Pompe's Glycogen Storage Disease

Synonyms: glycogen storage disease type II; acid maltase deficiency

Pompe's disease is one of the glycogen storage disorders. The deficiency of the lysosomal enzyme alpha-1,4-glucosidase (acid maltase) leads to the accumulation of glycogen in many tissues:

• The clinical spectrum is continuous and broad, with presentation in infants, children and adults.¹
• In the infantile form, accumulation of glycogen in cardiac muscle leads to cardiac failure.
• Accumulation may also occur in the liver, which results in hepatomegaly and elevation of hepatic enzymes.
• Glycogen accumulation in muscle and peripheral nerves causes hypotonia and weakness.
• Glycogen deposition in blood vessels may result in intracranial aneurysms.

• The overall prevalence has been estimated at 1 in 40,000, with 1 in 138,000 for the infantile form and 1 in 57,000 for the adult form.²
• Pompe's disease has an estimated frequency of 1 in 40,000 in African-American, 1 in 50,000 in Chinese, 1 in 40,000 in Dutch, and 1 in 146,000 in Australian populations.¹
• Infantile and adult forms are inherited as autosomal recessive conditions. The gene has been traced to chromosome 17.³

• Presentation later in life is associated with a less severe form of disease.
• There is a continuous spectrum between the classic infantile and adult forms.
• The infantile form presents with hypotonia at any time after birth, but usually presents at between 4-8 weeks.
• The adult form usually presents as skeletal and respiratory muscle weakness. The typical age of presentation is 20-40 years.

Symptoms

• The infantile form may present with feeding and breathing difficulties and dyspnoea.
• May present with muscle weakness later in childhood.
• The adult form may have limb-girdle weakness and weakness of respiratory muscles.⁴

Signs

• Infantile form:
  • Cardiomegaly and congestive heart failure.
  • Generalised hypotonia, absent or reduced reflexes.
  • Enlarged tongue.
  • Reflexes may be depressed or absent because of glycogen accumulation in spinal motor neurons.
  • Alertness may be impaired.
• Adult form:
  • Weakness may affect only specific muscle groups, e.g. upper arms, and may be asymmetrical.
  • Limb-girdle weakness is common and respiratory muscle involvement may be prominent.⁵

• Other glycogen storage disorders.
• Muscular dystrophy: Duchenne's muscular dystrophy (or less severe muscular dystrophies for older onset disease).

• Serum creatine kinase and aspartate aminotransferase are elevated.⁶
• Definitive diagnosis is made by the measurement of acid alpha-glucosidase activity in cultured skin fibroblasts or peripheral blood lymphocytes.³
• Intracranial aneurysms may be shown on angiography or magnetic resonance angiography.
• Echocardiogram to assess heart size and degree of left ventricular hypertrophy.
• ECG: short PR interval and elevated QRS complexes in the infantile form.
• Muscle biopsy for the evaluation of differential diagnosis of muscle weakness.

• Enzyme replacement therapy:
  • Enzyme replacement therapy has been shown to be very effective and substantially improves the prospects for patients.¹
  • Alglucosidase alfa (Myozyme®), an enzyme produced by recombinant DNA technology, is licensed for long-term replacement therapy in Pompe's disease.⁷ Myozyme® is available by referral to an expert centre:⁸
    • Paediatric centres in England: Addenbrooke's (Cambridge), Birmingham Children's Hospital, Great Ormond Street Hospital, Willink (Manchester)
    • Adult centres in England: Addenbrooke's, The Hope (Manchester), National Hospital for Neurology and Neurosurgery (London), The Royal Free (London)
  • Alglucosidase alfa therapy has been shown to improve cardiac and skeletal muscle function.^9,10 Therapy has been shown to achieve significant reductions in the risk of death and invasive ventilation among treated patients.¹¹
• Symptomatic treatment of cardiac and respiratory failure may be required but does not significantly alter the clinical course.
• Diet therapy may provide temporary improvement but does not alter the disease course: a high-protein, low-carbohydrate diet may be beneficial.¹²
• Physiotherapy and occupational therapy may be required.
• Genetic counselling and prenatal diagnosis: chorionic villus sampling and amniocentesis can be used to determine enzyme activity in a fetus.
• Gene therapy remains a potentially effective treatment for the future.¹³

• In the infantile form, cardiomegaly and congestive heart failure lead to death.
• Cardiomegaly with progressive obstruction to left ventricular outflow is a major cause of mortality.
• Aspiration pneumonia; weakness of ventilatory muscles increases the risk of pneumonia.
• The adult form manifests with dystrophy and respiratory muscle weakness.
• In the adult form, intracranial aneurysms present the greatest complication.
• Liver failure may occur.

• Without enzyme replacement therapy, the infantile form is usually fatal, with most deaths occurring within 1 year of birth.¹⁴
• Later clinical onset usually corresponds with more benign symptoms and disease course.
• The adult form is not necessarily fatal, but complications such as rupture of an aneurysm, or respiratory failure, may cause significant morbidity and mortality.

1. van der Ploeg AT, Reuser AJ; Pompe's disease. Lancet. 2008 Oct 11;372(9646):1342-53. [abstract]
2. 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 Sep;7(6):713-6. [abstract]
3. Online Mendelian Inheritance in Man; Glycogen Storage Disease II.
4. Sivak ED, Salanga VD, Wilbourn AJ, et al; Adult-onset acid maltase deficiency presenting as diaphragmatic paralysis. Ann Neurol. 1981 Jun;9(6):613-5. [abstract]
5. Trend PS, Wiles CM, Spencer GT, et al; Acid maltase deficiency in adults. Diagnosis and management in five cases. Brain. 1985 Dec;108 ( Pt 4):845-60. [abstract]
6. Ausems MG, Lochman P, van Diggelen OP, et al; A diagnostic protocol for adult-onset glycogen storage disease type II. Neurology. 1999 Mar 10;52(4):851-3. [abstract]
7. British National Formulary; 58th Edition (September 2009) British Medical Association and Royal Pharmaceutical Society of Great Britain, London (link to current BNF).
8. Association for Glycogen Storage Disease (UK); Pompe Disease Pages.
9. Amalfitano A, Bengur AR, Morse RP, et al; Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial. Genet Med. 2001 Mar-Apr;3(2):132-8. [abstract]
10. Brady RO, Schiffmann R; Enzyme-replacement therapy for metabolic storage disorders. Lancet Neurol. 2004 Dec;3(12):752-6. [abstract]
11. Ibrahim J, McGovern M; Glycogen-Storage Disease Type II; eMedicine, October 2009.
12. Isaacs H, Savage N, Badenhorst M, et al; Acid maltase deficiency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J Neurol Neurosurg Psychiatry. 1986 Sep;49(9):1011-8. [abstract]
13. Coutelle C, Themis M, Waddington SN, et al; Gene therapy progress and prospects: fetal gene therapy--first proofs of concept--some adverse effects.; Gene Ther. 2005 Nov;12(22):1601-7. [abstract]
14. 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 Aug;112(2):332-40. [abstract]

• Association for Glycogen Storage Disease UK; Pompe Pages