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Clinical Features

Pompe disease is a rare, autosomal-recessive condition caused by mutations in the GAA gene, which codes for acid alpha-1,4-glucosidase and is located on chromosome 17. Currently, approximately 560 mutations in the GAA gene have been described.¹ The degree of enzyme deficiency correlates with age at onset and severity of symptoms.² Pompe disease comprises a vast spectrum of clinical features, which are determined by the nature of the mutations and the level of residual enzymatic activity.¹

The general clinical presentation is similar to that of various musculoskeletal diseases, particularly muscular dystrophies causing limb-girdle muscle weakness. Pompe disease affects the pelvic muscles to a greater degree than the shoulder muscles. Winging of the scapula is remarkable. The neck flexors, trunk extensors, and abdominal muscles are all commonly and significantly affected. Facial involvement with dysphagia or ptosis is also seen. The striking phenotypic similarities between Pompe disease and those of other muscle illnesses may be responsible for the underdiagnosis and misdiagnosis of Pompe disease. In contrast to the respiratory symptoms of other neuromuscular disorders, in which respiratory insufficiency generally develops after loss of ambulation, those of Pompe disease may appear early in the disease course while the patient is still ambulatory. The respiratory muscles of the upper airways, chest inspiratory muscles, and diaphragm are all involved. The development of respiratory failure may be gradual or sudden in Pompe disease, and respiratory muscle involvement is the most frequent cause of death. Disease progression is characterized by loss of respiratory muscle function, decreased vital capacity, sleep-disordered breathing, impaired cough, chronic respiratory insufficiency, and eventually cor pulmonale and acute respiratory failure.³

The clinical features of Pompe disease range from those of the classic form, which manifests early and has a severe phenotype, to those of the nonclassic form, which manifests later and has a milder phenotype. The level of residual GAA activity in muscles correlates with the disease phenotype. In cases of severe infantile Pompe disease, enzyme activity is less than 3% of normal, whereas in less severe, late-onset variants, residual levels vary from 3% to 30% of normal.³

Clinical Features of Various Forms of Pompe Disease

Classic Infantile-Onset Pompe Disease

This form manifests within a few months after birth and is characterized by generalized severe muscle weakness, poor muscle tone (“floppy infant syndrome”), liver enlargement, respiratory problems, heart defects, failure to gain weight, and failure to grow at a normal rate, along with hypertrophic cardiomyopathy and cardiorespiratory failure. If infantile-onset Pompe disease is left untreated, mortality due to heart failure can occur within the first year of life.⁴ If the disease is not diagnosed and treated early, infants generally do not survive beyond 1 year of age.³

Nonclassic Infantile-Onset Pompe Disease

This form manifests at approximately 1 year of age with delayed development of motor skills (eg, rolling over and sitting) and progressively increasing muscular weakness. Although the heart is markedly enlarged, cardiac failure does not usually develop. Muscle weakness causes major respiratory issues, and most patients do not live beyond early childhood.^4,5

Late-Onset Pompe Disease

This form of Pompe disease manifests later in childhood, sometimes during adolescence or adulthood, and progresses slowly. The course is relatively mild compared with that of the infantile-onset forms. The first symptom is usually proximal muscular weakness, which is more pronounced in the lower than the upper limbs. With further involvement of the intercostal muscles and diaphragm, worsening weakness results in respiratory failure, and patients become ventilator-dependent. Cardiac involvement is limited or absent. Patients often live into their fourth or fifth decade.^4,6

References

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
Pompe disease information page. National Institute of Neurological Disorders and Stroke. Accessed February 27, 2022.
Manganelli F, Ruggiero L. Clinical features of Pompe disease. Acta Myol. 2013;32(2):82-84.
Pompe’s disease. Physiopedia. Accessed February 27, 2022.
Pompe disease. MedlinePlus. Accessed February 27, 2022.
Cabello Andrade JF, Marsden D. Pompe disease: clinical perspectives. Orphan Drugs Res Rev. 2017;7:1-10. doi:10.2147/ODRR.S69109

Reviewed by Hasan Avcu, MD, on 3/16/2022.

Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.

Pompe Disease (PD)