Pompe disease

Pompe disease
Name	Pompe disease
Synonyms	Glycogen storage disease type II, acid maltase deficiency
Caption	A diagram of a lysosome, the organelle where the deficient enzyme functions.
Pronounce	/pɒmp/
Field	Endocrinology, Neurology, Medical genetics
Symptoms	Muscle weakness, respiratory issues, cardiomyopathy
Complications	Respiratory failure, Cardiac arrest
Onset	Infancy to adulthood
Duration	Lifelong
Types	Infantile-onset, Late-onset
Causes	Mutations in the GAA gene
Risks	Autosomal recessive inheritance
Diagnosis	Enzyme assay, Genetic testing
Differential	Duchenne muscular dystrophy, Limb-girdle muscular dystrophy, Danon disease
Prevention	Genetic counseling
Treatment	Enzyme replacement therapy, supportive care
Medication	Alglucosidase alfa, Avalglucosidase alfa
Prognosis	Variable; severe in infantile form
Frequency	~1 in 40,000

Pompe disease. It is a rare, inherited metabolic disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase, leading to pathological accumulation of glycogen within cells. This autosomal recessive condition manifests across a clinical spectrum, from a rapidly progressive infantile form with severe cardiomyopathy to a slower-progressing late-onset disease primarily affecting skeletal muscle. The disease is named after the Dutch pathologist J. C. Pompe, who first described it in 1932.

Signs and symptoms

The classic infantile-onset form presents within the first few months of life with profound hypotonia, a markedly enlarged tongue, and progressive weakness, often described as a "floppy baby" appearance. Severe, life-threatening hypertrophic cardiomyopathy and hepatomegaly are cardinal features, with feeding difficulties and respiratory infections leading to respiratory failure. The late-onset form, which can present in children or adults, typically lacks significant cardiac involvement but features a slowly progressive myopathy of the limb-girdle and axial muscles. This leads to difficulty with ambulation, scoliosis, and eventually respiratory insufficiency due to weakness of the diaphragm and other respiratory muscles, often requiring non-invasive ventilation.

Genetics and pathophysiology

Pompe disease is caused by mutations in the GAA gene located on chromosome 17, which encodes the enzyme acid alpha-glucosidase. This enzyme is responsible for breaking down glycogen to glucose within the lysosome. Over 500 different pathogenic variants have been identified in the Human Gene Mutation Database, with varying effects on enzyme activity and stability. The resulting enzymatic deficiency leads to an accumulation of lysosomal glycogen, particularly in cells with high energy demands, such as cardiomyocytes, hepatocytes, and skeletal muscle fibers. This accumulation disrupts cellular architecture and function, ultimately causing cell death and the clinical manifestations of the disease.

Diagnosis

Diagnosis is confirmed through biochemical and genetic testing. The primary diagnostic test is an enzyme assay measuring acid alpha-glucosidase activity in dried blood spots, cultured skin fibroblasts, or lymphocytes from a blood sample. Significantly reduced or absent enzyme activity is diagnostic. Subsequent genetic testing of the GAA gene identifies the specific pathogenic variants, which can aid in predicting disease severity and is essential for carrier testing in family members. Muscle biopsy, once a mainstay, may show vacuolar myopathy with glycogen-filled lysosomes but is now less commonly required. Electromyography may show myopathic changes with characteristic irritability.

Treatment and management

The cornerstone of treatment is lifelong enzyme replacement therapy with recombinant human acid alpha-glucosidase. The first approved agent, alglucosidase alfa, and the next-generation therapy avalglucosidase alfa, are administered via intravenous infusion. This treatment can stabilize or improve cardiomyopathy and motor function, particularly when initiated early in the infantile form. Management is multidisciplinary, involving specialists in metabolic disease, cardiology, pulmonology, and physical therapy. Supportive care is critical and includes nutritional support, proactive respiratory care with mechanical ventilation, and monitoring for arrhythmias and osteoporosis.

Prognosis and epidemiology

Prognosis is highly dependent on the age of onset and the initiation of treatment. Untreated classic infantile-onset disease is universally fatal, typically from cardiorespiratory failure within the first year of life. With early enzyme replacement therapy, survival into childhood and adolescence is possible, though significant disability often remains. The late-onset form has a more variable course, with a slower progression of muscle weakness and respiratory decline; lifespan can extend into adulthood. Pompe disease has an estimated overall incidence of approximately 1 in 40,000 live births, though this varies across populations, with higher reported frequencies in the Afrikaner community of South Africa and in Southern China.

History

The disease was first described in 1932 by the Dutch pathologist J. C. Pompe in a report of a 7-month-old infant who died from idiopathic cardiomegaly. Subsequent investigations by other pioneers like G. T. Cori helped classify it as a glycogen storage disease. The fundamental defect—a deficiency of acid alpha-glucosidase—was identified in 1963 by Henri-Géry Hers, who coined the term "lysosomal storage disease." The cloning of the GAA gene in the late 1980s paved the way for the development of enzyme replacement therapy, which after decades of research led by scientists at Duke University and Erasmus MC, was first approved by the U.S. Food and Drug Administration in 2006.

Category:Lysosomal storage diseases Category:Glycogen storage diseases Category:Rare diseases