Pompe disease
Pompe disease is a rare metabolic disorder caused by mutations in the acid alpha-glucosidase (GAA) gene, which is critical for breaking down glycogen in cells. This condition leads to the accumulation of glycogen primarily in cardiac and skeletal muscles, resulting in progressive muscle weakness and organ dysfunction. The disease is classified into two main forms: the rapidly progressive infantile form, which typically manifests soon after birth, and the late-onset form, which can appear later in life, sometimes decades after birth. Pompe disease is inherited in an autosomal recessive manner, meaning both parents must carry a defective gene for their child to be affected.
Symptoms vary widely depending on the age of onset and the remaining GAA enzyme activity, ranging from heart enlargement and respiratory distress in infants to muscle weakness and pain in older individuals. Diagnosis is often complex, requiring specific tests to measure GAA activity or genetic analysis. Treatment has evolved from supportive care to include enzyme replacement therapy (ERT), which has shown positive outcomes, particularly in younger patients. Ongoing research into gene therapy also offers hope for improved treatments in the future. Overall, early diagnosis and intervention are crucial for managing Pompe disease and improving patient outcomes.
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Pompe disease
ALSO KNOWN AS: Lysosomal storage disease; acid maltase deficiency disease; glycogen storage disease type II
DEFINITION Pompe disease is a metabolic disorder caused by mutations in the acid alpha-glucosidase (GAA) gene. GAA, an enzyme responsible for breaking down glycogen in the cells, is either absent (resulting in the rapidly progressive infantile form of Pompe disease) or deficient (resulting in the late-onset juvenile or adult form). As a result, glycogen builds up in the lysosomes of cells and tissues, primarily in cardiac and skeletal muscles, affecting their function and causing progressive weakness and organ failure.
Risk Factors
This is an autosomal recessive disorder; therefore, each parent must carry a defective GAA gene, both of which are inherited by the affected child. The National Institute of Neurological Disorders and Stroke (NINDS) reports (2022) that the incidence is estimated at 1 in 40,000 people worldwide. About one-third of patients have the infantile-onset form. Both sexes are equally affected, although the incidence does vary by geography and ethnic group.
Etiology and Genetics
The GAA gene, located on the long arm of chromosome 17, is the only gene associated with Pompe disease. More than three hundred mutations have been identified throughout the gene. Some defects are more common than others. For example, more than half of Caucasians with late-onset Pompe disease share a common splice-site mutation. According to the Emory University School of Medicine, some infantile-onset mutations are observed more frequently in certain geographic regions (such as southern China and Taiwan) or ethnic populations (such as African Americans).
In general, the type and combination of mutations inherited determine the residual level of GAA activity and thus the severity of the disease. If both chromosomes are fully compromised, GAA activity is nonexistent. Combinations of one severely mutated allele and one mildly affected allele usually preserve some GAA activity, meaning a slower disease progression, although the age of onset can vary. Researchers are cautious about correlating genotype with clinical features, however, because both infantile and late-onset forms have been observed in the same family.
Several factors explain how glycogen buildup in the lysosomes likely disrupts muscle function. As the lysosomes become bloated, they can displace myofibrils in neighboring cells, disrupting the muscle’s ability to contract and transmit force. In late-onset Pompe disease, swollen lysosomes can rupture or release other enzymes into surrounding tissues, damaging muscles. Disuse and oxidative stress may also play a role in muscle wasting.
Symptoms
Manifestations of Pompe disease vary depending on age of onset and level of residual GAA activity. In the classic infantile-onset form, symptoms are observed shortly after birth and include an enlarged heart, poor muscle tone (inability to hold the head up, roll over), feeding problems (difficulty swallowing, enlarged tongue), and respiratory distress (frequent lung infections). In the nonclassic infantile form, cardiac involvement is moderate and muscle weakness is delayed. In late-onset Pompe disease, symptoms can appear from two to seventy years. Muscle weakness and pain, primarily in the legs and trunk (difficulty climbing stairs or playing sports, frequent falls) and respiratory distress (shortness of breath, sleep apnea) are typical. In all cases, early diagnosis is critical for disease management.
Screening and Diagnosis
Pompe disease shares many symptoms with other muscle disorders, complicating diagnosis. Initial clinical studies include chest radiography and electrocardiograms, as well as muscle tests, electromyography, and nerve conduction tests in adults. The diagnosis is confirmed through tests of GAA activity (blood tests, skin fibroblasts cultures, and/or muscle biopsy in adults) or through DNA analysis. DNA analysis is also useful for identifying familial mutations and carriers and for newborn screening.
Treatment and Therapy
Historically, patients with Pompe disease were given supportive care only. However, enzyme replacement therapy (ERT) using recombinant human GAA has become a promising treatment, especially in infants younger than six months who do not yet require ventilatory assistance. As reported by the National Center for Biotechnology Information (2012), clinical trials of ERT in late-onset Pompe disease showed promise. By 2021, the US Food and Drug Administration (FDA) had approved enzyme replacement therapy for Pompe disease under the brand name, Nexviazyme. Other treatment is multidisciplinary and aimed at preventing secondary complications such as infections, treating symptoms, and maintaining function as long as possible. These treatments include frequent cardiac evaluations, use of bronchodilators, steroids, and mechanical ventilation, and special diets and tube feeding. Physical, occupational, and speech therapies and immunizations are also advised.
Prevention and Outcomes
Before ERT, patients with infantile-onset Pompe disease typically died of cardiac and/or respiratory complications by one year of age. ERT has enhanced ventilator-free survival for many young patients; reduced heart size and improvements in cardiac and skeletal muscle function have also been seen. In late-onset Pompe disease, juvenile patients are usually more severely affected than adults and rarely survive past the second or third decade of life due to respiratory failure. They often require mechanical ventilation and wheelchairs. Older patients may also experience steadily progressive debilitation and premature mortality. However, improved screening techniques that enhance early diagnosis have become available. NINDS (2013) reports that not only ERT, but new drugs show promise for treatment.
In addition, researchers at several institutions, including Duke University, are conducting clinical trials in gene therapy in the hopes of helping patients with Pompe disease, especially those who do not respond to ERT. In clinical trials with mice, researchers observed that a single treatment cleared enough glycogen from the test subjects' muscles, sparking hope that the gene therapy could have similar results with fewer side effects in human patients.
Bibliography
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Hirschhorn, R., and A. J. Reuser. “Glycogen Storage Disease Type II: Acid Alpha-glucosidase (Acid Maltase) Deficiency.” The Metabolic and Molecular Bases of Inherited Disease. Ed. Charles Scriver, et al. 8th ed. New York: McGraw, 2001. Print.
Hoffman, Georg F., et al.Inherited Metabolic Diseases. New York: Springer, 2010. Print.
Houser, Christine N. Pediatric Genetics and Inborn Errors of Metabolism: A Practically Painless Review. New York: Springer, 2014. Print.
Kishnani, Priya S., et al. “Pompe Disease Diagnosis and Management Guidelines.” Genetics in Medicine 8.5 (2006): 267–88. Print.
Lim, Jeong-a, et al. "Pompe Disease: Shared and Unshared Features of Lysosomal Storage Disorders." Rare Diseases 3.1 (2015): n. pag. PDF file.
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"Pompe Disease." National Institute of Neurological Disorders and Stroke, 25 July 2022, www.ninds.nih.gov/health-information/disorders/pompe-disease. Accessed 4 Sept. 2024.
Smith EC et al. "Phase I Study of Liver Depot Gene Therapy in Late-Onset Pompe Disease." Molecular Therapy, 2023 July 5, Vol. 31, DOI: 10.1016/j.ymthe.2023.02.014. Accessed 4 Sept. 2024.