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Disease

Pathology

Pompe disease, also termed glycogen storage disease type II or acid maltase deficiency, is an inherited lysosomal storage disorder with an estimated frequency of 1 in 40,000 births [1]. The disease is characterized by a total or partial deficiency of the enzyme acid α-glucosidase. This enzyme is needed to break down glycogen that is stored within the lysosome, a cytoplasmic organelle involved in cellular recycling and tissue remodeling (figure 1). Deficiency of acid α-glucosidase leads to accumulation of lysosomal glycogen in virtually all cells of the body, but the effects are most notable in muscle (figure 2) [2-4]. The pathologic mechanisms by which glycogen accumulation eventually causes muscle malfunction are not fully understood. Muscle wasting in Pompe disease has been explained by increased tissue breakdown by autolytic enzymes released from ruptured lysosomes [5]. Another hypothesis is that glycogen-filled lysosomes and clusters of non-contractile material disturb the myofibrillar morphology and thus the transmission of force in the muscle cells [6].



Figure 1
Degradation of glycogen in the lysosomes by acid α-glucosidase.
In the cytoplasm, glucose is converted to glycogen, a glucose polymer, as a way to store energy. When energy is needed, glycogen is again degraded to glucose. Some of the glycogen in the cytoplasm is captured in a membrane and transported to the lysosomes in a process called 'autophagy'. In the lysosomes this glycogen is degraded by the enzyme acid α-glucosidase. When α-glucosidase is deficient, lysosomal glycogen is not degraded and accumulates.
 



Figure 2
Lysosomal glycogen storage in Pompe disease.
This high magnification electron microscopy picture shows a piece of skeletal muscle from a mouse with Pompe disease. The three dark oval structures are lysosomes filled with glycogen. The smaller structures at the left and right of two of these lysosomes are mitochondria, cellular compartments where energy is generated. The lightly stained striated areas are unaffected.
 




Clinical features

The classic infantile form of Pompe disease presents shortly after birth, at a median age of 1.6 months. Affected neonates have virtually no residual acid α-glucosidase activity and show generalized muscle weakness, hypotonia, a rapidly progressive cardiac hypertrophy, poor motor development and failure to thrive. Their growth deviates from the normal curve, even despite naso-gastric tube feeding. An enlarged liver and tongue are characteristically present. Important motor milestones like turning over, sitting and standing are not achieved. The median age of death is 6 to 8 months; patients rarely survive beyond the first year [4, 7].

Patients with milder or 'late-onset' forms of Pompe disease do have some residual acid α-glucosidase activity. In these patients the disease presents as a slowly progressive proximal myopathy without cardiac involvement, eventually leading to wheelchair dependency and use of respiratory support. The main cause of death is respiratory failure, sometimes associated with pulmonary infections [4, 8]. The course of the disease is very heterogeneous: onset of symptoms may range from the 1st to the 6th decade. This has led to a further sub-typing, based on age at onset and rate of progression, in non-classic infantile, childhood, juvenile and adult forms [4]. However, this division is rather arbitrary. In fact, Pompe disease comprises a continuous spectrum of phenotypes, with the generalized, rapidly progressive classic infantile form on one extreme, and adult patients presenting only with muscular symptoms on the other.

Genetic heterogeneity

The enzyme deficiency in Pompe disease is caused by pathogenic mutations in the acid α-glucosidase gene (GAA) located on chromosome 17. The mode of inheritance is autosomal recessive. A patient has two pathogenic mutations in the acid α-glucosidase gene, one on each chromosome. Basically, the nature of the mutations in the acid α-glucosidase gene and the combination of mutant alleles determine the level of residual lysosomal acid α-glucosidase activity and primarily the clinical phenotype of Pompe disease. Although exceptional cases have been described, in general a combination of two alleles with fully deleterious mutations leads to virtual absence of acid α-glucosidase activity and to the severe classic infantile phenotype. A severe mutation in one allele and a milder mutation in the other result in a slower progressive phenotype with residual activity up to 23% of average control activity. In these patients genotype and enzyme activity are not always predictive of the age at onset and the progression of the disease. For example, patients with the common c.-32-13T>G mutation, combined with a fully deleterious mutation on the other allele, all show significant residual enzyme activity and a protracted course of disease, but onset of symptoms varied from the 1st year of life to late adulthood [9].
At present more than 200 different mutations in the acid α-glucosidase gene are known. A list of all known mutations and their functional effects is given on this website under molecular aspects/ Mutations.

References

  • Ausems MG, Verbiest J, Hermans MP, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet 1999; 7:713-716.
  • De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem. J. 1955; 60:604-617.
  • Hers HG. a-Glucosidase deficiency in generalized glycogen storage disease (Pompe's disease). Biochem. J. 1963; 86:11-16.
  • Hirschhorn R, Reuser AJ. Glycogen storage disease type II; acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL, Sly W, Valle D (eds) The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2001: p 3389-3420.
  • Umpleby AM, Wiles CM, Trend PS, et al. Protein turnover in acid maltase deficiency before and after treatment with a high protein diet. J Neurol Neurosurg Psychiatry 1987; 50:587-592.
  • Drost MR, Hesselink RP, Oomens CW, Van der Vusse GJ. Effects of non-contractile inclusions on mechanical performance of skeletal muscle. J Biomech 2005; 38:1035-1043.
  • Van den Hout HM, Hop W, Van Diggelen OP, et al. The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature. Pediatrics 2003; 112:332-340.
  • 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; 128:671-677.
  • Kroos MA, Pomponio RJ, Hagemans ML, et al. Broad spectrum of Pompe disease in patients with the same c.-32-13T->G haplotype. Neurology 2007; 68:110-115.

Last updated 19-4-07 © Pompe Center, 2007.
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