Pompe Disease (GAA deficiency) can be distinguished from other diseases that cause cardiomyopathy and muscle weakness by the presence of elevated creatinine kinase (CK) and the absence of other metabolic abnormalities such as lactic acidosis, metabolic acidosis, and hypoglycemia. 

Differential Diagnosis for Infantile-Onset Hypertrophic Cardiomyopathy

A list of diseases associated with cardiomyopathy in infancy is detailed below:

  1. Lysosome-associated membrane protein 2 (LAMP2) deficiency
  2. Fatty acid oxidation disorders (FAODs):
  • Very-long-chain acyl-CoA dehydrogenase deficiency
  • Long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency
  • Carnitine transporter deficiency
  • Carnitine-acylcarnitine translocase deficiency
  • Carnitine palmitoyltransferase deficiency type 2
  1. Mitochondrial and respiratory chain disorders

LAMP2 deficiency, also known as Danon disease, is an X-linked disorder of autophagy that leads to an accumulation of autophagic vacuoles in affected tissues. It is characterized by cardiomyopathy, skeletal myopathy, intellectual disability, and visual problems.1 It can be diagnosed using muscle biopsy and DNA testing. Muscle biopsy typically shows intracytoplasmic vacuoles containing autophagic material and glycogen. The presence of DNA mutations in the LAMP2 gene is confirmatory.2

Fatty acid oxidation disorders are a group of innate errors of metabolism that affect beta oxidation of fatty acids or the carnitine transport system of fatty acids into the mitochondria. Age of onset is variable with severe forms, such as long-chain FAODs manifesting earlier in life. Signs that are common across FAODs include hypoketotic hypoglycemia, hyperammonemia, liver disease and liver failure, cardiac and skeletal myopathy, rhabdomyolysis, and retinal degeneration.3,4 Fatty acid oxidation disorders are usually diagnosed with newborn screening using tandem mass spectrometry. DNA testing can also be performed where available.4

Mitochondrial and respiratory chain disorders have high phenotypic variabilities, ranging from mild exercise intolerance to fatal infantile encephalomyopathy.5,6 Mitochondrial DNA studies aid in confirming the diagnosis.7 

Differential Diagnosis for Infantile-Onset Hypotonia without Cardiomyopathy

Spinal muscular atrophy (SMA) type 1 and glycogen storage disease (GSD) type IIIa are associated with infantile-onset hypotonia without cardiomyopathy. 

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder that leads to progressive weakness and loss of movement. It results from the degeneration of alpha motor neurons in the anterior horn of the spinal cord. Common symptoms include symmetrical muscle weakness, hypotonia, and muscular atrophy, typically of the proximal muscles and the lower extremities.8 Spinal muscular atrophy can be detected using newborn screening and confirmed with DNA testing, which reveals deletions of the SMN1 (survival motor neuron 1) gene in 95% of cases.9 Additional work-up includes CK levels, nerve conduction velocity studies, electromyography, and muscle biopsy. (See Spinal Muscular Atrophy – Diagnosis). 

Glycogen storage disease type IIIa is an autosomal recessive disorder of the glycogen debrancher enzyme.10 The liver is frequently involved, and GSD type IIIa may present as hypoglycemia and hepatomegaly in childhood. Additional features include ketoacidosis, hyperlipidemia, and growth retardation.11 Cardiomyopathy may develop later in life.12 Diagnosis is made with genetic testing, revealing mutations in the AGL gene, or by the measurement of debrancher enzyme activity in the fibroblasts.13 

Differential Diagnosis for Late-Onset Disease

Both GSD type V (McArdle disease) and GSD type VI (Hers disease) may manifest with findings later in life. Becker muscular dystrophy (BMD) is characterized by muscle weakness that can manifest as early as 5 years of age or as late as 60 years of age.14

McArdle disease is due to a deficiency in myophosphorylase, and it typically presents in adolescence or early adulthood with exercise intolerance, fatigue, myalgia, cramps, poor endurance, and weakness. Myoglobinuria and elevated CK are the most common lab findings. Myoglobin is toxic to the kidneys and may result in acute kidney injury following exercise.15 Diagnosis is confirmed with genetic testing. Additional tests include the forearm exercise test and muscle biopsy. 

Hers disease is due to a deficiency of liver phosphorylase that manifests with hepatomegaly, ketosis, hyperlipidemia, mild hypoglycemia, increased liver transaminases, and growth retardation.16 Triggers for hypoglycemia include infection and fasting.17 Diagnosis is obtained with molecular genetic testing for pathogenic variants of the PYGL gene and an enzyme assay for liver phosphorylase activity.18 

Becker muscular dystrophy is a disorder of dystrophin that results in progressive muscle weakness. Age of onset is variable, however, patients are usually capable of ambulation throughout their teenage years.19 Cardiomyopathy is a common feature of BMD.20 Lab testing can reveal elevated CK levels 5 times the upper limit of normal. Genetic testing confirms the diagnosis.19


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2. Taylor MRG, Ku L, Slavov D, et al.; Familial Cardiomyopathy Registry. Danon disease presenting with dilated cardiomyopathy and a complex phenotype. J Hum Genet. 2007;52(10):830-835. doi:10.1007/s10038-007-0184-8

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4. Merritt JL II, Norris M, Kanungo S. Fatty acid oxidation disorders. Ann Transl Med. 2018;6(24):473. doi:10.21037/atm.2018.10.57

5. Lalani SR, Vladutiu GD, Plunkett K, Lotze TE, Adesina AM, Scaglia F. Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency. Arch Neurol. 2005;62(2):317-320. doi:10.1001/archneur.62.2.317

6. Spiegel R, Saada A, Flannery PJ, et al. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. J Med Genet. 2016;53(2):127-131. doi:10.1136/jmedgenet-2015-103361

7. Taylor RW, Schaefer AM, Barron MJ, McFarland R, Turnbull DM. The diagnosis of mitochondrial muscle disease. Neuromuscul Disord. 2004;14(4):237-245. doi:10.1016/j.nmd.2003.12.004

8. Wirth B, Karakaya M, Kye MJ, Mendoza-Ferreira N. Twenty-five years of spinal muscular atrophy research: from phenotype to genotype to therapy, and what comes next. Annu Rev Genomics Hum Genet. 2020;21:231-261. doi:10.1146/annurev-genom-102319-103602

9. Spinal muscular atrophy fact sheet. National Institute of Neurological Disorders and Stroke. Accessed July 28, 2021.

10. Yang-Feng TL, Zheng K, Yu J, Yang BZ, Chen YT, Kao FT. Assignment of the human glycogen debrancher gene to chromosome 1p21. Genomics. 1992;13(4):931-934. doi:10.1016/0888-7543(92)90003-b

11. Geberhiwot T, Alger S, McKiernan P, et al. Serum lipid and lipoprotein profile of patients with glycogen storage disease types I, III and IX. J Inherit Metab Dis. 2007;30(3):406. doi:10.1007/s10545-007-0485-2

12. Hershkovitz E, Forschner I, Mandel H, et al. Glycogen storage disease type III in Israel: presentation and long-term outcome. Pediatr Endocrinol Rev. 2014;11(3):318-323.

13. Kishnani PS, Austin SL, Arn P, et al.; ACMG. Glycogen storage disease type III diagnosis and management guidelines. Genet Med. 2010;12(7):446-463. doi:10.1097/GIM.0b013e3181e655b6

14. Bradley WG, Jones MZ, Mussini JM, Fawcett PR. Becker-type muscular dystrophy. Muscle Nerve. 1978;1(2):111-132. doi:10.1002/mus.880010204

15. Quinlivan R, Buckley J, James M, et al. McArdle disease: a clinical review. J Neurol Neurosurg Psychiatry. 2010;81(11):1182-1188. doi:10.1136/jnnp.2009.195040

16. Beauchamp NJ, Taybert J, Champion MP, et al. High frequency of missense mutations in glycogen storage disease type VI. J Inherit Metab Dis. 2007;30(5):722-734. doi:10.1007/s10545-007-0499-9

17. Hoogeveen IJ, van der Ende RM, van Spronsen FJ, de Boer F, Heiner-Fokkema MR, Derks TGJ. Normoglycemic ketonemia as biochemical presentation in ketotic glycogen storage disease. JIMD Rep. 2016;28:41-47. doi:10.1007/8904_2015_511

18. Labrador E, Weinstein DA. Glycogen storage disease type VI. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2009.

19. Thada PK, Bhandari J, Umapathi KK. Becker muscular dystrophy. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2021.20. Melacini P, Fanin M, Danieli GA, et al. Myocardial involvement is very frequent among patients affected with subclinical Becker’s muscular dystrophy. Circulation. 1996;94(12):3168-3175. doi:10.1161/01.cir.94.12.3168

Reviewed by Debjyoti Talukdar, MD, on 7/29/2021.