# 232300

GLYCOGEN STORAGE DISEASE II; GSD2


Alternative titles; symbols

GSD II
ACID ALPHA-GLUCOSIDASE DEFICIENCY
GAA DEFICIENCY
POMPE DISEASE
GLYCOGENOSIS, GENERALIZED, CARDIAC FORM
CARDIOMEGALIA GLYCOGENICA DIFFUSA
ACID MALTASE DEFICIENCY; AMD
ALPHA-1,4-GLUCOSIDASE DEFICIENCY


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q25.3 Glycogen storage disease II 232300 AR 3 GAA 606800
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Ears
- Hearing loss
Mouth
- Macroglossia
CARDIOVASCULAR
Heart
- Cardiomegaly
- Shortened P-R interval on EKG
- Huge QRS complexes
- Wolf-Parkinson-White syndrome
Vascular
- Cerebral artery aneurysm
RESPIRATORY
- Respiratory failure due to muscle weakness
- Dyspnea
- Respiratory infections
CHEST
Ribs Sternum Clavicles & Scapulae
- Diaphragmatic paralysis
ABDOMEN
Liver
- Hepatomegaly
Spleen
- Splenomegaly
MUSCLE, SOFT TISSUES
- Weakness
- Proximal muscle weakness
- Myopathic pattern on EMG
- Firm muscles
NEUROLOGIC
Central Nervous System
- Hypotonia
- Abnormal brain myelination
Peripheral Nervous System
- Absent deep tendon reflexes
METABOLIC FEATURES
- Fever of central origin
LABORATORY ABNORMALITIES
- Elevated serum creatine kinase
- Elevated AST and LDH, especially infantile-onset
- Presence of vacuoles on muscle biopsy
- Deficiency of alpha-1,4-glucosidase (acid maltase)
MISCELLANEOUS
- Two presentations - rapid, fatal disorder of infancy and slowly progressive muscular disorder of childhood
- Patients with later onset have better prognosis
- Incidence of 1 in 40,000 infants worldwide
MOLECULAR BASIS
- Caused by mutation in the alpha-1,4-glucosidase gene (GAA, 606800.0002)
Glycogen storage disease - PS232200 - 24 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p31.3 Congenital disorder of glycosylation, type It AR 3 614921 PGM1 171900
1p21.2 Glycogen storage disease IIIb AR 3 232400 AGL 610860
1p21.2 Glycogen storage disease IIIa AR 3 232400 AGL 610860
3p12.2 Glycogen storage disease IV AR 3 232500 GBE1 607839
3q24 ?Glycogen storage disease XV AR 3 613507 GYG1 603942
7p13 Glycogen storage disease X AR 3 261670 PGAM2 612931
7q36.1 Glycogen storage disease of heart, lethal congenital AD 3 261740 PRKAG2 602743
11p15.1 Glycogen storage disease XI AR 3 612933 LDHA 150000
11q13.1 McArdle disease AR 3 232600 PYGM 608455
11q23.3 Glycogen storage disease Ib AR 3 232220 SLC37A4 602671
11q23.3 Glycogen storage disease Ic AR 3 232240 SLC37A4 602671
12p12.1 Glycogen storage disease 0, liver AR 3 240600 GYS2 138571
12q13.11 Glycogen storage disease VII AR 3 232800 PFKM 610681
14q22.1 Glycogen storage disease VI AR 3 232700 PYGL 613741
16p11.2 Glycogen storage disease XII AR 3 611881 ALDOA 103850
16p11.2 Glycogen storage disease IXc AR 3 613027 PHKG2 172471
16q12.1 Phosphorylase kinase deficiency of liver and muscle, autosomal recessive AR 3 261750 PHKB 172490
17p13.2 Glycogen storage disease XIII AR 3 612932 ENO3 131370
17q21.31 Glycogen storage disease Ia AR 3 232200 G6PC 613742
17q25.3 Glycogen storage disease II AR 3 232300 GAA 606800
19q13.33 Glycogen storage disease 0, muscle AR 3 611556 GYS1 138570
Xp22.13 Glycogen storage disease, type IXa2 XLR 3 306000 PHKA2 300798
Xp22.13 Glycogen storage disease, type IXa1 XLR 3 306000 PHKA2 300798
Xq13.1 Muscle glycogenosis XLR 3 300559 PHKA1 311870

TEXT

A number sign (#) is used with this entry because glycogen storage disease II (GSD2) is caused by homozygous or compound heterozygous mutation in the GAA gene (606800), which encodes acid alpha-1,4-glucosidase, also known as acid maltase, on chromosome 17q25.


Description

Glycogen storage disease II (GSD2), an autosomal recessive disorder, is the prototypic lysosomal storage disease. In the classic infantile form, 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).


Clinical Features

Infantile Onset

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.

Korlimarla et al. (2020) examined CNS involvement in 12 children with infantile-onset Pompe disease (IPD) and 2 children with late-onset Pompe disease (LOPD) who were receiving enzyme replacement therapy. They quantified brain white matter hyperintense foci by using the Fazekas scale (FS) grading system to score MRI findings in 10 brain areas. The FS scores were then compared to measurements of cognition and language. In 10 of the 12 children with IPD, with a median age of 10.6 years, mild to severe white matter hyperintense foci were seen. The lesions were seen throughout the corticospinal tracts of the brain. Two children with IPD had no white matter hyperintense foci. There were no significant relationships between total FS scores and age of the patient, anatomic areas of the brain, duration of treatment, duration of disease, or the patients' GAA mutations. No white matter hyperintense foci were seen in the 2 children with LOPD. Ten children with IPD and 2 children with LOPD completed cognitive assessments. Full-scale Wechsler IQ scores in patients with IPD ranged from significantly below average in 3 children to significantly above average in 1 child. These scores were average or above average in the 2 patients with LOPD. CELF-5 scores in patients with IPD on core language, language index, and expressive language index ranged from below average to above average. All language scores were above average in 1 LOPD patient and average and below average in the other LOPD patient. There were no significant relationships between FS scores and standard scores on each cognitive or language domain. Korlimarla et al. (2020) concluded that characterizing baseline and serial white matter hyperintense lesions in patients with Pompe disease is important for the longitudinal follow-up of disease.

Herbert et al. (2019) reported 4 patients who had onset of clinical features of Pompe disease between 20 days and 20 months of age and were compound heterozygous for the common GAA intron 1 mutation (IVS1-13T-G; 606800.0006), thought to lead to mild, adult-onset disease, and a different second GAA mutation. All 4 patients had delayed motor development and characteristic posture and movement abnormalities; 2 patients had feeding difficulty, and 2 patients had sleep apnea. None of the patients had cardiac involvement. Despite enzyme replacement therapy, all of the patients had residual muscle weakness.

Among a cohort of 41 children with infantile-onset Pompe disease (IPD) on enzyme replacement therapy, Tan et al. (2015) identified 8 who developed precocious pubarche (19.5%), including 4 males and 4 females. Of these, 5 had classic IPD and 3 had atypical IPD. The age at onset of pubarche ranged from 14 months to 4 years 2 months for those with classic IPD; the 3 patients with atypical IPD had a later age of onset at age 7 years. The etiology of precocious pubarche in IPD was unclear. The authors noted that monitoring for sexual development and function is needed for children and adolescents with IPD because premature pubarche can be associated with development of glucose intolerance, insulin resistance, and/or ovarian hyperandrogenism.

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; 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 intron 1 mutation in the GAA gene (IVS1-13T-G; 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.

Jones et al. (2021) assessed the tongue phenotype of 70 individuals with LOPD, including 10 individuals who had never received treatment, compared to 30 individuals with other forms of myopathy and 30 individuals with neuropathy. Patients with LOPD had reduced maximal lingual strength compared to individuals with other myopathies and individuals with neuropathy. Patients with LOPD also had reduced tongue muscle thickness as measured by ultrasound compared to individuals with other myopathies and individuals with neuropathy, suggesting fibrofatty replacement and muscle atrophy in LOPD.

Huggins et al. (2022) reported clinical features in 20 patients, aged 6 to 21 months, who were diagnosed with LOPD. All 20 patients were initially detected due to abnormal newborn screening and found to have mutations in the GAA gene. Four patients were homozygous for the c.-32-13T-G (606800.0006) mutation and 14 were heterozygous for the c.-32-13T-G mutation and a second mutation. None of the patients had cardiomyopathy or cardiac rhythm abnormalities. Laboratory abnormalities included increased CK, AST, and ALT in 8 patients and increased urine Glc4 in 2 patients. Nine patients, including the 4 patients who were homozygous for the c.-32-13T-G mutation, had normal CK, AST, and ALT. All of the patients had abnormal postural and kinematic findings, and the most common abnormalities included lack of appropriate use of hip extensors, increased hip external rotation while sitting, and tight iliotibial bands. Nine patients had mild feeding and swallowing impairment, but signs of dysphagia and aspiration were mild. Huggins et al. (2022) concluded that there is a great amount of clinical variability among patients with LOPD and that patients should be closely monitored for progression of symptoms.


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.


Pathogenesis

The defect in type II glycogen storage disease involves acid alpha-1,4-glucosidase (acid maltase), a lysosomal enzyme. Whereas the glycogen is distributed rather uniformly in the cytoplasm in the other glycogen storage diseases (e.g., GSD I; 232200), it is enclosed in lysosomal membranes in this form.

In a case of infantile acid alpha-glucosidase deficiency, Beratis et al. (1978) concluded that the defect was a structural mutation causing synthesis of a catalytically inactive, cross-reacting material (CRM)-positive, enzyme protein. On the other hand, the mutation in the adult form causes a reduction in the amount of enzyme protein. Of 9 fibroblast lines from patients with the infantile form of acid alpha-glucosidase deficiency, Beratis et al. (1983) found that 8 were CRM-negative and 1 was CRM-positive. No difference in apparent enzyme activity was detected between the 2 forms. In 2 fibroblast strains from the adult form, rocket immunoelectrophoresis showed a reduction in the amount of enzyme protein that was directly proportional to the reduction in enzyme activity. In another 'adult' fibroblast line, enzyme activity was in the same range as in the infantile form and no CRM was identified. Fibroblasts with phenotype 2 of acid alpha-glucosidase, considered a normal variant, showed reduction both in the amount of enzyme protein and in the ability to cleave glycogen; catalytic activity for maltose was normal, however.

Reuser et al. (1978) studied fibroblasts from the infantile, juvenile, and adult forms of acid alpha-glucosidase deficiency. An inverse correlation was found between the severity of clinical manifestations and the level of residual enzyme activity in fibroblasts. The kinetic and electrophoretic properties of residual enzyme in fibroblasts from adult patients were identical to those from controls. The mutation may, therefore, affect the production or degradation of enzyme rather than its catalytic function. Complementation studies by fusion of fibroblasts from different types yielded no sign of nonallelism of the several forms.

Reuser et al. (1987) investigated the nature of the acid alpha-glucosidase deficiency in cultured fibroblasts from 30 patients. Deficiency of catalytically active mature enzyme in lysosomes was common to all clinical phenotypes but, in most cases, was more profound in early-onset than in late-onset forms of the disease. The role of secondary factors cannot be excluded, however, because 3 adult patients were found with very low activity and little enzyme in the lysosomes.


Diagnosis

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.


Clinical Management

Slonim et al. (1983) and Margolis and Hill (1986) concluded that a high-protein diet is effective therapy in adults with acid maltase deficiency. Striking improvement in respiratory function was observed. The effect was serendipitously discovered when a high-protein diet for weight reduction was given. Correction of obesity was not thought to be the exclusive or even the major mechanism of the respiratory improvement. Isaacs et al. (1986) observed benefit from a high-protein, low-carbohydrate diet in a patient with adult acid maltase deficiency.

Amalfitano et al. (2001) reported the results of a phase I/II open-label single-dose study of recombinant human alpha-glucosidase infused intravenously twice weekly in 3 infants with infantile GSD II. The results of more than 250 infusions showed that recombinant human GAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all 3 infants. These infants lived well past the critical age of 1 year (16, 18, and 22 months old at the time of this study) and continued to have normal cardiac function. Improvements of skeletal muscle functions were also noted; 1 patient showed marked improvement and had normal muscle tone and strength as well as normal neurologic and developmental evaluations.

Van den Hout et al. (2003) studied the natural course of infantile Pompe disease in 20 Dutch patients and reviewed the findings in 133 published cases. They concluded that survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies.

Bembi et al. (2008) provided a detailed review of the clinical management of GSD II and emphasized a multidisciplinary approach. Enzyme replacement therapy with alglucosidase-alpha has been shown to be effective, particularly in infants.

Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.


Inheritance

Glycogen storage disease type II is inherited as an autosomal recessive trait.

Smith et al. (2007) studied sib phenotype discordance in classic infantile Pompe disease by reviewing the medical literature for affected sibships in which at least 1 sib had clinical or biochemical findings consistent with infantile Pompe disease, including symptoms beginning in infancy, early hypotonia, cardiomegaly by 6 months of age, and early death. Since 1931, the literature has documented 13 families with 31 affected infants (11 probands; 20 affected sibs). The median age at symptom onset for all affected infants was 3 months (range, 0-6 months) with a significant correlation between probands and affected sibs (R = 0.60, p = 0.04). The median age at death for all affected infants was 6 months (range, 1.5-13 months); probands were slightly older at death than their sibs. The median length of disease course for all affected infants was 3 months (range, 0-10 months) and was slightly longer for probands. There was phenotypic concordance, particularly with respect to cardiomyopathy. Smith et al. (2007) concluded that there is minimal phenotypic and life span variation among sibs with infantile Pompe disease, which is important for genetic counseling.


Molecular Genetics

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 (IVS1-13T-G; 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 the IVS1-13T-G mutation, present in heterozygosity in 34 (85%) of 40 patients (allele frequency 42.3%).

In a cohort of 84 patients with GSD II who had the common GAA IVS1-13T-G mutation, Herbert et al. (2019) identified 4 patients with different second mutations in GAA who had onset of clinical symptoms before age 2 years (range, 10 days to 20 months). Herbert et al. (2019) concluded that despite the prior impression that this common mutation leads to milder, adult-onset disease, it can lead to early-onset symptoms.

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).


Population Genetics

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: IVS1-13T-G (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.


Animal Model

Acid maltase-deficient Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position in the flip test. Kikuchi et al. (1998) injected 6 4-week-old acid maltase-deficient quails, with the clinical symptoms listed, with 14 or 4.2 mg/kg of the precursor form of recombinant human GAA enzyme or buffer alone every 2 to 3 days for 18 days (7 injections). On day 18, both high dose-treated birds (14 mg/kg) scored positive flip tests and flapped their wings, and 1 bird flew up more than 100 cm. GAA activity increased in most of the tissues examined. In heart and liver, glycogen levels dropped to normal and histopathology was normal. In pectoralis muscle, morphology was essentially normal, except for increased glycogen granules. In sharp contrast, sham-treated quail muscle had markedly increased glycogen granules, multivesicular autophagosomes, and inter- and intrafascicular fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved less biochemically and histopathologically than high dose birds, indicating a dose-dependent response. Additional experiments with intermediate doses and extended treatment halted the progression of the disease. Data were claimed to be the first to show that an exogenous protein can target to muscle and produce muscle improvement. The data also suggested that enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease.

In mice in whom the Gaa gene was disrupted by gene targeting in embryonic stem cells, Raben et al. (1998) found that homozygosity for the knockout was associated with lack of enzyme activity and accumulation of glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice had markedly reduced mobility and strength. They grew normally, however, reached adulthood, remained fertile, and, as in the human adult disease, older mice accumulated glycogen in the diaphragm. By 8 to 9 months of age, the animals developed obvious muscle wasting and a weak, waddling gait. In contrast, in a second model, mutant mice with deletion of exon 6, like the knockout mice with disruption of exon 13 reported by Bijvoet et al., 1998, had unimpaired strength and mobility (up to 6.5 months of age) despite indistinguishable biochemical and pathologic changes.

Bijvoet et al. (1999) produced recombinant human acid alpha-glucosidase on an industrial scale in the milk of transgenic rabbits, and administered the purified enzyme intravenously to knockout mice. Full correction of acid alpha-glucosidase activity was obtained in all tissues except brain after a single dose of 17mg/kg. Weekly enzyme infusions over a period of 6 months resulted in normalization of hepatic glycogen, but only partial degradation of lysosomal glycogen in heart, skeletal and smooth muscle. The tissue morphology improved substantially despite the advanced state of disease at the start of treatment. The authors stated that although neurologic symptoms had not been documented in human GSD II patients, the inability of the enzyme to cross the blood-brain barrier in the mouse model remained a point of concern.

Dennis et al. (2000) identified mutations in the bovine Gaa gene that led to generalized glycogenosis in Brahman and Shorthorn bovine breeds. All 3 mutations resulted in premature termination of translation. The authors also presented evidence for a missense mutation segregating with the Brahman population, which is responsible for a 70 to 80% reduction in alpha-glucosidase activity.

Using Gaa-knockout mice and transgenes containing cDNA for the human enzyme under muscle- or liver-specific promoters controlled by tetracycline, Raben et al. (2001) demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising less than 5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110-kD precursor form. Skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early.

DeRuisseau et al. (2009) found that Gaa-null mice had increased glycogen levels in cervical spinal cord motor neurons and larger soma size of phrenic neurons. Gaa-null mice had decreased ventilation during quiet breathing and hypercapnic challenge compared to wildtype mice, indicating respiratory insufficiency. Mice with skeletal muscle-specific Gaa expression (MTP) showed normal diaphragm force generation similar to wildtype mice, but decreased ventilation during quiet breathing, similar to Gaa-null mice. The compromised ventilation observed in both mutant mouse models was associated with decreased phrenic nerve motor output. Spinal cord samples from a patient with Pompe disease showed increased neuronal glycogen. DeRuisseau et al. (2009) suggested that respiratory impairment in individuals with Pompe disease results from a combination of muscular and neural deficits.

Douillard-Guilloux et al. (2010) analyzed the effect of a complete genetic elimination of glycogen synthesis in a murine GSDII model. Gaa/Gys1 (138570) double-knockout mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in Gaa/Gys1 double-knockout mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in Gaa/Gys1 double-knockout mice, resulting in improved exercise capacity. Douillard-Guilloux et al. (2010) concluded that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in the GSDII mouse model and offers a novel perspective for the treatment of Pompe disease.


REFERENCES

  1. Amalfitano, A., Bengur, A. R., Morse, R. P., Majure, J. M., Case, L. E., Veerling, D. L., Mackey, J., Kishnani, P., Smith, W., McVie-Wylie, A., Sullivan, J. A., Hoganson, G. E., Phillips, J. A., III, Schaefer, G. B., Charrow, J., Ware, R. E., Bossen, E. H., Chen, Y.-T. Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet. Med. 3: 132-138, 2001. [PubMed: 11286229, related citations]

  2. Amartino, H., Painceira, D., Pomponio, R. J., Niizawa, G., Sabio Paz, V., Blanco, M., Chamoles, N. Two clinical forms of glycogen-storage disease type II in two generations of the same family. (Letter) Clin. Genet. 69: 187-188, 2006. [PubMed: 16433701, related citations] [Full Text]

  3. Angelini, C., Engel, A. G., Titus, J. L. Adult acid maltase deficiency: abnormalities in fibroblasts cultured from patients. New Eng. J. Med. 287: 948-951, 1972. [PubMed: 4507329, related citations] [Full Text]

  4. Anneser, J. M. H., Pongratz, D. E., Podskarbi, T., Shin, Y. S., Schoser, B. G. H. Mutations in the acid alpha-glucosidase gene (M. Pompe) in a patient with an unusual phenotype. Neurology 64: 368-370, 2005. [PubMed: 15668445, related citations] [Full Text]

  5. Askanas, V., Engel, W. K., DiMauro, S., Brooks, B. R., Mehler, M. Adult-onset acid maltase deficiency: morphologic and biochemical abnormalities reproduced in cultured muscle. New Eng. J. Med. 294: 573-578, 1976. [PubMed: 1060914, related citations] [Full Text]

  6. Ausems, M. G. E. M., Lochman, P., van Diggelen, O. P., Ploos van Amstel, H. K., Reuser, A. J. J., Wokke, J. H. A. A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology 52: 851-853, 1999. [PubMed: 10078739, related citations] [Full Text]

  7. Ausems, M. G. E. M., Verbiest, J., Hermans, M. M. P., Kroos, M. A., Beemer, F. A., Wokke, J. H. J., Sandkuijl, L. A., Reuser, A. J. J., van der Ploeg, A. T. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Europ. J. Hum. Genet. 7: 713-716, 1999. [PubMed: 10482961, related citations] [Full Text]

  8. Banugaria, S. G., Prater, S. N., Ng, Y.-K., Kobori, J. A., Finkel, R. S., Ladda, R. L., Chen, Y.-T., Rosenberg, A. S., Kishnani, P. S. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet. Med. 13: 729-736, 2011. [PubMed: 21637107, images, related citations] [Full Text]

  9. Bashan, N., Potashnik, R., Barash, V., Gutman, A., Moses, S. W. Glycogen storage disease type II in Israel. Isr. J. Med. Sci. 24: 224-227, 1988. [PubMed: 3132435, related citations]

  10. Becker, J. A., Vlach, J., Raben, N., Nagaraju, K., Adams, E. M., Hermans, M. M., Reuser, A. J. J., Brooks, S. S., Tifft, C. J., Hirschhorn, R., Huie, M. L., Nicolino, M., Plotz, P. H. The African origin of the common mutation in African American patients with glycogen-storage disease type II. (Letter) Am. J. Hum. Genet. 62: 991-994, 1998. [PubMed: 9529346, related citations] [Full Text]

  11. Bembi, B., Cerini, E., Danesino, C., Donati, M. A., Gasperini, S., Morandi, L., Musumeci, O., Parenti, G., Ravaglia, S., Seidita, F., Toscano, A., Vianello, A. Diagnosis of glycogenosis type II. Neurology 71: S4-S11, 2008. [PubMed: 19047572, related citations] [Full Text]

  12. Bembi, B., Cerini, E., Danesino, C., Donati, M. A., Gasperini, S., Morandi, L., Musumeci, O., Parenti, G., Ravaglia, S., Seidita, F., Toscano, A., Vianello, A. Management and treatment of glycogenosis type II. Neurology 71: S12-S36, 2008. [PubMed: 19047571, related citations] [Full Text]

  13. Beratis, N. G., LaBadie, G. U., Hirschhorn, K. Characterization of the molecular defect in infantile and adult acid alpha-glucosidase deficiency fibroblasts. J. Clin. Invest. 62: 1264-1274, 1978. [PubMed: 34626, related citations] [Full Text]

  14. Beratis, N. G., LaBadie, G. U., Hirschhorn, K. Genetic heterogeneity in acid alpha-glucosidase deficiency. Am. J. Hum. Genet. 35: 21-33, 1983. [PubMed: 6401921, related citations]

  15. Besancon, A.-M., Castelnau, L., Nicolesco, H., Dumez, Y., Poenaru, L. Prenatal diagnosis of glycogenosis type II (Pompe's disease) using chorionic villi biopsy. Clin. Genet. 27: 479-482, 1985. [PubMed: 3891160, related citations] [Full Text]

  16. Bijvoet, A. G. A., Van Hirtum, H., Kroos, M. A., Van de Kamp, E. H. M., Schoneveld, O., Visser, P., Brakenhoff, J. P. J., Weggeman, M., van Corven, E. J., Van der Ploeg, A. T., Reuser, A. J. J. Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II. Hum. Molec. Genet. 8: 2145-2153, 1999. [PubMed: 10545593, related citations] [Full Text]

  17. Bijvoet, A. G., van de Kamp, E. H., Kroos, M. A., Ding, J. H., Yang, B. Z., Visser, P., Bakker, C. E., Verbeet, M. P., Oostra, B. A., Reuser, A. J. J., van der Ploeg, A. T. Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease. Hum. Molec. Genet. 7: 53-62, 1998. [PubMed: 9384603, related citations] [Full Text]

  18. Boerkoel, C. F., Exelbert, R., Nicastri, C., Nichols, R. C., Miller, F. W., Plotz, P. H., Raben, N. Leaky splicing mutation in the acid maltase gene is associated with delayed onset of glycogenosis type II. Am. J. Hum. Genet. 56: 887-897, 1995. [PubMed: 7717400, related citations]

  19. Bulkley, B. H., Hutchins, G. M. Pompe's disease presenting as hypertrophic myocardiopathy with Wolff-Parkinson-White syndrome. Am. Heart J. 96: 246-252, 1978. [PubMed: 277063, related citations] [Full Text]

  20. Byrne, E., Dennett, X., Crotty, B., Trounce, I., Sands, J. M., Hawkins, R., Hammond, J., Anderson, S., Haan, E. A., Pollard, A. Dominantly inherited cardioskeletal myopathy with lysosomal glycogen storage and normal acid maltase levels. Brain 109: 523-536, 1986. [PubMed: 3087571, related citations] [Full Text]

  21. Chancellor, A. M., Warlow, C. P., Webb, J. N., Lucas, M. G., Besley, G. T. N., Broadhead, D. M. Acid maltase deficiency presenting with a myopathy and exercise induced urinary incontinence in a 68 year old male. (Letter) J. Neurol. Neurosurg. Psychiat. 54: 659-660, 1991. [PubMed: 1895140, related citations] [Full Text]

  22. Danon, M. J., DiMauro, S., Shanske, S., Archer, F. L., Miranda, A. F. Juvenile-onset acid maltase deficiency with unusual familial features. Neurology 36: 818-822, 1986. [PubMed: 3084996, related citations] [Full Text]

  23. Davis, J., Goldman, M., Loh, L., Casson, M. Diaphragm function and alveolar hypoventilation. Quart. J. Med. 45: 87-100, 1976. [PubMed: 1062815, related citations]

  24. de Filippi, P., Ravaglia, S., Bembi, B., Costa, A., Moglia, A., Piccolo, G., Repetto, A., Dardis, A., Greco, G., Ciana, G., Canevari, F., Danesino, C. The angiotensin-converting enzyme insertion/deletion polymorphism modifies the clinical outcome in patients with Pompe disease. Genet. Med. 12: 206-211, 2010. [PubMed: 20308911, related citations] [Full Text]

  25. Dennis, J. A., Moran, C., Healy, P. J. The bovine alpha-glucosidase gene: coding region, genomic structure, and mutations that caused bovine generalized glycogenosis. Mammalian Genome 11: 206-212, 2000. [PubMed: 10723725, related citations] [Full Text]

  26. DeRuisseau, L. R., Fuller, D. D., Qiu, K., DeRuisseau, K. C., Donnelly, W. H., Jr., Mah, C., Reier, P. J., Byrne, B. J. Neural deficits contribute to respiratory insufficiency in Pompe disease. Proc. Nat. Acad. Sci. 106: 9419-9424, 2009. [PubMed: 19474295, images, related citations] [Full Text]

  27. Douillard-Guilloux, G., Raben, N., Takikita, S., Ferry, A., Vignaud, A., Guillet-Deniau, I., Favier, M., Thurberg, B. L., Roach, P. J., Caillaud, C., Richard, E. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Hum. Molec. Genet. 19: 684-696, 2010. [PubMed: 19959526, images, related citations] [Full Text]

  28. Dreyfus, J.-C., Poenaru, L. Alpha glucosidases in white blood cells, with reference to the detection of acid alpha 1-4 glucosidase deficiency. Biochem. Biophys. Res. Commun. 85: 615-622, 1978. [PubMed: 367369, related citations] [Full Text]

  29. Engel, A. G. Acid maltase deficiency in adults: studies in four cases of a syndrome which may mimic muscular dystrophy or other myopathies. Brain 93: 599-616, 1970. [PubMed: 4918728, related citations] [Full Text]

  30. Forsha, D., Li, J. S., Smith, P. B., van der Ploeg, A. T., Kishnani, P., Pasquali, S. K. Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy. Genet. Med. 13: 625-631, 2011. [PubMed: 21543987, related citations] [Full Text]

  31. Francesconi, M., Auff, E. Cardiac arrhythmias and the adult form of type II glycogenosis. (Letter) New Eng. J. Med. 306: 937-938, 1982. [PubMed: 6950223, related citations] [Full Text]

  32. Groen, W. B., Leen, W. G., Vos, A. M. C., Cruysberg, J. R. M., van Doorn, P. A., van Engelen, B. G. M. Ptosis as a feature of late-onset glycogenosis type II. Neurology 67: 2261-2262, 2006. [PubMed: 17190962, related citations] [Full Text]

  33. Hagemans, M. L. C., Winkel, L. P. F., Hop, W. C. J., Reuser, A. J. J., Van Doorn, P. A., Van der Ploeg, A. T. Disease severity in children and adults with Pompe disease related to age and disease duration. Neurology 64: 2139-2141, 2005. [PubMed: 15985590, related citations] [Full Text]

  34. Herbert, M., Case, L. E., Rairikar, M., Cope, H., Bailey, L., Austin, S. L., Kishnani, P. S. Early-onset of symptoms and clinical course of Pompe disease associated with the c.-32-13T-G variant. Molec. Genet. Metab. 126: 106-116, 2019. [PubMed: 30655185, related citations] [Full Text]

  35. Hers, H. G. Alpha-glucosidase deficiency in generalized glycogen-storage disease (Pompe's disease). Biochem. J. 86: 11-16, 1963. [PubMed: 13954110, related citations] [Full Text]

  36. Hirschhorn, K., Nadler, H. L., Waithe, W. I., Brown, B. I., Hirschhorn, R. Pompe's disease: detection of heterozygotes by lymphocyte stimulation. Science 166: 1632-1633, 1969. [PubMed: 5360584, related citations] [Full Text]

  37. Hoefsloot, L. H., van der Ploeg, A. T., Kroos, M. A., Hoogeveen-Westerveld, M., Oostra, B. A., Reuser, A. J. J. Adult and infantile glycogenosis type II in one family, explained by allelic diversity. Am. J. Hum. Genet. 46: 45-52, 1990. [PubMed: 2403755, related citations]

  38. Hudgson, P., Gardner-Medwin, D., Worsfold, M., Pennington, R. J. T., Walton, J. N. Adult myopathy from glycogen storage disease due to acid maltase deficiency. Brain 91: 435-462, 1968. [PubMed: 5247277, related citations] [Full Text]

  39. Huggins, E., Holland, M., Case, L. E., Blount, J., Landstrom, A. P., Jones, H. N., Kishnani, P. S. Early clinical phenotype of late onset Pompe disease: lessons learned from newborn screening. Molec. Genet. Metab. 135: 179-185, 2022. [PubMed: 35123877, related citations] [Full Text]

  40. Iancu, T. C., Lerner, A., Shiloh, H., Bashan, N., Moses, S. Juvenile acid maltase deficiency presenting as paravertebral pseudotumour. Europ. J. Pediat. 147: 372-376, 1988. [PubMed: 3135192, related citations] [Full Text]

  41. Isaacs, H., Savage, N., Badenhorst, M., Whistler, T. Acid maltase deficiency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J. Neurol. Neurosurg. Psychiat. 49: 1011-1018, 1986. [PubMed: 3093639, related citations] [Full Text]

  42. Jones, H. N., Hobson-Webb, L. D., Kuchibhatia, M., Crisp, K. D., Whyte-Rayson, A., Batten, M. T., Zwelling, P. J., Kishnani, P. S. Tongue weakness and atrophy differentiates late-onset Pompe disease from other forms of acquired/hereditary myopathy. Molec. Genet. Metab. 133: 261-268, 2021. [PubMed: 34053870, related citations] [Full Text]

  43. Kallwass, H., Carr, C., Gerrein, J., Titlow, M., Pomponio, R., Bali, D., Dai, J., Kishnani, P., Skrinar, A., Corzo, D., Keutzer, J. Rapid diagnosis of late-onset Pompe disease by fluorometric assay of alpha-glucosidase activities in dried blood spots. Molec. Genet. Metab. 90: 449-452, 2007. Note: Erratum: Molec. Genet. Metab. 92: 285 only, 2007. [PubMed: 17270480, related citations] [Full Text]

  44. Karpati, G., Carpenter, S., Eisen, A., Aube, M., DiMauro, S. The adult form of acid maltase (alpha-1,4-glucosidase) deficiency. Ann. Neurol. 1: 276-280, 1977. [PubMed: 889315, related citations] [Full Text]

  45. Kikuchi, T., Yang, H. W., Pennybacker, M., Ichihara, N., Mizutani, M., Van Hove, J. L. K., Chen, Y.-T. Clinical and metabolic correction of Pompe disease by enzyme therapy in acid maltase-deficient quail. J. Clin. Invest. 101: 827-833, 1998. [PubMed: 9466978, related citations] [Full Text]

  46. Korlimarla, A., Spiridigliozzi, G. A., Crisp, K., Herbert, M., Chen, S., Malinzak, M., Stefanescu, M., Austin, S. L., Cope, H., Zimmerman, K., Jones, H., Provenzale, J. M., Kishnani, P. S. Novel approaches to quantify CNS involvement in children with Pompe disease. Neurology 95: e718-e732, 2020. Note: Electronic Article. [PubMed: 32518148, related citations] [Full Text]

  47. Koster, J. F., Busch, H. F. M., Slee, R. G., van Weerden, T. W. Glycogenosis type II: the infantile- and late-onset acid maltase deficiency observed in one family. Clin. Chim. Acta 87: 451-453, 1978. [PubMed: 28188, related citations] [Full Text]

  48. Kretzschmar, H. A., Wagner, H., Hubner, G., Danek, A., Witt, T. N., Mehraein, P. Aneurysms and vacuolar degeneration of cerebral arteries in late-onset acid maltase deficiency. J. Neurol. Sci. 98: 169-183, 1990. [PubMed: 2243227, related citations] [Full Text]

  49. Kroos, M. A., Van der Kraan, M., Van Diggelen, O. P., Kleijer, W. J., Reuser, A. J. J., Van den Boogaard, M. J., Ausems, M. G. E. M., Ploos van Amstel, H. K., Poenaru, L., Nicolino, M., Wevers, R. Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients. J. Med. Genet. 32: 836-837, 1995. [PubMed: 8558570, related citations] [Full Text]

  50. Kroos, M. A., Van der Kraan, M., Van Diggelen, O. P., Kleijer, W. J., Reuser, A. J. J. Two extremes of the clinical spectrum of glycogen storage disease type II in one family: a matter of genotype. Hum. Mutat. 9: 17-22, 1997. [PubMed: 8990003, related citations] [Full Text]

  51. Laforet, P., Nicolino, M., Eymard, B., Puech, J. P., Caillaud, C., Poenaru, L., Fardeau, M. Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 55: 1122-1128, 2000. [PubMed: 11071489, related citations] [Full Text]

  52. Lam, C. W., Yuen, Y. P., Chan, K. Y., Tong, S. F., Lai, C. K., Chow, T. C., Lee, K. C., Chan, Y. W., Martiniuk, F. Juvenile-onset glycogen storage disease type II with novel mutations in acid alpha-glucosidase gene. Neurology 60: 715-717, 2003. [PubMed: 12601120, related citations] [Full Text]

  53. Loonen, M. C. B., Busch, H. F. M., Koster, J. F., Martin, J. J., Niermeijer, M. F., Schram, A. W., Brouwer-Kelder, B., Mekes, W., Slee, R. G., Tager, J. M. A family with different clinical forms of acid maltase deficiency (glycogenosis type II): biochemical and genetic studies. Neurology 31: 1209-1216, 1981. [PubMed: 6810200, related citations] [Full Text]

  54. Loonen, M. C. B., Schram, A. W., Koster, J. F., Niermeijer, M. F., Busch, H. F. M., Martin, J. J., Brouwer-Kelder, B., Mekes, W., Slee, R. G., Tager, J. M. Identification of heterozygotes for glycogenosis 2 (acid maltase deficiency). Clin. Genet. 19: 55-63, 1981. [PubMed: 7006871, related citations] [Full Text]

  55. Makos, M. M., McComb, R. D., Hart, M. N., Bennett, D. R. Alpha-glucosidase deficiency and basilar artery aneurysm: report of a sibship. Ann. Neurol. 22: 629-633, 1987. [PubMed: 3322184, related citations] [Full Text]

  56. Margolis, M. L., Hill, A. R. Acid maltase deficiency in an adult: evidence for improvement in respiratory function with high-protein dietary therapy. Am. Rev. Resp. Dis. 134: 328-331, 1986. [PubMed: 3090917, related citations] [Full Text]

  57. Martiniuk, F., Bodkin, M., Tzall, S., Hirschhorn, R. Identification of the base-pair substitution responsible for a human acid alpha glucosidase allele with lower 'affinity' for glycogen (GAA 2) and transient gene expression in deficient cells. Am. J. Hum. Genet. 47: 440-445, 1990. [PubMed: 2203258, related citations]

  58. Martiniuk, F., Chen, A., Mack, A., Arvanitopoulos, E., Chen, Y., Rom, W. N., Codd, W. J., Hanna, B., Alcabes, P., Raben, N., Plotz, P. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. (Letter) Am. J. Med. Genet. 79: 69-72, 1998. [PubMed: 9738873, related citations] [Full Text]

  59. Matsuishi, T., Yoshino, M., Terasawa, K., Nonaka, I. Childhood acid maltase deficiency: a clinical, biochemical, and morphologic study of three patients. Arch. Neurol. 41: 47-52, 1984. [PubMed: 6360103, related citations] [Full Text]

  60. Mehler, M., DiMauro, S. Residual acid maltase activity in late-onset acid maltase deficiency. Neurology 27: 178-184, 1977. [PubMed: 264606, related citations] [Full Text]

  61. Molho, M., Katz, I., Schwartz, E., Shemesh, Y., Sadeh, M., Wolf, E. Familial bilateral paralysis of diaphragm: adult onset. Chest 91: 466-467, 1987. [PubMed: 3816327, related citations] [Full Text]

  62. Montalvo, A. L. E., Bembi, B., Donnarumma, M., Filocamo, M., Parenti, G., Rossi, M., Merlini, L., Buratti, E., De Filippi, P., Dardis, A., Stroppiano, M., Ciana, G., Pittis, M. G. Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum. Mutat. 27: 999-1006, 2006. [PubMed: 16917947, related citations] [Full Text]

  63. Nishimoto, J., Inui, K., Okada, S., Ishigami, W., Hirota, S., Yamano, T., Yabuuchi, H. A family with pseudodeficiency of acid alpha-glucosidase. Clin. Genet. 33: 254-261, 1988. [PubMed: 3282727, related citations] [Full Text]

  64. Pompe, J. C. Over idiopathische hypertrophie van het hart. Ned. Tijdschr. Geneeskd. 76: 304-312, 1932.

  65. Pongratz, D., Schlossmacher, I., Koppenwallner, C., Hubner, G. An especially mild myopathic form of glycogenosis type II. Problems of clinical and light microscopic diagnosis. Path. Europ. 11: 39-44, 1976. [PubMed: 132627, related citations]

  66. Prater, S. N., Banugaria, S. G., DeArmey, S. M., Botha, E. G., Stege, E. M., Case, L. E., Jones, H. N., Phornphutkul, C., Wang, R. Y., Young, S. P., Kishnani, P. S. The emerging phenotype of long-term survivors with infantile Pompe disease. Genet. Med. 14: 800-810, 2012. [PubMed: 22538254, images, related citations] [Full Text]

  67. Raben, N., Lu, N., Nagaraju, K., Rivera, Y., Lee, A., Yan, B., Byrne, B., Meikle, P. J., Umapathysivam, K., Hopwood, J. J., Plotz, P. H. Conditional tissue-specific expression of the acid alpha-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy. Hum. Molec. Genet. 10: 2039-2047, 2001. [PubMed: 11590121, related citations] [Full Text]

  68. Raben, N., Nagaraju, K., Lee, E., Kessler, P., Byrne, B., Lee, L., LaMarca, M., King, C., Ward, J., Sauer, B., Plotz, P. Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J. Biol. Chem. 273: 19086-19092, 1998. [PubMed: 9668092, related citations] [Full Text]

  69. Reuser, A. J. J., Koster, J. F., Hoogeveen, A., Galjaard, H. Biochemical, immunological and cell genetic studies in glycogenosis type II. Am. J. Hum. Genet. 30: 132-143, 1978. [PubMed: 350041, related citations]

  70. Reuser, A. J. J., Kroos, M., Willemsen, R., Swallow, D., Tager, J. M., Galjaard, H. Clinical diversity in glycogenosis type II: biosynthesis and in situ localization of acid alpha-glucosidase in mutant fibroblasts. J. Clin. Invest. 79: 1689-1699, 1987. [PubMed: 3108320, related citations] [Full Text]

  71. Rosenow, E. C., Engel, A. G. Acid maltase deficiency in adults presenting as respiratory failure. Am. J. Med. 64: 485-491, 1978. [PubMed: 345804, related citations] [Full Text]

  72. Salafsky, I. S., Nadler, H. L. Deficiency of acid alpha glucosidase in the urine of patients with Pompe disease. J. Pediat. 82: 294-298, 1973. [PubMed: 4265199, related citations] [Full Text]

  73. Shanske, S., DiMauro, S. Late-onset acid maltase deficiency: biochemical studies of leukocytes. J. Neurol. Sci. 50: 57-62, 1981. [PubMed: 7014786, related citations] [Full Text]

  74. Sivak, E. D., Salanga, V. D., Wilbourn, A. J., Mitsumoto, H., Golish, J. Adult-onset acid maltase deficiency presenting as diaphragmatic paralysis. Ann. Neurol. 9: 613-615, 1981. [PubMed: 6789760, related citations] [Full Text]

  75. Slonim, A. E., Bulone, L., Ritz, S., Goldberg, T., Chen, A., Martiniuk, F. Identification of two subtypes of infantile acid maltase deficiency. J. Pediat. 137: 283-285, 2000. [PubMed: 10931430, related citations] [Full Text]

  76. Slonim, A. E., Coleman, R. A., McElligot, M. A., Najjar, J., Hirschhorn, K., Labadie, G. U., Mrak, R., Evans, O. B., Shipp, E., Presson, R. Improvement of muscle function in acid maltase deficiency by high-protein therapy. Neurology 33: 34-38, 1983. [PubMed: 6401355, related citations] [Full Text]

  77. Smith, H. L., Amick, L. D., Sidbury, J. B., Jr. Type II glycogenosis. Am. J. Dis. Child. 3: 475-481, 1966.

  78. Smith, J., Zellweger, H., Afifi, A. K. Muscular form of glycogenosis, type II (Pompe). Neurology 17: 537-549, 1967. [PubMed: 5229488, related citations] [Full Text]

  79. Smith, W. E., Sullivan-Saarela, J. A., Li, J. S., Cox, G. F., Corzo, D., Chen, Y.-T., Kishnani, P. S. Sibling phenotype concordance in classical infantile Pompe disease. Am. J. Med. Genet. 143A: 2493-2501, 2007. [PubMed: 17853454, related citations] [Full Text]

  80. Suzuki, Y., Tsuji, A., Omura, K., Nakamura, G., Awa, S., Kroos, M., Reuser, A. J. J. Km mutant of acid alpha-glucosidase in a case of cardiomyopathy without signs of skeletal muscle involvement. Clin. Genet. 33: 376-385, 1988. [PubMed: 3288378, related citations] [Full Text]

  81. Swaiman, K. F., Kennedy, W. R., Sauls, H. S. Late infantile acid maltase deficiency. Arch. Neurol. 18: 642-648, 1968. [PubMed: 5240358, related citations] [Full Text]

  82. Tan, Q. K.-G., Stockton, D. W., Pivnick, E., Choudhri, A. F., Hines-Dowell, S., Pena, L. D. M., Deimling, M. A., Freemark, M. S., Kishnani, P. S. Premature pubarche in children with Pompe disease. J. Pediat. 166: 1075-1078, 2015. [PubMed: 25687635, related citations] [Full Text]

  83. Taniguchi, N., Kato, E., Yoshida, H., Iwaki, S., Ohki, T., Koizumi, S. Alpha-glucosidase activity in human leukocytes: choice of lymphocytes for the diagnosis of Pompe's disease and the carrier state. Clin. Chim. Acta 89: 293-299, 1978. [PubMed: 361294, related citations] [Full Text]

  84. Trend, P. St. J., Wiles, C. M., Spencer, G. T., Morgan-Hughes, J. A., Lake, B. D., Patrick, A. D. Acid maltase deficiency in adults: diagnosis and management in five cases. Brain 108: 845-860, 1985. [PubMed: 3865697, related citations] [Full Text]

  85. van den Hout, H. M. P., Hop, W., van Diggelen, O. P., Smeitink, J. A. M., Smit, G. P. A., Poll-The, B.-T. T., Bakker, H. D., Loonen, M. C. B., de Klerk, J. B. C., Reuser, A. J. J., van der Ploeg, A. T. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature. Pediatrics 112: 332-340, 2003. [PubMed: 12897283, related citations] [Full Text]

  86. Walvoort, H. C., Dormans, J. A. M. A., van den Ingh, T. S. G. A. M. Comparative pathology of the canine model of glycogen storage disease type II (Pompe's disease). J. Inherit. Metab. Dis. 8: 38-46, 1985. [PubMed: 3921759, related citations] [Full Text]

  87. Wang, R. Y., Bodamer, O. A., Watson, M. S., Wilcox, W. R. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet. Med. 13: 457-484, 2011. [PubMed: 21502868, related citations] [Full Text]

  88. Wokke, J. H. J., Ausems, M. G. E. M., van den Boogaard, M.-J. H., Ippel, E. F., van Diggelen, O., Kroos, M. A., Boer, M., Jennekens, F. G. I., Reuser, A. J. J., Ploos van Amstel, H. K. Genotype-phenotype correlation in adult-onset acid maltase deficiency. Ann. Neurol. 38: 450-454, 1995. [PubMed: 7668832, related citations] [Full Text]

  89. Zellweger, H., Brown, B. I., McCormick, W. F., Jun-Bi, T. A mild form of muscular glycogenosis in two brothers with alpha-1,4-glucosidase deficiency. Ann. Paediat. 205: 413-437, 1965. [PubMed: 5217754, related citations]


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# 232300

GLYCOGEN STORAGE DISEASE II; GSD2


Alternative titles; symbols

GSD II
ACID ALPHA-GLUCOSIDASE DEFICIENCY
GAA DEFICIENCY
POMPE DISEASE
GLYCOGENOSIS, GENERALIZED, CARDIAC FORM
CARDIOMEGALIA GLYCOGENICA DIFFUSA
ACID MALTASE DEFICIENCY; AMD
ALPHA-1,4-GLUCOSIDASE DEFICIENCY


SNOMEDCT: 274864009;   ICD10CM: E74.02;   ORPHA: 308552, 365, 420429;   DO: 2752;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q25.3 Glycogen storage disease II 232300 Autosomal recessive 3 GAA 606800

TEXT

A number sign (#) is used with this entry because glycogen storage disease II (GSD2) is caused by homozygous or compound heterozygous mutation in the GAA gene (606800), which encodes acid alpha-1,4-glucosidase, also known as acid maltase, on chromosome 17q25.


Description

Glycogen storage disease II (GSD2), an autosomal recessive disorder, is the prototypic lysosomal storage disease. In the classic infantile form, 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).


Clinical Features

Infantile Onset

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.

Korlimarla et al. (2020) examined CNS involvement in 12 children with infantile-onset Pompe disease (IPD) and 2 children with late-onset Pompe disease (LOPD) who were receiving enzyme replacement therapy. They quantified brain white matter hyperintense foci by using the Fazekas scale (FS) grading system to score MRI findings in 10 brain areas. The FS scores were then compared to measurements of cognition and language. In 10 of the 12 children with IPD, with a median age of 10.6 years, mild to severe white matter hyperintense foci were seen. The lesions were seen throughout the corticospinal tracts of the brain. Two children with IPD had no white matter hyperintense foci. There were no significant relationships between total FS scores and age of the patient, anatomic areas of the brain, duration of treatment, duration of disease, or the patients' GAA mutations. No white matter hyperintense foci were seen in the 2 children with LOPD. Ten children with IPD and 2 children with LOPD completed cognitive assessments. Full-scale Wechsler IQ scores in patients with IPD ranged from significantly below average in 3 children to significantly above average in 1 child. These scores were average or above average in the 2 patients with LOPD. CELF-5 scores in patients with IPD on core language, language index, and expressive language index ranged from below average to above average. All language scores were above average in 1 LOPD patient and average and below average in the other LOPD patient. There were no significant relationships between FS scores and standard scores on each cognitive or language domain. Korlimarla et al. (2020) concluded that characterizing baseline and serial white matter hyperintense lesions in patients with Pompe disease is important for the longitudinal follow-up of disease.

Herbert et al. (2019) reported 4 patients who had onset of clinical features of Pompe disease between 20 days and 20 months of age and were compound heterozygous for the common GAA intron 1 mutation (IVS1-13T-G; 606800.0006), thought to lead to mild, adult-onset disease, and a different second GAA mutation. All 4 patients had delayed motor development and characteristic posture and movement abnormalities; 2 patients had feeding difficulty, and 2 patients had sleep apnea. None of the patients had cardiac involvement. Despite enzyme replacement therapy, all of the patients had residual muscle weakness.

Among a cohort of 41 children with infantile-onset Pompe disease (IPD) on enzyme replacement therapy, Tan et al. (2015) identified 8 who developed precocious pubarche (19.5%), including 4 males and 4 females. Of these, 5 had classic IPD and 3 had atypical IPD. The age at onset of pubarche ranged from 14 months to 4 years 2 months for those with classic IPD; the 3 patients with atypical IPD had a later age of onset at age 7 years. The etiology of precocious pubarche in IPD was unclear. The authors noted that monitoring for sexual development and function is needed for children and adolescents with IPD because premature pubarche can be associated with development of glucose intolerance, insulin resistance, and/or ovarian hyperandrogenism.

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; 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 intron 1 mutation in the GAA gene (IVS1-13T-G; 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.

Jones et al. (2021) assessed the tongue phenotype of 70 individuals with LOPD, including 10 individuals who had never received treatment, compared to 30 individuals with other forms of myopathy and 30 individuals with neuropathy. Patients with LOPD had reduced maximal lingual strength compared to individuals with other myopathies and individuals with neuropathy. Patients with LOPD also had reduced tongue muscle thickness as measured by ultrasound compared to individuals with other myopathies and individuals with neuropathy, suggesting fibrofatty replacement and muscle atrophy in LOPD.

Huggins et al. (2022) reported clinical features in 20 patients, aged 6 to 21 months, who were diagnosed with LOPD. All 20 patients were initially detected due to abnormal newborn screening and found to have mutations in the GAA gene. Four patients were homozygous for the c.-32-13T-G (606800.0006) mutation and 14 were heterozygous for the c.-32-13T-G mutation and a second mutation. None of the patients had cardiomyopathy or cardiac rhythm abnormalities. Laboratory abnormalities included increased CK, AST, and ALT in 8 patients and increased urine Glc4 in 2 patients. Nine patients, including the 4 patients who were homozygous for the c.-32-13T-G mutation, had normal CK, AST, and ALT. All of the patients had abnormal postural and kinematic findings, and the most common abnormalities included lack of appropriate use of hip extensors, increased hip external rotation while sitting, and tight iliotibial bands. Nine patients had mild feeding and swallowing impairment, but signs of dysphagia and aspiration were mild. Huggins et al. (2022) concluded that there is a great amount of clinical variability among patients with LOPD and that patients should be closely monitored for progression of symptoms.


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.


Pathogenesis

The defect in type II glycogen storage disease involves acid alpha-1,4-glucosidase (acid maltase), a lysosomal enzyme. Whereas the glycogen is distributed rather uniformly in the cytoplasm in the other glycogen storage diseases (e.g., GSD I; 232200), it is enclosed in lysosomal membranes in this form.

In a case of infantile acid alpha-glucosidase deficiency, Beratis et al. (1978) concluded that the defect was a structural mutation causing synthesis of a catalytically inactive, cross-reacting material (CRM)-positive, enzyme protein. On the other hand, the mutation in the adult form causes a reduction in the amount of enzyme protein. Of 9 fibroblast lines from patients with the infantile form of acid alpha-glucosidase deficiency, Beratis et al. (1983) found that 8 were CRM-negative and 1 was CRM-positive. No difference in apparent enzyme activity was detected between the 2 forms. In 2 fibroblast strains from the adult form, rocket immunoelectrophoresis showed a reduction in the amount of enzyme protein that was directly proportional to the reduction in enzyme activity. In another 'adult' fibroblast line, enzyme activity was in the same range as in the infantile form and no CRM was identified. Fibroblasts with phenotype 2 of acid alpha-glucosidase, considered a normal variant, showed reduction both in the amount of enzyme protein and in the ability to cleave glycogen; catalytic activity for maltose was normal, however.

Reuser et al. (1978) studied fibroblasts from the infantile, juvenile, and adult forms of acid alpha-glucosidase deficiency. An inverse correlation was found between the severity of clinical manifestations and the level of residual enzyme activity in fibroblasts. The kinetic and electrophoretic properties of residual enzyme in fibroblasts from adult patients were identical to those from controls. The mutation may, therefore, affect the production or degradation of enzyme rather than its catalytic function. Complementation studies by fusion of fibroblasts from different types yielded no sign of nonallelism of the several forms.

Reuser et al. (1987) investigated the nature of the acid alpha-glucosidase deficiency in cultured fibroblasts from 30 patients. Deficiency of catalytically active mature enzyme in lysosomes was common to all clinical phenotypes but, in most cases, was more profound in early-onset than in late-onset forms of the disease. The role of secondary factors cannot be excluded, however, because 3 adult patients were found with very low activity and little enzyme in the lysosomes.


Diagnosis

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.


Clinical Management

Slonim et al. (1983) and Margolis and Hill (1986) concluded that a high-protein diet is effective therapy in adults with acid maltase deficiency. Striking improvement in respiratory function was observed. The effect was serendipitously discovered when a high-protein diet for weight reduction was given. Correction of obesity was not thought to be the exclusive or even the major mechanism of the respiratory improvement. Isaacs et al. (1986) observed benefit from a high-protein, low-carbohydrate diet in a patient with adult acid maltase deficiency.

Amalfitano et al. (2001) reported the results of a phase I/II open-label single-dose study of recombinant human alpha-glucosidase infused intravenously twice weekly in 3 infants with infantile GSD II. The results of more than 250 infusions showed that recombinant human GAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all 3 infants. These infants lived well past the critical age of 1 year (16, 18, and 22 months old at the time of this study) and continued to have normal cardiac function. Improvements of skeletal muscle functions were also noted; 1 patient showed marked improvement and had normal muscle tone and strength as well as normal neurologic and developmental evaluations.

Van den Hout et al. (2003) studied the natural course of infantile Pompe disease in 20 Dutch patients and reviewed the findings in 133 published cases. They concluded that survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major motor milestones are valid endpoints for therapeutic studies.

Bembi et al. (2008) provided a detailed review of the clinical management of GSD II and emphasized a multidisciplinary approach. Enzyme replacement therapy with alglucosidase-alpha has been shown to be effective, particularly in infants.

Wang et al. (2011) described the ACMG standards and guidelines for the diagnostic confirmation and management of presymptomatic individuals with lysosomal storage diseases.


Inheritance

Glycogen storage disease type II is inherited as an autosomal recessive trait.

Smith et al. (2007) studied sib phenotype discordance in classic infantile Pompe disease by reviewing the medical literature for affected sibships in which at least 1 sib had clinical or biochemical findings consistent with infantile Pompe disease, including symptoms beginning in infancy, early hypotonia, cardiomegaly by 6 months of age, and early death. Since 1931, the literature has documented 13 families with 31 affected infants (11 probands; 20 affected sibs). The median age at symptom onset for all affected infants was 3 months (range, 0-6 months) with a significant correlation between probands and affected sibs (R = 0.60, p = 0.04). The median age at death for all affected infants was 6 months (range, 1.5-13 months); probands were slightly older at death than their sibs. The median length of disease course for all affected infants was 3 months (range, 0-10 months) and was slightly longer for probands. There was phenotypic concordance, particularly with respect to cardiomyopathy. Smith et al. (2007) concluded that there is minimal phenotypic and life span variation among sibs with infantile Pompe disease, which is important for genetic counseling.


Molecular Genetics

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 (IVS1-13T-G; 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 the IVS1-13T-G mutation, present in heterozygosity in 34 (85%) of 40 patients (allele frequency 42.3%).

In a cohort of 84 patients with GSD II who had the common GAA IVS1-13T-G mutation, Herbert et al. (2019) identified 4 patients with different second mutations in GAA who had onset of clinical symptoms before age 2 years (range, 10 days to 20 months). Herbert et al. (2019) concluded that despite the prior impression that this common mutation leads to milder, adult-onset disease, it can lead to early-onset symptoms.

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).


Population Genetics

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: IVS1-13T-G (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.


Animal Model

Acid maltase-deficient Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position in the flip test. Kikuchi et al. (1998) injected 6 4-week-old acid maltase-deficient quails, with the clinical symptoms listed, with 14 or 4.2 mg/kg of the precursor form of recombinant human GAA enzyme or buffer alone every 2 to 3 days for 18 days (7 injections). On day 18, both high dose-treated birds (14 mg/kg) scored positive flip tests and flapped their wings, and 1 bird flew up more than 100 cm. GAA activity increased in most of the tissues examined. In heart and liver, glycogen levels dropped to normal and histopathology was normal. In pectoralis muscle, morphology was essentially normal, except for increased glycogen granules. In sharp contrast, sham-treated quail muscle had markedly increased glycogen granules, multivesicular autophagosomes, and inter- and intrafascicular fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved less biochemically and histopathologically than high dose birds, indicating a dose-dependent response. Additional experiments with intermediate doses and extended treatment halted the progression of the disease. Data were claimed to be the first to show that an exogenous protein can target to muscle and produce muscle improvement. The data also suggested that enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease.

In mice in whom the Gaa gene was disrupted by gene targeting in embryonic stem cells, Raben et al. (1998) found that homozygosity for the knockout was associated with lack of enzyme activity and accumulation of glycogen in cardiac and skeletal muscle lysosomes by 3 weeks of age, with a progressive increase thereafter. By 3.5 weeks of age, these mice had markedly reduced mobility and strength. They grew normally, however, reached adulthood, remained fertile, and, as in the human adult disease, older mice accumulated glycogen in the diaphragm. By 8 to 9 months of age, the animals developed obvious muscle wasting and a weak, waddling gait. In contrast, in a second model, mutant mice with deletion of exon 6, like the knockout mice with disruption of exon 13 reported by Bijvoet et al., 1998, had unimpaired strength and mobility (up to 6.5 months of age) despite indistinguishable biochemical and pathologic changes.

Bijvoet et al. (1999) produced recombinant human acid alpha-glucosidase on an industrial scale in the milk of transgenic rabbits, and administered the purified enzyme intravenously to knockout mice. Full correction of acid alpha-glucosidase activity was obtained in all tissues except brain after a single dose of 17mg/kg. Weekly enzyme infusions over a period of 6 months resulted in normalization of hepatic glycogen, but only partial degradation of lysosomal glycogen in heart, skeletal and smooth muscle. The tissue morphology improved substantially despite the advanced state of disease at the start of treatment. The authors stated that although neurologic symptoms had not been documented in human GSD II patients, the inability of the enzyme to cross the blood-brain barrier in the mouse model remained a point of concern.

Dennis et al. (2000) identified mutations in the bovine Gaa gene that led to generalized glycogenosis in Brahman and Shorthorn bovine breeds. All 3 mutations resulted in premature termination of translation. The authors also presented evidence for a missense mutation segregating with the Brahman population, which is responsible for a 70 to 80% reduction in alpha-glucosidase activity.

Using Gaa-knockout mice and transgenes containing cDNA for the human enzyme under muscle- or liver-specific promoters controlled by tetracycline, Raben et al. (2001) demonstrated that the liver provided enzyme far more efficiently. The achievement of therapeutic levels with skeletal muscle transduction required the entire muscle mass to produce high levels of enzyme of which little found its way to the plasma, whereas liver, comprising less than 5% of body weight, secreted 100-fold more enzyme, all of which was in the active 110-kD precursor form. Skeletal and cardiac muscle pathology was completely reversible if the treatment was begun early.

DeRuisseau et al. (2009) found that Gaa-null mice had increased glycogen levels in cervical spinal cord motor neurons and larger soma size of phrenic neurons. Gaa-null mice had decreased ventilation during quiet breathing and hypercapnic challenge compared to wildtype mice, indicating respiratory insufficiency. Mice with skeletal muscle-specific Gaa expression (MTP) showed normal diaphragm force generation similar to wildtype mice, but decreased ventilation during quiet breathing, similar to Gaa-null mice. The compromised ventilation observed in both mutant mouse models was associated with decreased phrenic nerve motor output. Spinal cord samples from a patient with Pompe disease showed increased neuronal glycogen. DeRuisseau et al. (2009) suggested that respiratory impairment in individuals with Pompe disease results from a combination of muscular and neural deficits.

Douillard-Guilloux et al. (2010) analyzed the effect of a complete genetic elimination of glycogen synthesis in a murine GSDII model. Gaa/Gys1 (138570) double-knockout mice exhibited a profound reduction of the amount of glycogen in the heart and skeletal muscles, a significant decrease in lysosomal swelling and autophagic build-up as well as a complete correction of cardiomegaly. In addition, the abnormalities in glucose metabolism and insulin tolerance observed in the GSDII model were corrected in Gaa/Gys1 double-knockout mice. Muscle atrophy observed in 11-month-old GSDII mice was less pronounced in Gaa/Gys1 double-knockout mice, resulting in improved exercise capacity. Douillard-Guilloux et al. (2010) concluded that long-term elimination of muscle glycogen synthesis leads to a significant improvement of structural, metabolic and functional defects in the GSDII mouse model and offers a novel perspective for the treatment of Pompe disease.


See Also:

Becker et al. (1998); Besancon et al. (1985); Boerkoel et al. (1995); Bulkley and Hutchins (1978); Dreyfus and Poenaru (1978); Hers (1963); Hirschhorn et al. (1969); Karpati et al. (1977); Kroos et al. (1997); Loonen et al. (1981); Mehler and DiMauro (1977); Pongratz et al. (1976); Rosenow and Engel (1978); Salafsky and Nadler (1973); Shanske and DiMauro (1981); Taniguchi et al. (1978); Walvoort et al. (1985)

REFERENCES

  1. Amalfitano, A., Bengur, A. R., Morse, R. P., Majure, J. M., Case, L. E., Veerling, D. L., Mackey, J., Kishnani, P., Smith, W., McVie-Wylie, A., Sullivan, J. A., Hoganson, G. E., Phillips, J. A., III, Schaefer, G. B., Charrow, J., Ware, R. E., Bossen, E. H., Chen, Y.-T. Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet. Med. 3: 132-138, 2001. [PubMed: 11286229]

  2. Amartino, H., Painceira, D., Pomponio, R. J., Niizawa, G., Sabio Paz, V., Blanco, M., Chamoles, N. Two clinical forms of glycogen-storage disease type II in two generations of the same family. (Letter) Clin. Genet. 69: 187-188, 2006. [PubMed: 16433701] [Full Text: https://doi.org/10.1111/j.1399-0004.2005.00557.x]

  3. Angelini, C., Engel, A. G., Titus, J. L. Adult acid maltase deficiency: abnormalities in fibroblasts cultured from patients. New Eng. J. Med. 287: 948-951, 1972. [PubMed: 4507329] [Full Text: https://doi.org/10.1056/NEJM197211092871902]

  4. Anneser, J. M. H., Pongratz, D. E., Podskarbi, T., Shin, Y. S., Schoser, B. G. H. Mutations in the acid alpha-glucosidase gene (M. Pompe) in a patient with an unusual phenotype. Neurology 64: 368-370, 2005. [PubMed: 15668445] [Full Text: https://doi.org/10.1212/01.WNL.0000149528.95362.20]

  5. Askanas, V., Engel, W. K., DiMauro, S., Brooks, B. R., Mehler, M. Adult-onset acid maltase deficiency: morphologic and biochemical abnormalities reproduced in cultured muscle. New Eng. J. Med. 294: 573-578, 1976. [PubMed: 1060914] [Full Text: https://doi.org/10.1056/NEJM197603112941102]

  6. Ausems, M. G. E. M., Lochman, P., van Diggelen, O. P., Ploos van Amstel, H. K., Reuser, A. J. J., Wokke, J. H. A. A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology 52: 851-853, 1999. [PubMed: 10078739] [Full Text: https://doi.org/10.1212/wnl.52.4.851]

  7. Ausems, M. G. E. M., Verbiest, J., Hermans, M. M. P., Kroos, M. A., Beemer, F. A., Wokke, J. H. J., Sandkuijl, L. A., Reuser, A. J. J., van der Ploeg, A. T. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Europ. J. Hum. Genet. 7: 713-716, 1999. [PubMed: 10482961] [Full Text: https://doi.org/10.1038/sj.ejhg.5200367]

  8. Banugaria, S. G., Prater, S. N., Ng, Y.-K., Kobori, J. A., Finkel, R. S., Ladda, R. L., Chen, Y.-T., Rosenberg, A. S., Kishnani, P. S. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet. Med. 13: 729-736, 2011. [PubMed: 21637107] [Full Text: https://doi.org/10.1097/GIM.0b013e3182174703]

  9. Bashan, N., Potashnik, R., Barash, V., Gutman, A., Moses, S. W. Glycogen storage disease type II in Israel. Isr. J. Med. Sci. 24: 224-227, 1988. [PubMed: 3132435]

  10. Becker, J. A., Vlach, J., Raben, N., Nagaraju, K., Adams, E. M., Hermans, M. M., Reuser, A. J. J., Brooks, S. S., Tifft, C. J., Hirschhorn, R., Huie, M. L., Nicolino, M., Plotz, P. H. The African origin of the common mutation in African American patients with glycogen-storage disease type II. (Letter) Am. J. Hum. Genet. 62: 991-994, 1998. [PubMed: 9529346] [Full Text: https://doi.org/10.1086/301788]

  11. Bembi, B., Cerini, E., Danesino, C., Donati, M. A., Gasperini, S., Morandi, L., Musumeci, O., Parenti, G., Ravaglia, S., Seidita, F., Toscano, A., Vianello, A. Diagnosis of glycogenosis type II. Neurology 71: S4-S11, 2008. [PubMed: 19047572] [Full Text: https://doi.org/10.1212/WNL.0b013e31818da91e]

  12. Bembi, B., Cerini, E., Danesino, C., Donati, M. A., Gasperini, S., Morandi, L., Musumeci, O., Parenti, G., Ravaglia, S., Seidita, F., Toscano, A., Vianello, A. Management and treatment of glycogenosis type II. Neurology 71: S12-S36, 2008. [PubMed: 19047571] [Full Text: https://doi.org/10.1212/WNL.0b013e31818da93f]

  13. Beratis, N. G., LaBadie, G. U., Hirschhorn, K. Characterization of the molecular defect in infantile and adult acid alpha-glucosidase deficiency fibroblasts. J. Clin. Invest. 62: 1264-1274, 1978. [PubMed: 34626] [Full Text: https://doi.org/10.1172/JCI109247]

  14. Beratis, N. G., LaBadie, G. U., Hirschhorn, K. Genetic heterogeneity in acid alpha-glucosidase deficiency. Am. J. Hum. Genet. 35: 21-33, 1983. [PubMed: 6401921]

  15. Besancon, A.-M., Castelnau, L., Nicolesco, H., Dumez, Y., Poenaru, L. Prenatal diagnosis of glycogenosis type II (Pompe's disease) using chorionic villi biopsy. Clin. Genet. 27: 479-482, 1985. [PubMed: 3891160] [Full Text: https://doi.org/10.1111/j.1399-0004.1985.tb00235.x]

  16. Bijvoet, A. G. A., Van Hirtum, H., Kroos, M. A., Van de Kamp, E. H. M., Schoneveld, O., Visser, P., Brakenhoff, J. P. J., Weggeman, M., van Corven, E. J., Van der Ploeg, A. T., Reuser, A. J. J. Human acid alpha-glucosidase from rabbit milk has therapeutic effect in mice with glycogen storage disease type II. Hum. Molec. Genet. 8: 2145-2153, 1999. [PubMed: 10545593] [Full Text: https://doi.org/10.1093/hmg/8.12.2145]

  17. Bijvoet, A. G., van de Kamp, E. H., Kroos, M. A., Ding, J. H., Yang, B. Z., Visser, P., Bakker, C. E., Verbeet, M. P., Oostra, B. A., Reuser, A. J. J., van der Ploeg, A. T. Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease. Hum. Molec. Genet. 7: 53-62, 1998. [PubMed: 9384603] [Full Text: https://doi.org/10.1093/hmg/7.1.53]

  18. Boerkoel, C. F., Exelbert, R., Nicastri, C., Nichols, R. C., Miller, F. W., Plotz, P. H., Raben, N. Leaky splicing mutation in the acid maltase gene is associated with delayed onset of glycogenosis type II. Am. J. Hum. Genet. 56: 887-897, 1995. [PubMed: 7717400]

  19. Bulkley, B. H., Hutchins, G. M. Pompe's disease presenting as hypertrophic myocardiopathy with Wolff-Parkinson-White syndrome. Am. Heart J. 96: 246-252, 1978. [PubMed: 277063] [Full Text: https://doi.org/10.1016/0002-8703(78)90093-5]

  20. Byrne, E., Dennett, X., Crotty, B., Trounce, I., Sands, J. M., Hawkins, R., Hammond, J., Anderson, S., Haan, E. A., Pollard, A. Dominantly inherited cardioskeletal myopathy with lysosomal glycogen storage and normal acid maltase levels. Brain 109: 523-536, 1986. [PubMed: 3087571] [Full Text: https://doi.org/10.1093/brain/109.3.523]

  21. Chancellor, A. M., Warlow, C. P., Webb, J. N., Lucas, M. G., Besley, G. T. N., Broadhead, D. M. Acid maltase deficiency presenting with a myopathy and exercise induced urinary incontinence in a 68 year old male. (Letter) J. Neurol. Neurosurg. Psychiat. 54: 659-660, 1991. [PubMed: 1895140] [Full Text: https://doi.org/10.1136/jnnp.54.7.659]

  22. Danon, M. J., DiMauro, S., Shanske, S., Archer, F. L., Miranda, A. F. Juvenile-onset acid maltase deficiency with unusual familial features. Neurology 36: 818-822, 1986. [PubMed: 3084996] [Full Text: https://doi.org/10.1212/wnl.36.6.818]

  23. Davis, J., Goldman, M., Loh, L., Casson, M. Diaphragm function and alveolar hypoventilation. Quart. J. Med. 45: 87-100, 1976. [PubMed: 1062815]

  24. de Filippi, P., Ravaglia, S., Bembi, B., Costa, A., Moglia, A., Piccolo, G., Repetto, A., Dardis, A., Greco, G., Ciana, G., Canevari, F., Danesino, C. The angiotensin-converting enzyme insertion/deletion polymorphism modifies the clinical outcome in patients with Pompe disease. Genet. Med. 12: 206-211, 2010. [PubMed: 20308911] [Full Text: https://doi.org/10.1097/GIM.0b013e3181d2900e]

  25. Dennis, J. A., Moran, C., Healy, P. J. The bovine alpha-glucosidase gene: coding region, genomic structure, and mutations that caused bovine generalized glycogenosis. Mammalian Genome 11: 206-212, 2000. [PubMed: 10723725] [Full Text: https://doi.org/10.1007/s003350010038]

  26. DeRuisseau, L. R., Fuller, D. D., Qiu, K., DeRuisseau, K. C., Donnelly, W. H., Jr., Mah, C., Reier, P. J., Byrne, B. J. Neural deficits contribute to respiratory insufficiency in Pompe disease. Proc. Nat. Acad. Sci. 106: 9419-9424, 2009. [PubMed: 19474295] [Full Text: https://doi.org/10.1073/pnas.0902534106]

  27. Douillard-Guilloux, G., Raben, N., Takikita, S., Ferry, A., Vignaud, A., Guillet-Deniau, I., Favier, M., Thurberg, B. L., Roach, P. J., Caillaud, C., Richard, E. Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Hum. Molec. Genet. 19: 684-696, 2010. [PubMed: 19959526] [Full Text: https://doi.org/10.1093/hmg/ddp535]

  28. Dreyfus, J.-C., Poenaru, L. Alpha glucosidases in white blood cells, with reference to the detection of acid alpha 1-4 glucosidase deficiency. Biochem. Biophys. Res. Commun. 85: 615-622, 1978. [PubMed: 367369] [Full Text: https://doi.org/10.1016/0006-291x(78)91207-x]

  29. Engel, A. G. Acid maltase deficiency in adults: studies in four cases of a syndrome which may mimic muscular dystrophy or other myopathies. Brain 93: 599-616, 1970. [PubMed: 4918728] [Full Text: https://doi.org/10.1093/brain/93.3.599]

  30. Forsha, D., Li, J. S., Smith, P. B., van der Ploeg, A. T., Kishnani, P., Pasquali, S. K. Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy. Genet. Med. 13: 625-631, 2011. [PubMed: 21543987] [Full Text: https://doi.org/10.1097/GIM.0b013e3182142966]

  31. Francesconi, M., Auff, E. Cardiac arrhythmias and the adult form of type II glycogenosis. (Letter) New Eng. J. Med. 306: 937-938, 1982. [PubMed: 6950223] [Full Text: https://doi.org/10.1056/NEJM198204153061515]

  32. Groen, W. B., Leen, W. G., Vos, A. M. C., Cruysberg, J. R. M., van Doorn, P. A., van Engelen, B. G. M. Ptosis as a feature of late-onset glycogenosis type II. Neurology 67: 2261-2262, 2006. [PubMed: 17190962] [Full Text: https://doi.org/10.1212/01.wnl.0000249183.39952.3e]

  33. Hagemans, M. L. C., Winkel, L. P. F., Hop, W. C. J., Reuser, A. J. J., Van Doorn, P. A., Van der Ploeg, A. T. Disease severity in children and adults with Pompe disease related to age and disease duration. Neurology 64: 2139-2141, 2005. [PubMed: 15985590] [Full Text: https://doi.org/10.1212/01.WNL.0000165979.46537.56]

  34. Herbert, M., Case, L. E., Rairikar, M., Cope, H., Bailey, L., Austin, S. L., Kishnani, P. S. Early-onset of symptoms and clinical course of Pompe disease associated with the c.-32-13T-G variant. Molec. Genet. Metab. 126: 106-116, 2019. [PubMed: 30655185] [Full Text: https://doi.org/10.1016/j.ymgme.2018.08.009]

  35. Hers, H. G. Alpha-glucosidase deficiency in generalized glycogen-storage disease (Pompe's disease). Biochem. J. 86: 11-16, 1963. [PubMed: 13954110] [Full Text: https://doi.org/10.1042/bj0860011]

  36. Hirschhorn, K., Nadler, H. L., Waithe, W. I., Brown, B. I., Hirschhorn, R. Pompe's disease: detection of heterozygotes by lymphocyte stimulation. Science 166: 1632-1633, 1969. [PubMed: 5360584] [Full Text: https://doi.org/10.1126/science.166.3913.1632]

  37. Hoefsloot, L. H., van der Ploeg, A. T., Kroos, M. A., Hoogeveen-Westerveld, M., Oostra, B. A., Reuser, A. J. J. Adult and infantile glycogenosis type II in one family, explained by allelic diversity. Am. J. Hum. Genet. 46: 45-52, 1990. [PubMed: 2403755]

  38. Hudgson, P., Gardner-Medwin, D., Worsfold, M., Pennington, R. J. T., Walton, J. N. Adult myopathy from glycogen storage disease due to acid maltase deficiency. Brain 91: 435-462, 1968. [PubMed: 5247277] [Full Text: https://doi.org/10.1093/brain/91.3.435]

  39. Huggins, E., Holland, M., Case, L. E., Blount, J., Landstrom, A. P., Jones, H. N., Kishnani, P. S. Early clinical phenotype of late onset Pompe disease: lessons learned from newborn screening. Molec. Genet. Metab. 135: 179-185, 2022. [PubMed: 35123877] [Full Text: https://doi.org/10.1016/j.ymgme.2022.01.003]

  40. Iancu, T. C., Lerner, A., Shiloh, H., Bashan, N., Moses, S. Juvenile acid maltase deficiency presenting as paravertebral pseudotumour. Europ. J. Pediat. 147: 372-376, 1988. [PubMed: 3135192] [Full Text: https://doi.org/10.1007/BF00496413]

  41. Isaacs, H., Savage, N., Badenhorst, M., Whistler, T. Acid maltase deficiency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J. Neurol. Neurosurg. Psychiat. 49: 1011-1018, 1986. [PubMed: 3093639] [Full Text: https://doi.org/10.1136/jnnp.49.9.1011]

  42. Jones, H. N., Hobson-Webb, L. D., Kuchibhatia, M., Crisp, K. D., Whyte-Rayson, A., Batten, M. T., Zwelling, P. J., Kishnani, P. S. Tongue weakness and atrophy differentiates late-onset Pompe disease from other forms of acquired/hereditary myopathy. Molec. Genet. Metab. 133: 261-268, 2021. [PubMed: 34053870] [Full Text: https://doi.org/10.1016/j.ymgme.2021.05.005]

  43. Kallwass, H., Carr, C., Gerrein, J., Titlow, M., Pomponio, R., Bali, D., Dai, J., Kishnani, P., Skrinar, A., Corzo, D., Keutzer, J. Rapid diagnosis of late-onset Pompe disease by fluorometric assay of alpha-glucosidase activities in dried blood spots. Molec. Genet. Metab. 90: 449-452, 2007. Note: Erratum: Molec. Genet. Metab. 92: 285 only, 2007. [PubMed: 17270480] [Full Text: https://doi.org/10.1016/j.ymgme.2006.12.006]

  44. Karpati, G., Carpenter, S., Eisen, A., Aube, M., DiMauro, S. The adult form of acid maltase (alpha-1,4-glucosidase) deficiency. Ann. Neurol. 1: 276-280, 1977. [PubMed: 889315] [Full Text: https://doi.org/10.1002/ana.410010314]

  45. Kikuchi, T., Yang, H. W., Pennybacker, M., Ichihara, N., Mizutani, M., Van Hove, J. L. K., Chen, Y.-T. Clinical and metabolic correction of Pompe disease by enzyme therapy in acid maltase-deficient quail. J. Clin. Invest. 101: 827-833, 1998. [PubMed: 9466978] [Full Text: https://doi.org/10.1172/JCI1722]

  46. Korlimarla, A., Spiridigliozzi, G. A., Crisp, K., Herbert, M., Chen, S., Malinzak, M., Stefanescu, M., Austin, S. L., Cope, H., Zimmerman, K., Jones, H., Provenzale, J. M., Kishnani, P. S. Novel approaches to quantify CNS involvement in children with Pompe disease. Neurology 95: e718-e732, 2020. Note: Electronic Article. [PubMed: 32518148] [Full Text: https://doi.org/10.1212/WNL.0000000000009979]

  47. Koster, J. F., Busch, H. F. M., Slee, R. G., van Weerden, T. W. Glycogenosis type II: the infantile- and late-onset acid maltase deficiency observed in one family. Clin. Chim. Acta 87: 451-453, 1978. [PubMed: 28188] [Full Text: https://doi.org/10.1016/0009-8981(78)90191-2]

  48. Kretzschmar, H. A., Wagner, H., Hubner, G., Danek, A., Witt, T. N., Mehraein, P. Aneurysms and vacuolar degeneration of cerebral arteries in late-onset acid maltase deficiency. J. Neurol. Sci. 98: 169-183, 1990. [PubMed: 2243227] [Full Text: https://doi.org/10.1016/0022-510x(90)90258-o]

  49. Kroos, M. A., Van der Kraan, M., Van Diggelen, O. P., Kleijer, W. J., Reuser, A. J. J., Van den Boogaard, M. J., Ausems, M. G. E. M., Ploos van Amstel, H. K., Poenaru, L., Nicolino, M., Wevers, R. Glycogen storage disease type II: frequency of three common mutant alleles and their associated clinical phenotypes studied in 121 patients. J. Med. Genet. 32: 836-837, 1995. [PubMed: 8558570] [Full Text: https://doi.org/10.1136/jmg.32.10.836-a]

  50. Kroos, M. A., Van der Kraan, M., Van Diggelen, O. P., Kleijer, W. J., Reuser, A. J. J. Two extremes of the clinical spectrum of glycogen storage disease type II in one family: a matter of genotype. Hum. Mutat. 9: 17-22, 1997. [PubMed: 8990003] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)9:1<17::AID-HUMU3>3.0.CO;2-M]

  51. Laforet, P., Nicolino, M., Eymard, B., Puech, J. P., Caillaud, C., Poenaru, L., Fardeau, M. Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation. Neurology 55: 1122-1128, 2000. [PubMed: 11071489] [Full Text: https://doi.org/10.1212/wnl.55.8.1122]

  52. Lam, C. W., Yuen, Y. P., Chan, K. Y., Tong, S. F., Lai, C. K., Chow, T. C., Lee, K. C., Chan, Y. W., Martiniuk, F. Juvenile-onset glycogen storage disease type II with novel mutations in acid alpha-glucosidase gene. Neurology 60: 715-717, 2003. [PubMed: 12601120] [Full Text: https://doi.org/10.1212/01.wnl.0000048661.95327.bf]

  53. Loonen, M. C. B., Busch, H. F. M., Koster, J. F., Martin, J. J., Niermeijer, M. F., Schram, A. W., Brouwer-Kelder, B., Mekes, W., Slee, R. G., Tager, J. M. A family with different clinical forms of acid maltase deficiency (glycogenosis type II): biochemical and genetic studies. Neurology 31: 1209-1216, 1981. [PubMed: 6810200] [Full Text: https://doi.org/10.1212/wnl.31.10.1209]

  54. Loonen, M. C. B., Schram, A. W., Koster, J. F., Niermeijer, M. F., Busch, H. F. M., Martin, J. J., Brouwer-Kelder, B., Mekes, W., Slee, R. G., Tager, J. M. Identification of heterozygotes for glycogenosis 2 (acid maltase deficiency). Clin. Genet. 19: 55-63, 1981. [PubMed: 7006871] [Full Text: https://doi.org/10.1111/j.1399-0004.1981.tb00668.x]

  55. Makos, M. M., McComb, R. D., Hart, M. N., Bennett, D. R. Alpha-glucosidase deficiency and basilar artery aneurysm: report of a sibship. Ann. Neurol. 22: 629-633, 1987. [PubMed: 3322184] [Full Text: https://doi.org/10.1002/ana.410220512]

  56. Margolis, M. L., Hill, A. R. Acid maltase deficiency in an adult: evidence for improvement in respiratory function with high-protein dietary therapy. Am. Rev. Resp. Dis. 134: 328-331, 1986. [PubMed: 3090917] [Full Text: https://doi.org/10.1164/arrd.1986.134.2.328]

  57. Martiniuk, F., Bodkin, M., Tzall, S., Hirschhorn, R. Identification of the base-pair substitution responsible for a human acid alpha glucosidase allele with lower 'affinity' for glycogen (GAA 2) and transient gene expression in deficient cells. Am. J. Hum. Genet. 47: 440-445, 1990. [PubMed: 2203258]

  58. Martiniuk, F., Chen, A., Mack, A., Arvanitopoulos, E., Chen, Y., Rom, W. N., Codd, W. J., Hanna, B., Alcabes, P., Raben, N., Plotz, P. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. (Letter) Am. J. Med. Genet. 79: 69-72, 1998. [PubMed: 9738873] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980827)79:1<69::aid-ajmg16>3.0.co;2-k]

  59. Matsuishi, T., Yoshino, M., Terasawa, K., Nonaka, I. Childhood acid maltase deficiency: a clinical, biochemical, and morphologic study of three patients. Arch. Neurol. 41: 47-52, 1984. [PubMed: 6360103] [Full Text: https://doi.org/10.1001/archneur.1984.04050130053022]

  60. Mehler, M., DiMauro, S. Residual acid maltase activity in late-onset acid maltase deficiency. Neurology 27: 178-184, 1977. [PubMed: 264606] [Full Text: https://doi.org/10.1212/wnl.27.2.178]

  61. Molho, M., Katz, I., Schwartz, E., Shemesh, Y., Sadeh, M., Wolf, E. Familial bilateral paralysis of diaphragm: adult onset. Chest 91: 466-467, 1987. [PubMed: 3816327] [Full Text: https://doi.org/10.1378/chest.91.3.466]

  62. Montalvo, A. L. E., Bembi, B., Donnarumma, M., Filocamo, M., Parenti, G., Rossi, M., Merlini, L., Buratti, E., De Filippi, P., Dardis, A., Stroppiano, M., Ciana, G., Pittis, M. G. Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II. Hum. Mutat. 27: 999-1006, 2006. [PubMed: 16917947] [Full Text: https://doi.org/10.1002/humu.20374]

  63. Nishimoto, J., Inui, K., Okada, S., Ishigami, W., Hirota, S., Yamano, T., Yabuuchi, H. A family with pseudodeficiency of acid alpha-glucosidase. Clin. Genet. 33: 254-261, 1988. [PubMed: 3282727] [Full Text: https://doi.org/10.1111/j.1399-0004.1988.tb03446.x]

  64. Pompe, J. C. Over idiopathische hypertrophie van het hart. Ned. Tijdschr. Geneeskd. 76: 304-312, 1932.

  65. Pongratz, D., Schlossmacher, I., Koppenwallner, C., Hubner, G. An especially mild myopathic form of glycogenosis type II. Problems of clinical and light microscopic diagnosis. Path. Europ. 11: 39-44, 1976. [PubMed: 132627]

  66. Prater, S. N., Banugaria, S. G., DeArmey, S. M., Botha, E. G., Stege, E. M., Case, L. E., Jones, H. N., Phornphutkul, C., Wang, R. Y., Young, S. P., Kishnani, P. S. The emerging phenotype of long-term survivors with infantile Pompe disease. Genet. Med. 14: 800-810, 2012. [PubMed: 22538254] [Full Text: https://doi.org/10.1038/gim.2012.44]

  67. Raben, N., Lu, N., Nagaraju, K., Rivera, Y., Lee, A., Yan, B., Byrne, B., Meikle, P. J., Umapathysivam, K., Hopwood, J. J., Plotz, P. H. Conditional tissue-specific expression of the acid alpha-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy. Hum. Molec. Genet. 10: 2039-2047, 2001. [PubMed: 11590121] [Full Text: https://doi.org/10.1093/hmg/10.19.2039]

  68. Raben, N., Nagaraju, K., Lee, E., Kessler, P., Byrne, B., Lee, L., LaMarca, M., King, C., Ward, J., Sauer, B., Plotz, P. Targeted disruption of the acid alpha-glucosidase gene in mice causes an illness with critical features of both infantile and adult human glycogen storage disease type II. J. Biol. Chem. 273: 19086-19092, 1998. [PubMed: 9668092] [Full Text: https://doi.org/10.1074/jbc.273.30.19086]

  69. Reuser, A. J. J., Koster, J. F., Hoogeveen, A., Galjaard, H. Biochemical, immunological and cell genetic studies in glycogenosis type II. Am. J. Hum. Genet. 30: 132-143, 1978. [PubMed: 350041]

  70. Reuser, A. J. J., Kroos, M., Willemsen, R., Swallow, D., Tager, J. M., Galjaard, H. Clinical diversity in glycogenosis type II: biosynthesis and in situ localization of acid alpha-glucosidase in mutant fibroblasts. J. Clin. Invest. 79: 1689-1699, 1987. [PubMed: 3108320] [Full Text: https://doi.org/10.1172/JCI113008]

  71. Rosenow, E. C., Engel, A. G. Acid maltase deficiency in adults presenting as respiratory failure. Am. J. Med. 64: 485-491, 1978. [PubMed: 345804] [Full Text: https://doi.org/10.1016/0002-9343(78)90235-8]

  72. Salafsky, I. S., Nadler, H. L. Deficiency of acid alpha glucosidase in the urine of patients with Pompe disease. J. Pediat. 82: 294-298, 1973. [PubMed: 4265199] [Full Text: https://doi.org/10.1016/s0022-3476(73)80174-x]

  73. Shanske, S., DiMauro, S. Late-onset acid maltase deficiency: biochemical studies of leukocytes. J. Neurol. Sci. 50: 57-62, 1981. [PubMed: 7014786] [Full Text: https://doi.org/10.1016/0022-510x(81)90041-1]

  74. Sivak, E. D., Salanga, V. D., Wilbourn, A. J., Mitsumoto, H., Golish, J. Adult-onset acid maltase deficiency presenting as diaphragmatic paralysis. Ann. Neurol. 9: 613-615, 1981. [PubMed: 6789760] [Full Text: https://doi.org/10.1002/ana.410090618]

  75. Slonim, A. E., Bulone, L., Ritz, S., Goldberg, T., Chen, A., Martiniuk, F. Identification of two subtypes of infantile acid maltase deficiency. J. Pediat. 137: 283-285, 2000. [PubMed: 10931430] [Full Text: https://doi.org/10.1067/mpd.2000.107112]

  76. Slonim, A. E., Coleman, R. A., McElligot, M. A., Najjar, J., Hirschhorn, K., Labadie, G. U., Mrak, R., Evans, O. B., Shipp, E., Presson, R. Improvement of muscle function in acid maltase deficiency by high-protein therapy. Neurology 33: 34-38, 1983. [PubMed: 6401355] [Full Text: https://doi.org/10.1212/wnl.33.1.34]

  77. Smith, H. L., Amick, L. D., Sidbury, J. B., Jr. Type II glycogenosis. Am. J. Dis. Child. 3: 475-481, 1966.

  78. Smith, J., Zellweger, H., Afifi, A. K. Muscular form of glycogenosis, type II (Pompe). Neurology 17: 537-549, 1967. [PubMed: 5229488] [Full Text: https://doi.org/10.1212/wnl.17.6.537]

  79. Smith, W. E., Sullivan-Saarela, J. A., Li, J. S., Cox, G. F., Corzo, D., Chen, Y.-T., Kishnani, P. S. Sibling phenotype concordance in classical infantile Pompe disease. Am. J. Med. Genet. 143A: 2493-2501, 2007. [PubMed: 17853454] [Full Text: https://doi.org/10.1002/ajmg.a.31936]

  80. Suzuki, Y., Tsuji, A., Omura, K., Nakamura, G., Awa, S., Kroos, M., Reuser, A. J. J. Km mutant of acid alpha-glucosidase in a case of cardiomyopathy without signs of skeletal muscle involvement. Clin. Genet. 33: 376-385, 1988. [PubMed: 3288378] [Full Text: https://doi.org/10.1111/j.1399-0004.1988.tb03465.x]

  81. Swaiman, K. F., Kennedy, W. R., Sauls, H. S. Late infantile acid maltase deficiency. Arch. Neurol. 18: 642-648, 1968. [PubMed: 5240358] [Full Text: https://doi.org/10.1001/archneur.1968.00470360064006]

  82. Tan, Q. K.-G., Stockton, D. W., Pivnick, E., Choudhri, A. F., Hines-Dowell, S., Pena, L. D. M., Deimling, M. A., Freemark, M. S., Kishnani, P. S. Premature pubarche in children with Pompe disease. J. Pediat. 166: 1075-1078, 2015. [PubMed: 25687635] [Full Text: https://doi.org/10.1016/j.jpeds.2014.12.074]

  83. Taniguchi, N., Kato, E., Yoshida, H., Iwaki, S., Ohki, T., Koizumi, S. Alpha-glucosidase activity in human leukocytes: choice of lymphocytes for the diagnosis of Pompe's disease and the carrier state. Clin. Chim. Acta 89: 293-299, 1978. [PubMed: 361294] [Full Text: https://doi.org/10.1016/0009-8981(78)90328-5]

  84. Trend, P. St. J., Wiles, C. M., Spencer, G. T., Morgan-Hughes, J. A., Lake, B. D., Patrick, A. D. Acid maltase deficiency in adults: diagnosis and management in five cases. Brain 108: 845-860, 1985. [PubMed: 3865697] [Full Text: https://doi.org/10.1093/brain/108.4.845]

  85. van den Hout, H. M. P., Hop, W., van Diggelen, O. P., Smeitink, J. A. M., Smit, G. P. A., Poll-The, B.-T. T., Bakker, H. D., Loonen, M. C. B., de Klerk, J. B. C., Reuser, A. J. J., van der Ploeg, A. T. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature. Pediatrics 112: 332-340, 2003. [PubMed: 12897283] [Full Text: https://doi.org/10.1542/peds.112.2.332]

  86. Walvoort, H. C., Dormans, J. A. M. A., van den Ingh, T. S. G. A. M. Comparative pathology of the canine model of glycogen storage disease type II (Pompe's disease). J. Inherit. Metab. Dis. 8: 38-46, 1985. [PubMed: 3921759] [Full Text: https://doi.org/10.1007/BF01805484]

  87. Wang, R. Y., Bodamer, O. A., Watson, M. S., Wilcox, W. R. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet. Med. 13: 457-484, 2011. [PubMed: 21502868] [Full Text: https://doi.org/10.1097/GIM.0b013e318211a7e1]

  88. Wokke, J. H. J., Ausems, M. G. E. M., van den Boogaard, M.-J. H., Ippel, E. F., van Diggelen, O., Kroos, M. A., Boer, M., Jennekens, F. G. I., Reuser, A. J. J., Ploos van Amstel, H. K. Genotype-phenotype correlation in adult-onset acid maltase deficiency. Ann. Neurol. 38: 450-454, 1995. [PubMed: 7668832] [Full Text: https://doi.org/10.1002/ana.410380316]

  89. Zellweger, H., Brown, B. I., McCormick, W. F., Jun-Bi, T. A mild form of muscular glycogenosis in two brothers with alpha-1,4-glucosidase deficiency. Ann. Paediat. 205: 413-437, 1965. [PubMed: 5217754]


Contributors:
Sonja A. Rasmussen - updated : 07/19/2022
Hilary J. Vernon - updated : 04/07/2022
Hilary J. Vernon - updated : 07/15/2021
Hilary J. Vernon - updated : 07/07/2021
Hilary J. Vernon - updated : 10/14/2020
Ada Hamosh - updated : 10/3/2012
Ada Hamosh - updated : 9/28/2012
Ada Hamosh - updated : 9/28/2012
George E. Tiller - updated : 2/8/2011
Ada Hamosh - updated : 7/30/2010
Cassandra L. Kniffin - updated : 11/25/2009
Cassandra L. Kniffin - updated : 3/12/2009
Cassandra L. Kniffin - updated : 3/4/2009
Cassandra L. Kniffin - updated : 12/5/2007
Ada Hamosh - updated : 6/14/2007
Cassandra L. Kniffin - updated : 10/4/2006
Cassandra L. Kniffin - updated : 5/30/2006
Marla J. F. O'Neill - updated : 3/20/2006
Cassandra L. Kniffin - updated : 11/2/2005
Cassandra L. Kniffin - updated : 6/9/2005
Natalie E. Krasikov - updated : 3/12/2004
Natalie E. Krasikov - updated : 2/19/2004
Patricia A. Hartz - updated : 3/25/2002
George E. Tiller - updated : 2/6/2002
Victor A. McKusick - updated : 9/19/2001
Ada Hamosh - updated : 8/29/2001
Victor A. McKusick - updated : 3/24/2000
George E. Tiller - updated : 3/23/2000
Victor A. McKusick - updated : 11/8/1999
Victor A. McKusick - updated : 5/14/1999
Orest Hurko - updated : 4/2/1999
Victor A. McKusick - updated : 9/16/1998
Victor A. McKusick - updated : 8/18/1998
Victor A. McKusick - updated : 5/13/1998
Victor A. McKusick - updated : 5/11/1998
Victor A. McKusick - updated : 4/29/1998
Victor A. McKusick - updated : 3/25/1998
Victor A. McKusick - updated : 2/21/1997
Iosif W. Lurie - updated : 10/1/1996
Moyra Smith - updated : 3/15/1996
Orest Hurko - updated : 2/5/1996

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mark : 3/15/1996
mark : 3/4/1996
terry : 2/21/1996
mark : 2/5/1996
terry : 1/31/1996
mark : 6/11/1995
pfoster : 11/30/1994
davew : 6/2/1994
terry : 5/16/1994
carol : 5/11/1994
mimadm : 4/18/1994