstrated in a child with infantile-onset disease [Burrow et al 2010].
GAA enzyme activity may correlate with age of onset and rate of progression as a "rough" general rule:...
Genotype-Phenotype Correlations
GAA enzyme activity may correlate with age of onset and rate of progression as a "rough" general rule:It is assumed that a combination of two mutated alleles that produce essentially no enzyme activity results in infantile-onset Pompe disease. Infants who have infantile Pompe with no cross-reactive material (CRIM-negative) are likely to have two null mutations [Bali et al 2012].Various combinations of other alleles resulting in some residual enzyme activity likely cause disease but the age of onset and progression are most likely directly proportional to the residual GAA enzyme activity.Although a number of mutations seen in homozygosity may suggest a genotype-phenotype correlation, the existence of a number of case reports of both infantile and late-onset Pompe disease in the same family suggests strong caution in extrapolation of these observances [Hoefsloot et al 1990].Mutations that introduce mRNA instability, such as nonsense mutations, are more commonly seen in the infantile-onset form of Pompe disease as they result in nearly complete absence of GAA enzyme activity.Missense and splicing mutations may result in either complete or partial absence of GAA enzyme activity and therefore may be seen in both infantile-onset and late-onset Pompe disease [Zampieri et al 2011]. The following are observations about genotype-phenotype correlations with specific mutations (see Table 3):p.Glu176Argfs*45 (c.525delT) is an especially common mutation among the Dutch [Van der Kraan et al 1994]. It results in negligible GAA enzyme activity and must be considered one of the more severe alterations. Either in the homozygous state or in the compound heterozygous state with another severe mutation, p.Glu176Argfs*45 predicts the infantile-onset form of Pompe disease, although the correlation is not absolute.Deletion of exon 18 (p.Gly828_Asn882del; c.2482_2646del) is also a common mutation, particularly among the Dutch [Van der Kraan et al 1994]. It results in negligible GAA enzyme activity and must be considered one of the more severe mutations. Deletion of exon 18, either in the homozygous state or in the compound heterozygous state with another severe mutation, predicts the infantile-onset form.c.336-13T>G is seen in 36% to 90% of late-onset Pompe disease and is not associated with the infantile-onset form [Hermans et al 2004, Montalvo et al 2006]. The mutation leads to a leaky splice site resulting in greatly diminished, but not absent, GAA enzyme activity.The mutation p.Asp645Glu, seen among a high proportion (≤80%) of infantile cases in Taiwan and China, is associated with a haplotype, suggesting a founder effect [Shieh & Lin 1998].The mutation p.Arg854* is frequently associated with infantile-onset Pompe disease. Found among different ethnicities, the mutation has been observed in up to 60% of individuals of African descent who had a common haplotype, suggesting a founder effect [Becker et al 1998].Table 3. Proportion of Individuals with Select GAA Pathologic VariantsView in own windowGAA Pathologic Variant% of Affected IndividualsReferencep.Glu176Argfs*45
34% of Dutch casesVan der Kraan et al [1994]9% of US casesHirschhorn & Huie [1999]p.Gly828_Asn882del 25% of infantile Dutch and Canadian casesVan der Kraan et al [1994]5% of US casesHirschhorn & Huie [1999]c.336-13T>G 36%-90% of late-onset casesHermans et al [2004], Montalvo et al [2006]p.Asp645Glu Up to 80% of infantile Taiwanese and Chinese casesShieh & Lin [1998]p.Arg854*Up to 60% of individuals of African descent with a common phenotypeBecker et al [1998]
Infantile-onset Pompe disease. Disorders to be considered in the differential diagnosis:...
Differential Diagnosis
Infantile-onset Pompe disease. Disorders to be considered in the differential diagnosis:Spinal muscular atrophy 1 (Werdnig-Hoffman disease). Hypotonia, feeding difficulties, progressive proximal muscle weakness, and areflexia; no cardiac involvement. Caused by a defect in SMN. Inheritance is autosomal recessive.Danon disease. Similar presentation of hypotonia, hypertrophic cardiomyopathy, and myopathy as a result of excessive glycogen storage caused by defects in lysosome-associated membrane protein 2 (LAMP2) [Arad et al 2005]. Inheritance is X-linked.Endocardial fibroelastosis. Respiratory and feeding difficulties, cardiomegaly, and heart failure without significant muscle weakness. Etiology is often viral but familial cases with X-linked, autosomal dominant, and autosomal recessive inheritance have been described.Carnitine uptake disorder. Muscle weakness and cardiomyopathy without elevated serum concentration of creatine kinase (CK). Inheritance is autosomal recessive.Glycogen storage disease type IIIa (debrancher deficiency). Hypotonia, cardiomegaly, muscle weakness, and elevated serum concentration of creatine kinase with more dramatic liver involvement than typically seen in Pompe disease. Inheritance is autosomal recessive.Glycogen storage disease type IV (branching enzyme deficiency). Hypotonia, cardiomegaly, muscle weakness, and elevated serum concentration of creatine kinase with more dramatic liver involvement than typically seen in Pompe disease (similar to GSD IIIa). Inheritance is autosomal recessive.Idiopathic hypertrophic cardiomyopathy. Biventricular hypertrophy without hypotonia or pronounced muscle weaknessMyocarditis. Inflammation of the myocardium leading to cardiomegaly without hypotonia or muscle weaknessMitochondrial/respiratory chain disorders. Wide variation in clinical presentation; may include hypotonia, respiratory failure, cardiomyopathy, hepatomegaly, seizures, deafness, and elevated serum concentration of creatine kinase; often distinguishable from Pompe disease by the absence of hypotonia and presence of cognitive involvement. See Mitochondrial Disorders Overview.Late-onset Pompe disease (i.e., childhood, juvenile, and adult-onset). The early involvement of the respiratory muscles is often useful in distinguishing juvenile-onset Pompe disease from many neuromuscular disorders.Disorders to be considered in the differential diagnosis:Limb-girdle muscular dystrophy. Progressive muscle weakness in the legs, pelvis, and shoulders sparing the truncal muscles.Duchenne-Becker muscular dystrophy. Progressive proximal muscle weakness, respiratory insufficiency, and difficulty ambulating; primarily affects males. Inheritance is X-linked.Polymyositis. Progressive, symmetric, unexplained muscle weaknessGlycogen storage disease type V (McArdle disease; muscle phosphorylase deficiency). Elevated serum concentration of creatine kinase and muscle cramping with exertion. Inheritance is autosomal recessive.Glycogen storage disease type VI. Hypotonia, hepatomegaly, muscle weakness, and elevated serum concentration of creatine kinase. Inheritance is autosomal recessive.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Infantile-onset GSD IILate-onset GSD II:JuvenileAdult
To establish the extent of disease in an individual diagnosed with glycogen storage disease type II (GSD II; Pompe disease), the following guidelines for the initial evaluation of infantile Pompe disease put forth by an expert panel from the American College of Medical Genetics [Kishnani et al 2006b] are recommended (see ):...
Management
Evaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with glycogen storage disease type II (GSD II; Pompe disease), the following guidelines for the initial evaluation of infantile Pompe disease put forth by an expert panel from the American College of Medical Genetics [Kishnani et al 2006b] are recommended (see ):Chest radiography. In infantile-onset Pompe disease nearly all affected infants have cardiomegaly on chest x-ray [van den Hout et al 2003]. Further, evaluation of apparent lung volume reduction, areas of atelectasis, and any pulmonary fluid may be helpful in directing other therapies. In late-onset disease, baseline radiographic evaluation of the lungs and heart silhouette is indicated but only rarely reveals cardiomegaly.Electrocardiography (ECG). In infantile Pompe disease the majority of affected infants have left ventricular hypertrophy and many have biventricular hypertrophy [van den Hout et al 2003]. Conduction disturbance is often seen.Echocardiography. Typically in the infantile forms, echocardiography demonstrates hypertrophic cardiomyopathy with or without left ventricular outflow tract obstruction in the early phases of the disease process. In later stages, dilated cardiomyopathy may be seen.Pulmonary assessment. Most infants have varying degrees of respiratory insufficiency. Respiratory status should be established with regard to cough, presence of wheezing or labored breathing, and/or feeding difficulties. Diaphragmatic weakness caused by excessive glycogen deposits results in mild to moderate reduction of vital capacity; however, objective assessment of pulmonary functions in infants is difficult at best. Most infants display respiratory difficulty with feeds or sleep disturbance [Kravitz et al 2005]. Persons with late-onset disease should be evaluated for cough, wheezing, dyspnea, energy level, exercise tolerance, and fatigability. Formal pulmonary function tests in the late-onset forms show pulmonary insufficiency. An attempt to assess ventilatory capacity in the supine position can detect early ventilatory insufficiency. Pulse oximetry, respiratory rate, and venous bicarbonate and/or pCO2 should be obtained to assess for alveolar hypoventilation [van der Beek et al 2011].Nutrition/feeding. Patients should be evaluated for possible feeding difficulties (e.g., facial hypotonia, macroglossia, tongue weakness, and/or poor oromotor skills) [Jones et al 2009, van Gelder et al 2012]. Assessment of growth (i.e., height, weight, head circumference), energy intake, and feeding (including video swallow study) is appropriate. All infants should be evaluated for gastroesophageal reflux.Audiologic. Baseline hearing evaluation including tympanometry is appropriate. See Deafness and Hereditary Hearing Loss Overview for a discussion of age-related methods of hearing evaluation. Sensorineural hearing loss is now documented in children with infantile Pompe disease, and hearing aids may be of benefit [van Capelle et al 2010].Disability inventory. All patients should undergo assessment of motor skills and overall functioning to guide subsequent therapies and monitor progression of the disease.Medical genetics consultationNote: Guidelines for the evaluation of individuals with late-onset Pompe disease [Cupler et al 2012] differ in methodology from those detailed above for infantile Pompe disease, but many of the same systems (particularly pulmonary, nutrition, musculoskeletal, and disability inventory) are common to all forms of Pompe disease. Treatment of ManifestationsGuidelines for the management of Pompe disease have been put forth by an expert panel from the American College of Medical Genetics [Kishnani et al 2006b] (see ):Cardiomyopathy. Medical intervention needs to be individualized as use of standard drugs may be contraindicated in certain stages of the disease process (see Agents/Circumstances to Avoid) [Kishnani et al 2006b]. Enzyme replacement therapy (ERT) reduces cardiac mass to varying degrees and improves the ejection fraction, although there may be a transient decrease in the ejection fraction after the first several weeks of ERT [Levine et al 2008].Arteriopathy. Treatment does not differ from that in the general population.Conduction disturbances. Patients with hypertrophic cardiomyopathy are at high risk for tachyarrhythmia and sudden death [Tabarki et al 2002]. Twenty-four hour Holter monitoring is useful in characterizing the type and severity of rhythm disturbance. Management includes avoidance of stress, infection, fever, dehydration, and anesthesia. Medical therapy, if indicated, often necessitates a careful balance of ventricular function and should be undertaken by a cardiologist familiar with Pompe disease. ERT results in an increase of the PR interval and a decrease in the left ventricular voltage [Ansong et al 2006].Muscle weakness. Physical therapy is appropriate to maintain range of motion and assist in ambulation. Proximal motor weakness can result in contractures of the pelvic girdle in infants and children, necessitating aggressive management including surgery [Case et al 2012]. Scoliosis is frequent, particularly in individuals with infantile or childhood onset disease [Roberts et al 2011].Nutrition/feeding. Infants may need specialized diets and maximal nutrition, with some requiring gastric feedings. Persons with late-onset disease may also develop feeding concerns and are often managed on a soft diet, with a few requiring gastric or jejunal feedings. Some of these manifestations may improve on ERT [Bernstein et al 2010].Respiratory insufficiency. Respiratory support including CPAP and BiPAP may be required. Inspiratory/ expiratory training has improved respiratory muscle strength in adults with late onset Pompe [Jones et al 2011]. Macroglossia and severe respiratory insufficiency in the infantile form may necessitate tracheostomy.Prevention of Primary ManifestationsEnzyme replacement therapy (ERT) should be initiated as soon as the diagnosis of Pompe disease is established.The FDA approved the use of Myozyme® (alglucosidase alfa) for infantile Pompe disease in 2006. Studies on later-onset forms of Pompe disease have been completed, and Lumizyme® was approved by the FDA in 2010 for use in late-onset Pompe disease. Lumizyme is currently being studied in children with infantile onset Pompe. Myozyme® and Lumizyme® are administered by slow IV infusion at 20-40 mg/kg/dose every two weeks.In clinical studies, infusion reactions were observed in half of those treated with Myozyme®. The majority of treated children developed IgG antibodies to Myozyme® within the first three months of treatment. Infusion reactions appear to be more common in individuals with IgG antibodies. Development of IgE antibodies is less common but may be associated with anaphylactic reaction. Some affected individuals with high sustained IgG titers may have a poor clinical response to treatment (see Testing, Acid alpha-glucosidase protein quantitation). Most infusion-associated reactions can be modified by slowing the rate of infusion or administration of antipyretics, antihistamines, or glucocorticoids. However, anaphylaxis requiring life support measures has been reported. For these reasons – and because many individuals with Pompe disease have preexisting compromise of respiratory and cardiac function – initiation of therapy in centers equipped to provide emergency care is recommended. Transition to home infusion therapy is possible in those who have tolerated several months of infusions without clinical reaction. Home infusion therapy may have benefits to the affected individual and family, but the decision to initiate home infusions requires consideration of multiple factors, including venous access, medical stability, antibody status, and access to skilled home care providers. Enzyme therapy in infants with known or suspected CRIM negative status requires immunomodulation very early in the treatment course, optimally before the first infusion. There are multiple immunomodulation protocols in use, most of which use rituximab with additional drugs (including mycophenylate mofetil, methotrexate, and sirolimus) [Messinger et al 2012, Elder et al 2013]. Genotyping may play a role in the rapid classification of CRIM status [Bali et al 2012]. However, clinical outcomes are poorer in infants who develop high titer anti-rhGAA antibodies, regardless of CRIM status [Banugararia et al 2011], and additional tools to identify those at risk for this outcome are needed.In addition to drug-related reactions, children with infantile Pompe disease may have difficulty with anesthesia for procedures related to placement of venous access devices.The relative resistance of skeletal muscle to effective glycogen depletion with administered alpha glucosidase has been observed in animals and humans, and varies with different enzyme preparations. Type II muscle fibers appear to be quite resistant to therapy. From a clinical viewpoint, the failure of most ventilator-dependent individuals to achieve independence from invasive ventilation is not surprising. Perhaps more disappointing is that five of the 18 infants treated before age six months made no meaningful gains in motor function and six of 18 became dependent on ventilatory assistance. A variety of predictors of poor prognosis were observed, including increase in muscle glycogen during therapy, high IgG titers to alpha glucosidase, and CRIM negativity. In summary, when compared to an untreated cohort, a majority of those in whom ERT was initiated before age six months and before the need for ventilatory assistance had improved survival, improved ventilator-independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills. Longer-term survivors who underwent early ERT may show sustained improvement in cardiac and motor function [Prater et al 2012]. Factors predicting poor response are incompletely understood and may only be deduced for any given individual by therapeutic trial. While the long-term prognosis is as yet unknown, available studies suggest better cognitive outcomes than had been predicted. Assessment of cognitive abilities is difficult in young children (age <5 years) with infantile Pompe disease, and typical assessment tools frequently underestimate the cognitive abilities of these children [Kishnani et al 2009, Nicolino et al 2009, Ebbink et al 2012]. In late-onset disease, the major morbidities are motor disability and respiratory insufficiency. In a randomized double-blind placebo-controlled study of 90 affected individuals age eight years and older who were ambulatory and free of invasive ventilatory support at baseline, those receiving the active agent had better preservation of motor function and forced vital capacity at the 78th week evaluation point [van der Ploeg et al 2010]. Similar findings were demonstrated in an open label trial [Strothotte et al 2010]. Prevention of Secondary ComplicationsInfections need to be aggressively managed.Immunizations need to be kept current.Patients and household members should receive annual influenza vaccinations.Respiratory syncytial virus (RSV) prophylaxis (palivizumab) should be administered in the first two years.Anesthesia should be used only when absolutely necessary because reduced cardiovascular return and underlying respiratory insufficiency pose significant risks.SurveillanceClose follow up is indicated. Management and surveillance guidelines have been proposed by the ACMG Work Group on Management of Pompe Disease [Kishnani et al 2006b]:Twice-yearly clinical review of development, clinical status, growth, and use of adaptive equipmentAssessment of respiratory status with each visit with regard to cough, difficulty breathing, wheezing, fatigability, and exercise tolerance:Chest x-rays at regular intervalsPulmonary function tests; yearly or more frequently as indicatedPeriodic sleep evaluation, which may include regular capnography and pulse oximetryMonitoring of overall musculoskeletal and functional status to guide therapies aimed at preventing or minimizing physical impairment and its complications. This may include assessment for scoliosis and bone densitometry.Regular nutritional and feeding assessmentAt least annual renal function studies to monitor for secondary complications related to cardiac and/or pulmonary impairment as well as medication effectsAnnual cardiology evaluation in late-onset disease and as needed for infantile-onset disease:Periodic echocardiography. Aortic dilatation has been detected by echocardiography in late-onset Pompe disease [El-Gharbawy et al 2011]. Twenty-four-hour ambulatory ECG at baseline and at regular intervals [Cook et al 2006]Screening for cerebral arteriopathy with aneurysmal dilation and rupture leading to cerebral infarcts (strokes) and death, which have also been reported [Laforêt et al 2008, Sacconi et al 2010]. Screening strategies for these findings are being developed, but care teams should have a high index of suspicion for cerebral arteriopathy if an individual with late-onset Pompe disease develops unexplained stroke-like symptoms [Sacconi et al 2010]. Annual hearing evaluationAgents/Circumstances to AvoidUse of standard drugs for treatment of cardiac manifestations may be contraindicated in certain stages of the disease. The use of digoxin, ionotropes, diuretics, and afterload-reducing agents may worsen left ventricular outflow obstruction, although they may be indicated in later stages of the disease.Hypotension and volume depletion should be avoided.Exposure to infectious agents is to be avoided.Evaluation of Relatives at RiskIt is appropriate to offer sibs of a proband either testing of GAA enzyme activity or molecular genetic testing (if the disease-causing mutations have been identified in an affected family member) so that morbidity and mortality can be reduced by early diagnosis and treatment with ERT.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Most individuals with infantile Pompe disease have not reproduced. Many adults with late-onset disease have reproduced. At least one woman treated with ERT during pregnancy and lactation with no adverse effects on the fetus has been reported [de Vries et al 2011]. As would be expected in a woman with a myopathy and respiratory insufficiency, the growing fetus may pose additional complications to the mother’s health. Careful respiratory and cardiac surveillance should be initiated in consultation with maternal fetal medicine specialists.Therapies Under InvestigationGene therapy to correct the underlying enzyme defect is under investigation [Raben et al 2002, DeRuisseau et al 2009, Mah et al 2010]. A Phase I/II trial to investigate the ability of AAV- alpha glucosidase to improve ventilation is currently in progress [Byrne et al 2011]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherExperience with bone marrow transplantation in both humans and cattle with acid alpha-glucosidase deficiency is limited; to date, such treatment is not considered successful [Hirschhorn & Reuser 2001].
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Glycogen Storage Disease Type II (Pompe Disease): Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGAA17q25.3
Lysosomal alpha-glucosidaseGlucosidase, alpha, acid (Pompe disease) (GAA) @ LOVD CCHMC - Human Genetics Mutation DatabaseGAAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Glycogen Storage Disease Type II (Pompe Disease) (View All in OMIM) View in own window 232300GLYCOGEN STORAGE DISEASE II 606800GLUCOSIDASE, ALPHA, ACID; GAANormal allelic variants. GAA is approximately 20 kb in length and contains 20 exons. The cDNA is over 3.6 kb in length with 2859 nucleotides of coding sequence. At least 47 normal allelic variants are known in GAA. Two polymorphic variants (and the "normal" variant) are responsible for the three known alloenzymes (GAA1, GAA2, and GAA4).Pathologic allelic variants. More than 150 mutations in GAA have been identified in individuals with Pompe disease. See Table A.Nonsense mutations, large and small gene rearrangements, and splicing defects have been observed. Many mutations are potentially specific to families, geographic regions, or ethnicities. Combinations of mutations that result in complete absence of GAA enzyme activity are seen more commonly in individuals with infantile-onset disease, whereas those combinations that allow partial enzyme activity typically have a later-onset presentation.Table 5. GAA Pathologic Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change Reference Sequencesc.525delTp.Glu176Argfs*45NM_000152.3 NP_000143.2c.336-13T>G (IVS1 -13T>G)--c.1935C>Ap.Asp645Gluc.2560C>Tp.Arg854*c.2482_2646del (Exon 18 del)p.Gly828_Asn882delSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. GAA is a lysosomal enzyme that catalyzes α-1,4- and α-1,6-glucosidic linkages at acid pH. There are seven glycosylation sites. The immature protein consists of 952 amino acids with a predicted non-glycosylated weight of 105 kd. The mature enzyme exists in either 76-kd or 70-kd form as a monomer.Abnormal gene product. GAA mutations result in mRNA instability and/or severely truncated acid alpha-glucosidase or an enzyme with markedly decreased activity.