Genetics of Glycogen-Storage Disease Type II (Pompe Disease) Differential Diagnoses

Updated: Oct 12, 2023
  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
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Diagnostic Considerations

Infantile-onset (classic and non-classic variant) Pompe disease

Disorders to be considered in the differential diagnoses include the following:

  • Spinal muscular atrophy 1 (Werdnig-Hoffman disease): Hypotonia, feeding difficulties, progressive proximal muscle weakness, and areflexia; no cardiac involvement; caused by a defect in the SMN1 gene located on chromosome 5; inheritance is autosomal recessive
  • Danon disease: Hypotonia, hypertrophic cardiomyopathy, and myopathy due to excessive glycogen storage caused by defects in lysosome-associated membrane protein 2 (LAMP2); inheritance is X-linked–dominant with LAMP2 gene locus of Xq24
  • Endocardial fibroelastosis: Respiratory and feeding difficulties, cardiomegaly, and heart failure without significant muscle weakness; etiology often is viral, but familial cases with X- linked, autosomal-dominant, and autosomal-recessive inheritance have been described
  • Carnitine uptake disorder: Muscle weakness and cardiomyopathy without elevated serum concentration of creatine kinase (CK); inheritance is autosomal recessive; mutations in the SLC22A5 gene (cytogenetic location on chromosome 5) cause primary carnitine deficiency
  • Glycogen storage disease type IIIa (Cori disease; debrancher deficiency; GSD IIIa): Hypotonia, cardiomegaly, muscle weakness, and elevated serum concentration of CK with more dramatic liver involvement than typically seen in GSD II; inheritance is autosomal recessive and results from mutation of the AGL gene located on chromosome 1
  • Glycogen storage disease type IV (Andersen disease; branching-enzyme deficiency; GSD IV): Hypotonia, cardiomegaly, muscle weakness, and elevated serum concentration of CK with more dramatic liver involvement than typically seen in GSD II (similar to GSD IIIa); inheritance is autosomal recessive
  • Idiopathic hypertrophic cardiomyopathy: Biventricular hypertrophy without hypotonia or pronounced muscle weakness
  • Myocarditis: Inflammation of the myocardium leading to cardiomegaly without hypotonia or muscle weakness
  • Mitochondrial/respiratory chain disorders: Wide variation in clinical presentation; may include hypotonia, respiratory failure, cardiomyopathy, hepatomegaly, seizures, deafness, and elevated serum concentration of CK ; distinguishable from GSD II by the absence of hypotonia and presence of cognitive involvement [18]

Late-onset Pompe disease (ie, childhood, juvenile, and adult-onset)

Early involvement of the respiratory muscles is useful in distinguishing juvenile-onset Pompe disease from many other neuromuscular disorders. The following disorders are to be considered in the differential diagnoses:

  • Limb-girdle muscular dystrophy: Progressive muscle weakness in the legs, pelvis, and shoulders with sparing of the truncal muscles
  • Duchenne-Becker muscular dystrophy: Progressive proximal muscle weakness, respiratory insufficiency, and difficulty ambulating; primarily affects males; inheritance is X-linked
  • Polymyositis: Progressive, symmetric, unexplained muscle weakness
  • Glycogen-storage disease type V (McArdle disease; muscle phosphorylase deficiency; GSD V): Elevated serum concentration of CK and muscle cramping with exertion; inheritance is autosomal recessive; GSD V is caused by mutations in the PYGM gene, which codes for the myophosphorylase enzyme; the PYGM gene locus is on chromosome 11 at 11q13
  • Glycogen-storage disease type VI (Hers disease; GSD VI): Hypotonia, hepatomegaly, muscle weakness, and elevated serum concentration of CK; inheritance is autosomal recessive; GSD VI is caused by mutations of the liver glycogen phosphorylase ( PYGL) gene located on chromosome 14 (14q21-q22) [18]

Differential Diagnoses