Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Pompe disease is a rare autosomal recessive disorder also known as Type II glycogen storage disease (GSDII).1,2 This is a severe multisystemic metabolic disorder that is often fatal and exists in either infantile or childhood/adult forms.2
The hallmark of Pompe disease is the absence or reduced levels of lysosomal acid alpha-glucosidase (GAA) activity due to defects in the GAA gene. These defects ultimately lead to glycogen accumulation in the lysosomes of several tissues. The muscle tissue is particularly affected.2 It leads to a severe compromise of the skeletal muscle activity in patients of all ages, with progressive muscle weakness and mobility impairment. It leads also to weakness of the respiratory system due to impairment of the diaphragm and intercostal muscles.3
Enzyme replacement therapy (ERT) is the only approved therapy for the treatment of Pompe disease.1
Genetics of Pompe Disease
The GAA gene is located in the long arm of chromosome 17 (17q25.2-q25.3) and is composed of 20 exons.2 Pompe disease is caused by a pathogenic variant in both GAA gene copies. There are several genetic variants described for the GAA gene which lead to the reduced enzymatic activity.2 There are 562 GAA variants, including the 422 variants that are correlated with the disease, which are reported in the Pompe disease GAA variant database (http://www.pompevariantdatabase.nl/).These variants include point mutations, deletions and insertions that negatively impact the splicing and transcription processes and protein function.2
The severity of the disease is linked to the nature of the defect that is affecting the gene in addition to the residual activity of the enzyme.1 There are 2 major clinical phenotypes described for Pompe disease. These phenotypes are distinguished by their onset of presentation and by the absence or presence of cardiomyopathy.1 The infantile onset type (IOPD) is the most severe phenotype and includes patients that present GAA activity lower than 1%. Symptoms in these patients develop during the first year of life and progress steadily to hypertrophic cardiomyopathy.
The disease can lead to cerebrovascular defects and also to bone, gastrointestinal and urinary tract events.4 In the late-onset Pompe disease (LOPD) type, patients develop symptoms later in life, including during adulthood. This is a milder form of the disease, where GAA activity is shown higher than in IOPD.1
Pathophysiology Of Muscle Damage in Pompe Disease
GAA is synthesized as a 110-KD membrane bound precursor, containing an amino-terminal signal peptide.1,2 This precursor is glycosylated and phosphorylated in the endoplasmic reticulum (ER) and in the Golgi apparatus, respectively. Once in the lysosomes, post-translational modifications lead the precursor to fully processed lysosomal forms that have high affinity for glycogen.5,6
GAA is responsible for the total hydrolysis of glycogen to glucose that occurs within the lysosomes.2 The breakdown of this glycogen releases α-glucose that in this way is readily available for the cells.7 In Pompe disease, GAA levels are compromised in the tissues of the human body, leading to an accumulation of glycogen in the lysosomes of those tissues, with particular incidence in the skeletal muscle, smooth muscle and cardiac tissue.2,3 This glycogen buildup often results in lysosomal enlargement and rupture with subsequent cellular damage and organelle dysfunction.2,8 Pompe disease is known as the first identified lysosomal storage disorder.1
In addition to the abnormal intra-lysosomal storage, there is an increase in the autophagic material in the fibers of the skeletal muscle. Autophagy is an important catabolic process that allows the degradation of intracellular components of the cytosol in the lysosome, contributing for metabolic homeostasis and to cellular energy.9,10
For this process to occur, autophagosomes are formed, which take up the cytosolic components targeted for degradation and then fuse with the lysosomes. When glycogen is accumulating within the lysosomes, a damage to the lysosomal membrane is observed with a consequent release of the hydrolytic material. This material scatters and accumulates through the cytoplasm, compromising the muscle contractile units and this noncontractile material accumulated in the cell disrupts contractility.2,8 The dysfunction of the autophagic process is known to be responsible for muscle wasting.11
Autophagy can also compromise GAA maturation and glycogen clearance.12,13 A dysfunctional autophagic process is also correlated with a reduced mitochondrial function, further compromising the neuromuscular system.7 Glycophagy, a specific type of autophagy, has been recently described and is responsible for sustaining the degradation of cellular glycogen within autophagic vacuoles. This process is described to be involved in the capture of glycogen that is further degraded by GAA.2
Studies report that glycophagy modification can be involved in Pompe disease and also in diabetic cardiomyopathy. A protective role of this process in IOPD has been suggested due to the possibility of allowing a reduction of the glycogen-rich lysosomes.12
- Meena NK, Raben N. Pompe disease: new developments in an old lysosomal storage disorder. Biomolecules. 2020;10(9):1339. doi:10.3390/biom10091339
- Taverna S, Cammarata G, Colomba P, Sciarrino S, Zizzo C, Francofonte D et al. Pompe disease: pathogenesis, molecular genetics and diagnosis. Aging (Albany NY). 2020;12(15):15856-15874. doi:10.18632/aging.103794
- Pompe Disease. National Organization for Rare Disorders. Accessed July 18, 2021.
- Toscano A, Rodolico C, Musumeci O. Multisystem late onset pompe disease (LOPD): an update on clinical aspects. Ann Transl Med. 2019;7(13):284. doi:10.21037/atm.2019.07.24
- Wisselaar HA, Kroos MA, Hermans MM, van Beeumen J, Reuser AJ. Structural and functional changes of lysosomal acid alpha-glucosidase during intracellular transport and maturation. J Biol Chem. 1993;268(3):2223-31.
- Moreland RJ, Jin X, Zhang XK, Decker RW, Albee KL, Lee KL et al. Lysosomal acid alpha-glucosidase consists of four different peptides processed from a single chain precursor. J Biol Chem. 2005;;280(8):6780-91. doi: 10.1074/jbc.M404008200
- Palhegyi AM, Seranova E, Dimova S, Hoque S, Sarkar S. Biomedical implications of autophagy in macromolecule storage disorders. Front Cell Dev Biol. 2019;7:179. doi:10.3389/fcell.2019.00179
- 8.Kohler L, Puertollano R, Raben N. Pompe disease: from basic science to therapy. Neurotherapeutics. 2018;15(4):928-942. doi:10.1007/s13311-018-0655-y
- Kuma A, Mizushima N. Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin Cell Dev Biol. 201021(7):683-90. doi:10.1016/j.semcdb.2010.03.002
- Singh R, Cuervo AM. Autophagy in the cellular energetic balance. Cell Metab. 2011;13(5):495-504. doi:10.1016/j.cmet.2011.04.004
- Masiero E, Sandri M. Autophagy inhibition induces atrophy and myopathy in adult skeletal muscles. Autophagy. 2010;6(2):307-9. doi:10.4161/auto.6.2.11137
- Zhao H, Tang M, Liu M, Chen L. Glycophagy: an emerging target in pathology. Clin Chim Acta. 2018 Sep;484:298-303. doi: 10.1016/j.cca.2018.06.014
- Nascimbeni AC, Fanin M, Tasca E, Angelini C, Sandri M. Impaired autophagy affects acid α-glucosidase processing and enzyme replacement therapy efficacy in late-onset glycogen storage disease type II.Neuropathol Appl Neurobiol. 2015;41(5):672-5. doi: 10.1111/nan.12214
Reviewed by Harshi Dhingra, MD, on 7/27/2021.