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Mutations in the GAA gene have been found to be associ- ated with GLYCOGEN STORAGE DISEASE II; GSD2 (OMIM #232300)[1], is an autosomal recessive lysosomal storage disease. Pompe disease has been classified into: classic infantile, juvenile and adult forms involvement of skeletal muscles dominates the clinical picture Matsuishi et al. (1984).

Classic infantile-onset: Age of onset is usually in the first two to six months of life, with hypotonia and muscle weak- ness, motor developmental delay, feeding difficulties, fail- ure to thrive, respiratory distress or infections, cardiac prob- lems (cardiomegaly, generalised hypertrophy, a murmur and cardiomyopathy) and hepatomegaly. Children with this form usually have a severe deficiency of the acid alpha-glu- cosidase enzyme. If not treated, the symptoms progress rapidly and the hypertrophic cardiomyopathy may develop a left ventricular outflow tract obstruction or compress adja- cent respiratory structures. Cardiorespiratory failure could result in death within the first year of life.compress adjacent respiratory structures. Cardiorespiratory failure could result in death within the first year of life.

INon Classic infantile-onset: Age of onset is within the first year of life, with motor developmental delay and weakness. Cardiomegaly is less common, and cardiac involvement is not present in all the patients. The rate of clinical progression is slower and without treatment, death will usually occur in childhood as a result of respiratory insufficiency.

Late or adult onset form: The late-onset type of Pompe disease may not become apparent until later in childhood, adolescence or adulthood. Late-onset Pompe disease is usually milder than infantile-onset and is less likely to in- volve the heart. Clinical features include proximal muscle weakness, fatigue, orthopnoea, sleep apnea and respira- tory failure. Individuals affected by late-onset have a par- tial deficiency (2-40%) of the enzyme acid alpha-glucosi- dase. Without treatment, morbidity and mortality occur mainly as a result of respiratory insufficiency and failure, with death occurring anytime from the third decade on- wards mainly as a result of respiratory insufficiency and fail- ure, with death occurring anytime from the third decade on- wards.


Patient born of 3° consanguineous marriage presented with peripheral hypotonia with quadriparesis, hypertrophic car- diomyopathy, and has been evaluated for glycogen storage pompe disease type II.

Tests Prescribed

  1. Enzyme analysis for Alpha glucosidase
  2. Clinical Exome Sequencingt

About the Prescribed Tests

Test Name Sample Type Method Description
Enzyme analysis for Alpha glucosidase 2-4 ml sodium heparin blood Fluorometry assay with artificial substrate Assay carried on leukocytes
Clinical Exome Sequencing 2-4 ml EDTA blood Next Generation Sequencing Mean coverage of 80-100X coverage. Target coverage 200X

Test Results

  1. Enzyme analysis: Baby was found to have reduced alpha glucosidase enzyme activity (19.1 nmol/hr/mg) vs. biological reference range 56-296 (88.5±23.7) nmol/hr/mg.
  2. Clinical Exome Sequencing: In Exome data, missense mutations in GAA gene on Exon 19 of Chr 17: 78092588(c.2783A>G / p.Tyr928Cys) and on Exon 6 of Chr 17: 78082136 (c.2783A>G / p.Tyr928Cys) was ob- served and is suspected to be a double or compound heterozygous in Autosomal recessive pattern of inheritance.


In such type of carrier status cases, Validation of the variant by Sanger sequencing and/or Parental segregation analysis can be recommended.


  1. The recommended first-tier test for glycogen storage disease type II (Pompe disease) is Alpha glucosidase(acid maltase), Leukocytes .
  2. Individuals with GAA activity below the reference range for these tests are more likely to have variants in the GAA gene that are identifiable by molecular genetic testing.
  3. Exome sequencing along with measurement of enzyme activity can significantly improve the diagnostic yield.

This bulletin is compiled by

Name Designation Contribution
Ms. Bushan Niharika Research Officer Compilation
Ms. S Ramya Research Officer Compilation
Ms. Divya Borkar Sr. Manager, Enzymology Enzyme Assay
Ms. Vineeta Singh Vice President - Scientific Affairs Exome Analysis


  2. Matsuishi, T., Yoshino, M., Terasawa, K., Nonaka, I. Childhood acid maltase deficiency: a clinical, biochemical, and morphologic study of three patients. Arch. Neurol. 41: 47-52, 1984.[PubMed: 6360103] [Full Text].