Pompe Disease (PD)

Pompe disease is a metabolic neuromuscular condition caused by a lack of the lysosomal enzyme acid alpha-glucosidase (GAA). The inheritance is autosomal-recessive. The clinical features range widely, with considerable disparities seen among patients in age at onset, rate of progression, and phenotype. Pompe disease is usually divided into infantile and late-onset variants on the basis of whether clinical signs appear before or after the age of 1 year. It is thought that the underlying pathophysiology causing tissue destruction is triggered by the expansion and rupture of glycogen-filled lysosomes.¹ 

Although muscle biopsy has drawbacks, it has become an indispensable technique for acquiring a thorough understanding of the pathology of Pompe disease, which can facilitate the development of better therapies. The evaluation of biopsy specimens has revealed that dysfunction of autophagy, an intracellular lysosome-dependent degradation pathway, contributes significantly to the pathogenesis of Pompe disease and interferes with drug delivery to lysosomes.² 

Muscle Biopsy Findings

Muscle fibers in muscle biopsy specimens stained with hematoxylin and eosin show glycogen-containing vacuoles, indicating a glycogen storage disorder. The vacuoles stain strongly with periodic acid Schiff (PAS). However, the muscle-specific alterations may be absent in 20% to 30% of patients who have late-onset Pompe disease with partial GAA enzyme deficiency. Additionally, although histochemical evidence consisting of PAS staining of accumulated glycogen in muscle is suggestive of a glycogen storage disease, it is not specific to Pompe disease.^3,4 Involvement in specimens of muscle tissue is heterogeneous. Glycogen accumulation has also been found in eccrine glands, pericytes, endothelial cells, fibroblasts, smooth muscle cells, and Schwann cells of skin and muscle small nerve fibers.⁵ 

Formerly, muscle biopsy was the preferred method of diagnosis. The presence of accumulated glycogen within myocytes has been used to make the diagnosis. The deposition of glycogen is not consistent in adult patients with Pompe disease, and affected muscle may be missed in biopsy specimens. In mildly damaged muscle, or muscle with notably increased fibrosis or lipid content, glycogen is not always evident. Lipofuscin inclusions can be detected in patients of any age. Muscle biopsy should not be performed routinely unless the diagnosis is ambiguous. Because a muscle biopsy result can be negative in 30% of affected individuals, this test should not be used to rule out Pompe disease.⁵ 

Liver Histology

On gross examination, the liver is enlarged. The surface is smooth and covered with purple dots. The dots are also observed on the cut parenchymal surface of the subcapsular region of the liver. Histologic examination of the liver shows vacuolization in hepatocytes, which are packed with material that stains with PAS.⁶ 

Cardiac Muscle Histology

On gross examination, the heart of an infant with Pompe disease appears enlarged and pale with thick walls. On microscopic examination, the cardiac myofibers are filled with glycogen. On cross-sectional specimens, the myofibrils appear to be pushed to the periphery. Although the walls are thick, hypertrophy is absent. Congestive heart failure is noted in these patients.⁷

References

1. Prater SN, Patel TT, Buckley AF, et al. Skeletal muscle pathology of infantile Pompe disease during long-term enzyme replacement therapy. Orphanet J Rare Dis. 2013;8(90). doi:10.1186/1750-1172-8-90
2. Feeney EJ, Austin S, Chien Y-H, et al. The value of muscle biopsies in Pompe disease: identifying lipofuscin inclusions in juvenile- and adult-onset patients. Acta Neuropathol Commun. 2014;2:2. doi:10.1186/2051-5960-2-2
3. ​​Fu Liong, Hiew et al. Late-onset glycogen storage disease type II (Pompe’s disease) with a novel mutation: a Malaysian experience. Case Rep Neurol Med. 2014;2014:926510. doi:10.1155/2014/926510
4. Leslie N, Bailey L. Pompe disease. GeneReviews® [Internet]. Updated May 11, 2017. Accessed March 1, 2022.
5. Murphy AP, Straub V. Pompe disease. SpringerLink. Posted February 28, 2018. Accessed March 1, 2022. 
6. dos Santos OC, Schultz R. The infantile-onset form of Pompe disease: an autopsy diagnosis. Autops Case Rep. 2015;5(4):45-51. doi:10.4322/acr.2015.022
7. Glycogen storage disease II. Brown Biology and Medicine. Pathology Residency and Fellowship Program. Accessed March 1, 2022. 

Reviewed by Kyle Habet, MD, on 3/18/2022.

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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.