eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Danon Disease: Differential Diagnoses & Workup

Author: Christopher C Erickson, MD, Associate Professor, Departments of Pediatrics and Internal Medicine, Electrophysiology and Pacing, University of Nebraska College of Medicine; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine
Coauthor(s): Janice L McAllister, MD, Assistant Professor, Department of Pediatrics, University of Nebraska College of Medicine; Consulting Staff, University of Nebraska Medical Associates, St Joseph Hospital, Children's Hospital of Omaha; Stanley J Radio, MD, Professor, Department of Pathology and Microbiology, University of Nebraska Medical Center
Contributor Information and Disclosures

Updated: May 22, 2008

Differential Diagnoses

Cardiomyopathy, Dilated
Cardiomyopathy, Hypertrophic
Cardiomyopathy, Restrictive
Supraventricular Tachycardia, Wolff-Parkinson-White Syndrome

Other Problems to Be Considered

  • X-linked myopathy with excessive autophagy (XMEA)
  • Infantile autophagic vacuolar myopathy
  • Acid maltase deficiency (Pompe disease, glycogen-storage disease type II)
  • PRKAG2 mutation form of hypertrophic cardiomyopathy (HCM)
  • Wolff-Parkinson-White syndrome
  • Becker muscular dystrophy
  • Other limb-girdle muscular dystrophies such as caveolinopathy type 3: Limb-girdle muscular dystrophies manifest with weakness in the shoulder and hip-girdle muscles and are subtyped according to the affected muscle-cell protein. At least 20 genes cause symptoms of limb-girdle muscular dystrophy.

Workup

Laboratory Studies

  • Serum CK levels are elevated in male patients at 2-3 times the normal value, even if clinical myopathy is mild.2,10,15,11,4,6,1,8,12
  • Levels of brain natriuretic peptide (heart failure peptide) may be elevated when patients have a dilated form of the disease with symptoms of CHF.
  • Liver enzyme levels are persistently elevated, although liver dysfunction does not seem to occur. Aspartate transaminase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and serum aldolase concentrations all tend to be elevated in at least one half of patients.2,10,15,4,6,8

Imaging Studies

  • Echocardiography2,9,10,4,6
    • Findings are abnormal in all patients with Danon disease (see Media files 1-3).
    • Either concentric or asymmetric hypertrophy is present in most male patients, although some can present with late-stage dilated cardiomyopathy. Female patients usually present with dilated cardiomyopathy.
  • MRI
    • Cardiac MRI may be useful for assessing hypertrophy and function and to detect possible areas of poor gadolinium uptake that indicate scarring.
    • MRI of the brain may reveal areas of involvement including hyperintensities of supratentorial white matter and cortical atrophy.16,11,17

Other Tests

  • Molecular genetics studies
    • Mutations in the LAMP2 gene were found in many patients with Danon disease.7,11,4,6,1,8,17
    • The LAMP2 gene is on chromosome Xq24 and contains 9 coding exons, with 2 alternate last exons: 9a and 9b.18,4,6,1
    • LAMP2a and LAMP2b are created with alternative splicing of exon 9a and 9b. LAMP2b is expressed most prominently in muscle and brain, and LAMP2a is expressed in greatest quantity in other tissues.19,20
    • Mutations in LAMP2 have included single or multiple base-pair deletions, additions, and substitutions that result in frameshift or nonsense mutations.7,11,4,6,1,8,17
    • In addition, intronic mutations that produce skipping of one or more entire exons has been reported.
  • Electrocardiography2,9,10,4,6
    • All patients have abnormal ECG findings.
    • Pre-excitation (Wolff-Parkinson-White syndrome) is more common in Danon disease than in classic hypertrophic cardiomyopathy (HCM) due to sarcomeric mutation.
    • Large voltage can be seen.
    • Other conduction abnormalities are reported, including the following:
  • Holter monitoring: This should be used to monitor for atrioventricular blocks and atrial or ventricular arrhythmias.
  • Event recording: Event recorders are used to record the cardiac rhythm during the time the patient has symptoms. Event monitors are worn for most of each day for as long as one month at a time to increase the likelihood of recording the rhythm during an event.
  • Electroencephalography (EEG): Electroencephalography has revealed mild abnormalities, such as background rhythm slowing, in a minority of patients.
  • Electromyography (EMG): Electromyography reveals myopathic units in male patients and myotonic discharges in a few male patients.1

Procedures

  • Biopsy of skeletal muscle: Skeletal muscle biopsy is indicated to look for characteristic changes, including an absence of LAMP2 protein. This finding is diagnostic even without the molecular genetic testing, although lack of a LAMP2 mutation leave considerable doubt about the biopsy findings.
  • Cardiac catheterization: Cardiac catheterization is not needed for the diagnosis of Danon disease. However, if the patient is a candidate for cardiac transplantation, cardiac catheterization is indicated.
  • Electrophysiologic study with ablation: If evidence suggests the presence of arrhythmias due to an accessory pathway in the presence of Wolff-Parkinson-White syndrome on ECG, ablation may be necessary to eliminate the accessory pathway. Otherwise, electrophysiologic study is not indicated in patients with Danon disease.

Histologic Findings

  • Vacuolar myopathy is present with many vacuolar contents reacting positively with periodic acid-Schiff (PAS) stain and revealing increased acid phosphatase and nonspecific esterase activity. Normal architecture is seen on acetylcholine (ACH) stains without evidence of fiber grouping. No ragged red fibers are seen. Inflammation and fibrosis are absent.2,10 LAMP2 is absent on immunofluorescence or Western blots, whereas antibody stains for dystrophin and lysosomal-associated membrane protein-1 (LAMP1) are usually positive.7,4,17
  • Electron microscopy reveals autophagic vacuoles and excess glycogen. The glycogen is both membrane bound and free between myofibrils.2,9,10,4
  • Regarding pathology of the cardiac muscle, endomyocardial biopsy samples may have scattered vacuoles or granules, which stain positively for PAS. Ultrastructural examination of biopsy samples demonstrate changes similar to those observed with skeletal muscle biopsy. Findings include increased amounts of glycogen, both free and membrane bound, along with autophagic vacuoles. Mitochondria have normal morphology without atypical cristae patterns.10,21,15
  • Autopsy or explant specimens examined at the time of transplantation reveal cardiomegaly with ventricular hypertrophy and biatrial and biventricular dilatation.10,15 Interstitial fibrosis is often prominent, whereas myocardial vacuoles may not contain abundant PAS-positive material as commonly as is seen in biopsy material (see Media files 4-5).

More on Danon Disease

Overview: Danon Disease
Differential Diagnoses & Workup: Danon Disease
Treatment & Medication: Danon Disease
Follow-up: Danon Disease
Multimedia: Danon Disease
References
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References

  1. Arad M, Maron BJ, Gorham JM, et al. Glycogen storage diseases presenting as hypertrophic cardiomyopathy. N Engl J Med. Jan 27 2005;352(4):362-72. [Medline].

  2. Danon MJ, Oh SJ, DiMauro S, et al. Lysosomal glycogen storage disease with normal acid maltase. Neurology. Jan 1981;31(1):51-7. [Medline].

  3. Morisawa Y, Fujieda M, Murakami N, et al. Lysosomal glycogen storage disease with normal acid maltase with early fatal outcome. J Neurol Sci. Oct 8 1998;160(2):175-9. [Medline].

  4. Sugie K, Yamamoto A, Murayama K, et al. Clinicopathological features of genetically confirmed Danon disease. Neurology. Jun 25 2002;58(12):1773-8. [Medline].

  5. Maron BJ, Gardin JM, Flack JM, et al. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. Aug 15 1995;92(4):785-9. [Medline].

  6. Charron P, Villard E, Sebillon P, et al. Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey. Heart. Aug 2004;90(8):842-6. [Medline].

  7. Nishino I, Fu J, Tanji K, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature. Aug 24 2000;406(6798):906-10. [Medline].

  8. Yang Z, McMahon CJ, Smith LR, et al. Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation. Sep 13 2005;112(11):1612-7. [Medline].

  9. Riggs JE, Schochet SS, Gutmann L, et al. Lysosomal glycogen storage disease without acid maltase deficiency. Neurology. Jul 1983;33(7):873-7. [Medline].

  10. Byrne E, Dennett X, Crotty B, et al. Dominantly inherited cardioskeletal myopathy with lysosomal glycogen storage and normal acid maltase levels. Brain. Jun 1986;109 (Pt 3):523-36. [Medline].

  11. Lacoste-Collin L, Garcia V, Uro-Coste E, et al. Danon's disease (X-linked vacuolar cardiomyopathy and myopathy): a case with a novel Lamp-2 gene mutation. Neuromuscul Disord. Nov 2002;12(9):882-5. [Medline].

  12. Fanin M, Nascimbeni AC, Fulizio L, et al. Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon disease. Am J Pathol. Apr 2006;168(4):1309-20. [Medline].

  13. Laforet P, Charron P, Maisonobe T, et al. Charcot-Marie-Tooth features and maculopathy in a patient with Danon disease [case report]. Neurology. Oct 26 2004;63(8):1535. [Medline].

  14. Prall, F. R.; Drack, A.; Taylor, M.; Ku, L.; Olson, J. L.; Gregory, et al. Ophthalmic manifestations of Danon disease. Ophthalmology. 2006;113:1010-1013.

  15. Dworzak F, Casazza F, Mora M, et al. Lysosomal glycogen storage with normal acid maltase: a familial study with successful heart transplant. Neuromuscul Disord. May 1994;4(3):243-7. [Medline].

  16. Kashio N, Usuki F, Akamine T, et al. Cardiomyopathy, mental retardation, and autophagic vacuolar myopathy. Abnormal MRI findings in the head. J Neurol Sci. Sep 1991;105(1):1-5. [Medline].

  17. Echaniz-Laguna A, Mohr M, Epailly E, et al. Novel Lamp-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease. Muscle Nerve. Mar 2006;33(3):393-7. [Medline].

  18. Froissart R, Maire I. Danon Disease. Orphanet Encyclopedia. 2002. [Full Text].

  19. Konecki DS, Foetisch K, Zimmer KP, et al. An alternatively spliced form of the human lysosome-associated membrane protein-2 gene is expressed in a tissue-specific manner. Biochem Biophys Res Commun. Oct 13 1995;215(2):757-67. [Medline].

  20. Furuta K, Yang XL, Chen JS, et al. Differential expression of the lysosome-associated membrane proteins in normal human tissues. Arch Biochem Biophys. May 1 1999;365(1):75-82. [Medline].

  21. Tachi N, Tachi M, Sasaki K, et al. Glycogen storage disease with normal acid maltase: skeletal and cardiac muscles. Pediatr Neurol. Jan-Feb 1989;5(1):60-3. [Medline].

  22. Spirito P, Bellone P, Harris KM, et al. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. Jun 15 2000;342(24):1778-85. [Medline].

  23. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. Jan 20 2005;352(3):225-37. [Medline].

  24. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. May 28 2003;289(20):2685-94. [Medline].

  25. Maron BJ, Ackerman MJ, Nishimura RA, et al. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol. Apr 19 2005;45(8):1340-5. [Medline].

  26. Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. Jun 8 2004;109(22):2807-16. [Medline].

  27. Stuberg WA. Muscular dystrophy and muscular atrophy. In: Campbell SK, Vander Linden DW, Palisano RJ, eds. Physical Therapy for Children. 3rd ed. Philadelphia, Pa: WB Saunders;. 2005: 421-52.

  28. Maron BJ, Estes NA, Maron MS, et al. Primary prevention of sudden death as a novel treatment strategy in hypertrophic cardiomyopathy. Circulation. Jun 17 2003;107(23):2872-5. [Medline].

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Further Reading

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Keywords

Danon disease, Danon syndrome, Danon's disease, Danon's syndrome, lysosomal-associated membrane protein-2 deficiency, LAMP2, LAMP-2 deficiency, glycogen storage disease, glycogen-storage disease, lysosomal glycogen storage disease with normal acid maltase activity, hypertrophic cardiomyopathy with muscular dystrophy, HCM, hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome, WPW syndrome, idiopathic hypertrophic subaortic stenosis, IHSS, aortic stenosis, hypertension, Pompe disease, Fabry disease, maltase deficiency, dilated cardiomyopathy, skeletal myopathy, mental retardation, congestive heart failure, CHF, syncope, sudden death, learning disorder, maculopathy, hepatomegaly, splenomegaly, foot deformities, atrioventricular block, left bundle-branch block, bradycardia, ventricular tachycardia

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Contributor Information and Disclosures

Author

Christopher C Erickson, MD, Associate Professor, Departments of Pediatrics and Internal Medicine, Electrophysiology and Pacing, University of Nebraska College of Medicine; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine
Christopher C Erickson, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Heart Association, Heart Rhythm Society, International Society for Holter and Noninvasive Electrocardiology, and Pediatric and Congential Electrophysiology Society
Disclosure: Nothing to disclose.

Coauthor(s)

Janice L McAllister, MD, Assistant Professor, Department of Pediatrics, University of Nebraska College of Medicine; Consulting Staff, University of Nebraska Medical Associates, St Joseph Hospital, Children's Hospital of Omaha
Janice L McAllister, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society
Disclosure: Nothing to disclose.

Stanley J Radio, MD, Professor, Department of Pathology and Microbiology, University of Nebraska Medical Center
Stanley J Radio, MD is a member of the following medical societies: American Society of Clinical Pathologists, American Society of Cytopathology, College of American Pathologists, and International Academy of Pathology
Disclosure: Nothing to disclose.

Medical Editor

James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago
James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Pathologists, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia
David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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