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Pompe disease (GSD II)

Autosomal recessive (AR) disorder caused by deficiency of the lysosomal enzyme acid-α-glucosidase (GAA), leading to generalized accumulation of lysosomal glycogen especially in the heart, skeletal and smooth muscle, and the nervous system.

Introduction

Pompe disease, also called glycogen storage disease type II, is a genetically inherited condition caused by insufficient functioning of an enzyme called lysosomal acid alpha-1,4-glucosidase, or just acid alpha-glucosidase, due to a mutation of the GAA gene.

Autosomal recessive (AR) disorder caused by deficiency of the lysosomal enzyme acid-α-glucosidase (GAA), leading to generalized accumulation of lysosomal glycogen especially in the heart, skeletal and smooth muscle, and the nervous system.

  • Only glycogen storage disease (GSD II) that is also a lysosomal storage disease (LSD)

History

The disease is named after Joannes Cassianus Pompe, who characterized it in 1932. Pompe described accumulation of glycogen in muscle tissue in some cases of a previously unknown disorder. This accumulation was difficult to explain as the enzymes involved in the usual metabolism of glucose and glycogen were all present and functioning.

The basis for the disease remained a puzzle until Christian de Duve’s discovery of lysosomes in 1955 for which he won the Nobel Prize in 1974. His co-worker Henri G. Hers realised in 1965 that the deficiency of a lysosomal enzyme (α-glucosidase) for the breakdown of glycogen could explain the symptoms of Pompe disease. This discovery led to establishing the concept of lysosomal storage diseases, of which 49 have been described (to date).

Classification

Glycogen storage diseases (GSD):

Inherited metabolic disorders of glycogen metabolism
Simplified pathway of glycogen synthesis and degradation. | Ozen H. (2007). Glycogen storage diseases: new perspectives. World journal of gastroenterology, 13(18), 2541–2553. https://doi.org/10.3748/wjg.v13.i18.2541
Schematic of the pathways linked to glycogen metabolism. Glycogen breakdown produces glucose-1-phosphate (via glycogenolysis) and glucose (via glycophagy and debranching enzyme activity). Both products enter into the glycolytic pathway giving rise to pyruvate which acts as a key precursor for the TCA cycle, fatty acid synthesis and gluconeogenesis. The interconversion of pyruvate to lactate and alanine further integrate the metabolism of the liver and muscle tissues. Additionally, fructose-6-phosphate generated in glycolysis can also shunt to the pentose phosphate pathway for nucleotide synthesis. | Ellingwood, S. S., & Cheng, A. (2018). Biochemical and clinical aspects of glycogen storage diseases. The Journal of endocrinology, 238(3), R131–R141. https://doi.org/10.1530/JOE-18-0120

Pompe’s disease:

  • Infantile-onset PD (IOPD): Onset before 12 months with cardiomyopathy (Classic Pompe disease: ) or without cardiomyopathy (Non-classic Pompe disease)
  • Late-onset PD (LOPD): Onset after 12 months with cardiomyopathy (childhood, juvenile and adult-onset)

Clinical features

IOPD typical presentation:

  • Hypotonia (52-96% cases)
  • Progressive weakness
  • Macroglossia (29-62% cases)
  • Hepatomegaly (29-90% cases)
  • Cardiac involvement:
    • Left ventricular hypertrophy (83-100% cases)
    • Cardiomegaly (92-100% cases)
    • Hypertrophic cardiomyopathy (88% cases)
    • Murmur (46-75% cases)
  • Respiratory distress (41-78% cases)
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Photographs of patients with infantile onset Pompe disease. The sib pair (A, B; patients 1 and 2 respectively) have non-classical IOPD while patient 3 (C) has classical IOPD with macroglossia, tracheostomy and severe hypotonia. Abnormal EKG of patient 3 shows sinus tachycardia, short PR interval, ST segment and T wave abnormalities as well as left ventricular hypertrophy. | Dasouki, M., Jawdat, O., Almadhoun, O., Pasnoor, M., McVey, A. L., Abuzinadah, A., … Dimachkie, M. M. (2014). Pompe disease: literature review and case series. Neurologic Clinics, 32(3), 751–ix. https://doi.org/10.1016/j.ncl.2014.04.010

LOPD presentation:

  • Slowly progressive limb-girdle type weakness (95% cases)
  • Respiratory insufficiency without significant cardiomyopathy
  • Cardiac involvement:
    • Wolff-Parkinson-White syndrome
    • Left ventricular hypertrophy
    • Dilatation of ascending aorta
  • Rigid spine syndrome (progressive limitation of the neck and trunk)
  • Scoliosis
  • Low body weight 

Diagnosis

  • Muscle biopsies
  • GAA mutation analysis
  • GAA enzyme activity of muscle, skin fibroblasts, amniocytes
  • Dried blood spots (DBS)
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Histological examination of muscle biopsies of patients 9 (A, B) and 4 (C, D). H&E stained muscle biopsy (A) from patient 9 shows extensive vacuolar changes (asterisk) and positive acid phosphatase aggregates (#) in panel B. The H&E stained muscle biopsy (C) from patient 4 is essentially unremarkable while the muscle electron micrograph (D) showed membrane bound glycogen deposits and mildly distorted mitochondrial morphology. | Dasouki, M., Jawdat, O., Almadhoun, O., Pasnoor, M., McVey, A. L., Abuzinadah, A., … Dimachkie, M. M. (2014). Pompe disease: literature review and case series. Neurologic Clinics, 32(3), 751–ix. https://doi.org/10.1016/j.ncl.2014.04.010

Management

  • Alglucosidase alfa (Myozyme) (recombinant enzyme)

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