History

Danon disease usually manifests with the clinical triad of cardiomyopathy, skeletal myopathy, and intellectual disability.^{[4, 5, 6]}The skeletal myopathy and intellectual disability are less common in females than in males. Regardless of sex, cardiomyopathy can present as a result of symptoms or congestive heart failure (CHF) or an arrhythmia-related event, such as syncope or sudden death.^[11]Patients are also newly identified when asymptomatic relatives of patients with established Danon disease are evaluated and are found to have the disease.

Specific cardiac symptoms^[26]
- Male patients may present with palpitations or documented arrhythmias, syncope, chest pain, or cardiac arrest.^{[2, 11, 10, 1, 8]}
- Female patients most typically present more with symptoms of dilated cardiomyopathy and CHF.^{[11, 4]}
Specific neurologic symptoms
- Male patients with Danon disease have weakness of the proximal extremities and neck muscles in the pattern of a limb-girdle muscular dystrophy. The weakness slowly progresses over time but can remain stable.
- Female patients have relatively little difficulty with weakness or none at all.^[4]
- Most male patients have intellectual disability or a learning disorder.^{[4, 8, 12]}
- Some male patients present with neurologic symptoms in infancy, including difficulties in walking and delay in achieving developmental milestones.^{[2, 9]}
- Spinazzi reported 3 patients that had cardioembolic strokes. All 3 patients had a history of atrial fibrillation.^[27]

Physical

See the list below:

Cardiac findings^[26]
- Heart murmurs can be noted upon examination. However, cardiac findings may be normal.^{[2, 7]}
- With advanced disease, signs of CHF (eg, dyspnea upon exertion, decreased exercise tolerance) can occur.
- In addition, signs of poor cardiac output (eg, poor capillary refill in the extremities or kneecaps) can be seen.
- Signs of CHF are often seen in female patients upon initial presentation.
Neurologic findings
- Male patients with Danon disease have mild weakness in the proximal extremities and neck muscles in a pattern of limb-girdle muscular dystrophy. As the muscles weaken, the deep tendon reflexes diminish, and, in rare cases, muscular atrophy is seen.^[4]
- Peripheral neuropathy and maculopathy were reported in one patient with Danon syndrome.^[15]
- Cerebellar and cranial-nerve problems have not been reported.
Ophthalmologic findings
- Males
  - Moderate loss of central visual acuity
  - Depigmentation of the peripheral retina^[8]
  - Decreased visual acuity with diffuse choriocapillary atrophy^[9]
- Females^[12]
  - Peripheral pigmentary retinopathy
  - Lamellar opacities in the lens
  - Nonspecific changes on electroretinography
Other findings: Hepatomegaly and splenomegaly, as well as foot deformities, were reported in several patients.^{[2, 7, 4]}

Causes

The transmission of Danon disease is often X-linked dominant; however, spontaneous mutations have been documented.^[1]Phenotypic expression varies.^[10]

Differential Diagnoses

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Media Gallery

Echocardiogram of a patient with Danon disease and severe hypertrophy. The septum is between the arrows. Note the asymmetry between the septum and the posterior wall of the left ventricle. Also see Media files 2-3. Calibration markings are in centimeters. Ao = ascending aorta just above the aortic valve; LV = left ventricle; LVPW = left ventricular posterior wall.
Echocardiogram, short-axis view in diastole, in the same patient as in Media files 1 and 3. Because of the degree of hypertrophy, the cavitary volume is smaller than normal. Calibration markings are in centimeters. Ao = ascending aorta just above the aortic valve; LV = left ventricle; LVPW = left ventricular posterior wall.
Echocardiogram, short-axis view in systole, in the same patient as in Media files 1-2. Note the increased thickening of the septum. Calibration markings are in centimeters. Ao = ascending aorta just above the aortic valve; LV = left ventricle; LVPW = left ventricular posterior wall.
Horizontal ventricular sections of the heart from 16-year-old male adolescent with Danon disease obtained after orthotopic cardiac transplantation. Massive hypertrophy is present (heart weight, 785 g), with diffuse severe fibrosis and marked ventricular dilatation.
Myocyte hypertrophy and vacuolization with interstitial fibrosis in the myocardium of a heart removed during cardiac transplantation (periodic acid-Schiff [PAS] stain; original magnification, X400).
Electron photomicrograph shows autophagic vacuoles with glycogen in a heart removed during cardiac transplantation (uranyl acetate and Reynolds lead citrate; original magnification X20,000).
Electron photomicrograph shows increased amounts of intermyofibrillar glycogen in the myocardium (uranyl acetate and Reynolds lead citrate; original magnification, X13,000).

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Author

Keith K Vaux, MD Professor of Medicine, Clinical Chief and Division Director, Division of Medical Genetics, Department of Medicine, University of California, San Diego, School of Medicine; Director, Rare Disease Program, Rady Children's Hospital San Diego and UC San Diego

Keith K Vaux, MD is a member of the following medical societies: American Academy of Pediatrics, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

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 for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical and Translational Research, College of American Pathologists

Disclosure: Nothing to disclose.

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, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Acknowledgements

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, Cardiac Electrophysiology Society, International Society for Holter and Noninvasive Electrocardiology, and Pediatric and Congenital Electrophysiology Society

Disclosure: Nothing to disclose. 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 for Clinical Pathology, American Society of Cytopathology, College of American Pathologists, and International Academy of Pathology

Disclosure: Nothing to disclose.