Pompe disease (PD), also known as acid alpha-glucosidase deficiency or glycogen storage disease type II, is caused by mutations in the GAA gene that codes for alpha acid glucosidase (also called acid maltase), an enzyme that normally breaks down glycogen into glucose within the cells. Mutations in the GAA gene result in defects in acid alpha-glucosidase, which prevent its normal function and eventually cause a buildup of glycogen in the cell. This toxic buildup of glycogen damages organs and tissues, particularly the muscles, causing characteristic symptoms such as muscle weakness and poor muscle tone.1
The clinical symptom spectrum of PD is broad and depends on the nature of the mutations and the residual enzymatic activity levels.2
Based on the age of onset, severity, presence of cardiomyopathy, and rate of progression, PD is classified into 3 forms – classic infantile-onset PD (CIOPD) in which symptoms appear within a few months of birth, non-classic infantile-onset PD (NCIOPD) in which symptoms appear around the age of 1 year, and late-onset PD (LOPD) in which symptoms appear later in childhood or in adulthood. In general, the earlier the onset of clinical manifestations, the faster the rate of symptom progression.3
Classic Infantile-Onset Pompe Disease
Classic IOPD appears at birth or within the first few months of life. The median age of onset is 2 months,3 however, some of the clinical features, such as ventricular hypertrophy, may be visible in utero.
CIOPD is a rapidly progressive disease characterized by significant cardiomegaly, hepatomegaly, muscle weakness (“floppy babies”), poor or diminished muscle tone (hypotonia), hyporeflexia or areflexia, feeding difficulties, failure to thrive, respiratory distress, and hypertrophic cardiomyopathy (abnormal thickening of the walls of the heart, especially the posterior wall of the left ventricle and the interventricular septum).
Heart enlargement, lung volume reduction, and areas of atelectasis can be observed in the chest X-rays of babies with CIOPD. Some infants can also have moderate liver enlargement.
Infants with CIOPD also develop feeding and swallowing problems that may result from tongue weakness, a large protruding tongue (macroglossia), facial hypotonia, or poor oral motor skills. These problems may result in failure to thrive.
Affected infants may experience recurrent upper respiratory tract infection and pneumonia due to respiratory muscle weakness and changes in cough and swallowing mechanisms.
Developmental milestones such as rolling over, sitting up, and standing may be delayed or not achieved. Affected infants often rest their legs in a frog position, with the legs feeling firm on palpation (pseudohypertrophy).4 Loss of hearing is common in CIOPD.
Heart manifestations due to progressive glycogen deposition include conduction disorders (shortening of the PR interval on electrocardiogram), severe ventricular arrhythmias, inadequate coronary perfusion, subendocardial ischemia, diminished cardiac function, and sudden death. If left untreated, cardiorespiratory failure often results in death by 2 years of age due to progressive left ventricular outflow obstruction and respiratory insufficiency.5,6
Non-Classic Infantile-Onset Pompe Disease
Non-classic IOPD usually occurs around the age of 1 year. It is characterized by slower progression of symptoms and less severe cardiomyopathy than CIOPD. The early symptoms of NCIOPD include delays in motor skill maturation (such as rolling over and sitting) and progressive muscle weakness. Lifting of the head while lying down may be hindered due to weakness in the neck flexor muscles. Affected children may fall frequently and have difficulty climbing stairs or running due to muscle weakness in the limbs. Cardiomegaly may be present but heart failure is usually not observed. About 48% of affected children have a reduced forced vital capacity and may require assisted ventilation. They may experience sleep-disordered breathing, which may be accompanied with irritability, fatigue, or sleep apnea. Most children with NCIOPD survive only until early childhood due to respiratory problems.3,5
Late-Onset Pompe Disease
Late-onset PD is generally less severe than IOPD and is less likely to involve the heart. The slowly progressive disease can occur during childhood, adolescence, or adulthood, presenting as late as age 60. Patients experience slowly progressive muscle weakness that causes motor difficulties and respiratory failure over time. Generally, cardiomyopathy is not observed in individuals with LOPD.
It mainly affects skeletal muscles and the respiratory system. Signs and symptoms include skeletal myopathy, exercise intolerance, muscle weakness and dysfunction (particularly in the proximal muscles of the lower limbs, paratruncal muscles, diaphragm, and accessory respiratory muscles), low back pain, breathing failure, sleep apnea, dyspnea, and respiratory infections. Macroglossia and hepatomegaly are rare. Patients may have brain alterations; a study7 showed that vasculopathy with a Fazekas score > 2 and vertebrobasilar dolichoectasia were observed in more than 50% of patients with LOPD, and aneurysms were detectable in more than 10% of patients with LOPD. The age of death varies depending on the rate of disease progression, extent of respiratory muscle involvement, and other coexisting conditions.2-4
- Pompe disease. MedlinePlus. Updated May 20, 2021. Accessed July 23, 2021.
- Taverna S, Cammarata G, Colomba P, et al. Pompe disease: pathogenesis, molecular genetics and diagnosis. Aging (Albany NY). 2020;12(15):15856-15874. doi:10.18632/aging.103794
- Bay LB, Denzler I, Durand C, et al. Infantile-onset Pompe disease: diagnosis and management. Arch Argent Pediatr. 2019;117(4):271-278. doi:10.5546/aap.2019.eng.271
- Pompe Disease. NORD (National Organization for Rare Disorders). Accessed July 24, 2021.
- Leslie N, Bailey L. Pompe disease. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2007.
- Limongelli G, Fratta F. S1.4 cardiovascular involvement in Pompe disease. Acta Myol. 2011;30(3):202-203.
- Musumeci O, Marino S, Granata F, et al. Central nervous system involvement in late-onset Pompe disease: clues from neuroimaging and neuropsychological analysis. Eur J Neurol. 2019;26(3):442-e35. doi:10.1111/ene.13835
Reviewed by Debjyoti Talukdar, MD, on 7/27/2021.