Pompe disease is a progressive, multisystemic, debilitating and potentially fatal neuromuscular disorder. It was first described in 1932 by Dutch pathologist Johannes C. Pompe, who reported the case of a 7 month old infant who died of idiopathic cardiac hypertrophy1. This infant was found to have massive glycogen accumulation in many tissues, but predominantly in skeletal and cardiac muscles. In 1963 the disease was linked to an inherited deficiency of the lysosomal enzyme, acid alpha-glucosidase (GAA)2, which is responsible for the breakdown of glycogen to glucose. The result is intra-lysosomal accumulation of glycogen, primarily in muscle cells, that leads to a progressive loss of muscle function.
A gene located on chromosome 17 (17q25.2-q25.3) encodes for the production of acid alpha-glucosidase (GAA), an enzyme responsible for the breakdown of glycogen to glucose inside lysosomes2,3. Mutations in this gene cause marked deficiency or absence of GAA enzyme activity, resulting in intra-lysosomal accumulation of glycogen, primarily in muscle cells3.
Cellular and tissue damage
Continuous accumulation of glycogen causes lysosomes to swell and rupture, resulting in cellular damage. This in turn leads to progressive degeneration of skeletal and respiratory muscles (together with cardiac muscle primarily in infants), eventually resulting in loss of function2,4.
The following microscopy image is an example of glycogen accumulation and resultant muscle pathology, which often occurs before any clinically detectable signs or symptoms:
This electron micrograph of a human infant’s skeletal muscle cell is characteristic of patients with Pompe disease. As glycogen accumulates, it causes lysosomes to enlarge and abnormally invade cellular space (see arrows). Although some healthy myofibrils may still be present early in the course of the condition, myofibrils are almost completely replaced by glycogen in advanced Pompe disease, eventually impairing muscle function. Adapted from Thurberg et al., 20065.
The glycogen build-up in Pompe disease does NOT typically cause abnormalities of glucose metabolism, such as hypoglycemia, because glycogen stored in lysosomes is not part of the gluconeogenic pathway.
Single pathology, variable disease progression
Enzyme level variability
While Pompe disease is always described by lower than normal GAA activity, the exact degree of residual enzyme activity varies among patients and patient populations:
- Infants with Pompe disease usually have less than 1% of average normal GAA activity6.
- Children and adults with Pompe disease may show residual GAA activity of 1−30% of average normal levels6.
In general, there is poor correlation between residual GAA activity and clinical manifestations in children and adults, although infants are always severely affected.
Patients with classic infantile Pompe disease usually show an almost complete absence of GAA enzyme activity, with marked cardiomegaly and rapid glycogen accumulation in skeletal muscle that may be 10 times more than normal.2 In this patient population, disease progresses very rapidly and is usually fatal within the first year of life without treatment7.
In children and adults, the disease generally progresses at a slower rate than in classic infantile patients, with little or no cardiac involvement. However, Pompe disease is relentlessly progressive and associated with significant morbidity and/or premature mortality8-10.
- Pompe JC. Over idiopathische hypertrofie van het hart. Ned Tijdschr Geneeskd 1932; 76:304-311.
- Hirschhorn R, Reuser AJ. Glycogen Storage Disease Type II: Acid α-Glucosidase (Acid Maltase) Deficiency. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G., eds. The Online Metabolic and Molecular Bases of Inherited Disease. OMMBID. Available at: http://ommbid.mhmedical.com/book.aspx?bookid=971. Accessed February 2015.
- Pittis MG, Filocamo M. Molecular genetics of late onset glycogen storage disease II in Italy. Acta Myol. 2007;26(1):67-71.
- Muller-Felber W, Horvath R, Gempel K, Podskarbi T, Shin Y, Pongratz D, et al. Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients. Neuromuscul Disord. 2007.17;698-706.
- Thurberg BL, Lynch Maloney C, Vaccaro C, Afonso K, Tsai AC, Bossen E, Kishnani PS, O'Callaghan M. Characterization of pre- and post-treatment pathology after enzyme replacement therapy for Pompe disease. Lab Invest. 2006;86(12):1208-20.
- van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet. 2008;372(9646):1342-53.
- Kishnani PS, Howell RR. Pompe disease in infants and children. J Pediatr 2004; 144(5 Suppl): S35-S43.
- Hagemans ML, Winkel LP, Van Doorn PA, et al. Clinical manifestation and natural course of late-onset Pompe’s disease in 54 Dutch patients. Brain 2005; 128:671-7.
- Wokke J, Escolar D, Pestronk A, Jaffe K, Carter G, van den Berg L, et al. Clinical features of late-onset Pompe disease: A prospective cohort study. Muscle Nerve 2008;38:1236-45.
- Gungor D, de Vries JM, Hop WC, et al. Survival and associated factors in 268 adults with Pompe disease prior to treatment with enzyme replacement therapy. Orphanet J Rare Dis 2011; 6: 34
GZEMEA.PD.14.11.0313 (1) – June 2018