|Synonym||GSD II, acid maltase deficiency|
|Genetics||Biallelic pathogenic variant in the GAA gene|
|Pathophysiology||GAA deficiency causes glycogen to accumulate in lysosomes and cytoplasm, resulting in tissue damage and various clinical features depending on the form of the disease.|
|Classification||Pompe disease presents in two forms: infantile-onset, characterized by hypertrophic cardiomyopathy and hypotonia, and late-onset, characterized by limb girdle and axial weakness and respiratory insufficiency in late disease.|
|Clinical Features||Limb girdle weakness, exercise intolerance, chronic pain|
|Tests||Blood test for enzyme activity, genetic testing for GAA gene mutations, and muscle biopsy in some cases|
|DDX||Other glycogen storage diseases, muscular dystrophies, and metabolic myopathies|
|Treatment||Enzyme replacement therapy with intravenous alglucosidase alfa and supported by multidisciplinary care|
Pompe disease is a Lysosomal Storage Disease (LSD), also a type of Glycogen Storage Disease (GSD II), that is caused by a deficiency in acid alpha-glucosidase (GAA), also known as acid maltase. GAA deficiency results in the accumulation of glycogen in lysosomes in all tissues. Unlike other GSDs, which affect glycogen synthesis or regulation of energy production, GAA deficiency affects lysosomal-mediated degradation of glycogen. GAA deficiency can present in two forms: an infantile-onset form, which typically involves hypertrophic cardiomyopathy and hypotonia, and a late-onset form, which is characterised by limb girdle and axial weakness and respiratory insufficiency in late disease.
According to a study in the Netherlands that screened newborn blood spots for the three common variant alleles in that population, the estimated incidence of GAA deficiency was 1 in 40,000. Based on carrier frequencies, the predicted incidence was 1 in 138,000 for classic infantile disease and 1 in 57,000 for late-onset disease. However, studies in Austria and the United States investigating strategies for newborn screening found a higher incidence (1 in 8686 and 1 in 21,979, respectively) for the combined early- and late-onset forms.
Lysosomal GAA plays a crucial role in breaking down both alpha-1,4- and alpha-1,6-glucosidic linkages in the acidic environment of the lysosome. When the enzyme is deficient, glycogen accumulates in lysosomes and cytoplasm, leading to tissue damage. This deficiency may also affect vesicle systems linked to lysosomes and receptors, including glucose transporter 4, that move through these organelles.
The activity of the enzyme is linked to genotype and is either absent or very low in individuals with infantile-onset phenotype. In those with the late-onset phenotype, the enzyme activity is reduced to varying degrees.
GAA deficiency is an autosomal-recessive disorder with significant genetic diversity. The disease is caused by mutations in the gene that encodes lysosomal acid alpha-1,4-glucosidase (GAA), which is located at 17q25.2-q25.3. It has high allelic heterogeneity with hundreds of different mutations having been identified as the cause of the disorder. There are also some pseudodeficiency alleles which don't cause the disease but result in lower GAA enzyme activity leading to a false-positive diagnosis.
Infants with infantile-onset GAA deficiency typically present in the first few months of life with cardiomyopathy and severe muscular hypotonia.
Late Onset Form
Patients with late-onset GAA deficiency present at any age and have variable age of onset and clinical and histologic features. They do not experience cardiomyopathy. The primary clinical finding in late-onset GAA deficiency is a limb girdle and axial pattern of skeletal muscle myopathy, which can range from asymptomatic to severe. The myopathy is typically progressive over time. Chronic pain and exercise intolerance are common. Ptosis (often unilateral) and bulbar weakness occur in around a quarter of patients, and scapular winging in around a third.
Patients typically experience delayed gross-motor development and progressive weakness in a limb-girdle distribution. Involvement of the diaphragm is common, leading to respiratory insufficiency early in the course of the disease. Camptocormia can occur.
Other symptoms, including gastrointestinal symptoms, dilative arteriopathy, carotid artery dissection, and basilar artery dolichoectasia, may also occur in some patients.
Affective individuals typically have moderately elevated serum creatine kinase levels (around +/- 500) and decreased leukocyte GAA activity. However normal CK does not rule out the disease, especially in later stages. GAA activity is typically less than 10 percent of normal in tissues such as fibroblasts and muscle.
Muscle biopsy reveals vacuolar myopathy with glycogen storage in lysosomes and free glycogen in the cytoplasm seen by electron microscopy.
Infantile-onset GAA deficiency should be suspected in infants presenting with severe hypotonia and cardiac insufficiency. Commonly seen laboratory abnormalities include elevated levels of creatine kinase (CK), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST). The electrocardiogram typically shows a short PR interval with giant QRS complexes in all leads, which may suggest biventricular hypertrophy, but this is not unique to GAA deficiency.
Late-onset GAA deficiency should be suspected in individuals with progressive proximal weakness in a limb-girdle distribution. The electromyogram may show characteristic myopathic discharges that are sometimes associated with abundant myotonic and complex repetitive discharges, especially in the paraspinal muscles. Pulmonary function testing typically reveals a substantially reduced forced vital capacity (FVC) in adults. The forearm ischaemic lactate test is normal in patients with GAA deficiency.
GAA enzyme activity can be measured in white blood cells or dried blood spots, and the addition of acarbose is recommended to improve the sensitivity of the assay. Gene sequencing is the preferred test for confirming the diagnosis. Confirmation of the diagnosis requires the identification of two pathogenic variants in the GAA gene. GAA enzyme activity measurement in fibroblasts or muscle biopsy can be performed if blood tests are inconclusive. However, muscle biopsy is more invasive and has a higher risk of false positives due to poor sample processing.
At the time of writing the New Zealand Newborn Metabolic Screening Programme does not include testing for Pompe disease.
In the absence of treatment, most patients with the classic infantile form of GAA deficiency experience unremitting deterioration and die within the first two years of life from cardiac insufficiency, although prolonged survival has been reported in infants with less severe cardiomyopathy. Early diagnosis and prompt initiation of enzyme replacement therapy (ERT) are essential for improving outcomes.
The rate of progression and sequence of respiratory and skeletal involvement vary significantly among patients with late-onset disease. Disease severity is related to disease duration rather than age, with the odds for wheelchair use and respiratory support increasing by 13 and 8 percent, respectively, for every additional year since diagnosis. A two-year follow-up of 52 Dutch patients with untreated late-onset GAA deficiency indicated a progressive decline in functional activities, respiratory function, handicap, and survival at the group level.
The main treatment for GAA deficiency is intravenous alglucosidase alfa enzyme replacement therapy (ERT). A randomised controlled trial has been conducted proving efficacy. ERT enhances survival. However many patients still develop progressive pelvic girdle weakness.
A multidisciplinary team is necessary for the coordination of care. Many patients require some level of respiratory support, with some patients progressing to require mechanical ventilation.
https://www.nzpompe.network/ - New Zealand charity.
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