eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Danon Disease

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: Jan 6, 2010

Introduction

Background

Hypertrophic cardiomyopathy (HCM) is a well-recognized cardiac muscle disorder that has been known by various names, including idiopathic hypertrophic subaortic stenosis (IHSS). On echocardiography, the characteristic appearance includes a thickened ventricular septum and left ventricular posterior wall without an obvious etiology (eg, hypertension, aortic stenosis). The most common cause of HCM is now known to be one of over 200 possible mutations in at least 10 genes that involve sarcomeric proteins.¹

Forms of HCM without evidence of mutations in sarcomeric proteins have also been identified. These diseases are a result of storage in cellular vacuoles and include Danon disease, Pompe disease, Fabry disease, and a form of HCM related to a mutation in the adenosine monophosphate (AMP)–activated, gamma-2 noncatalytic subunit of protein kinase (PRKG2).

In 1981, Danon described a multisystemic, lysosomal, glycogen-storage disease different from the previously described Pompe disease.² Danon disease is also known as lysosomal glycogen-storage disease with normal acid maltase. Danon disease is a rare form of HCM and muscular dystrophy.

Pathophysiology

Various genetic causes result in HCM as an isolated finding. However, in Danon disease, HCM is a major feature and also involves other organ systems; it includes a component of skeletal myopathy with proximal-limb muscle weakness, mild muscular atrophy, elevated plasma concentrations of creatine kinase (CK), ophthalmologic involvement, possible mental retardation, and elevated hepatic enzyme levels.³

Lysosomal-associated membrane protein-2 (LAMP2) is a heavily glycosylated protein found inside the lysosomal membrane.⁴ Microscopic characteristics of LAMP2 deficiency include small autophagic vacuoles in muscle fibers and excessive glycogen accumulation similar to that observed with maltase deficiency; however, acid maltase activity is normal.³ The excessive intrasarcomeric glycogen is mostly responsible for the severe myocardial hypertrophy and is possibly responsible for pre-excitation.

Frequency

United States

The incidence of Danon disease has not been determined. HCM is estimated to be present in 2 of every 1000 young adults, according to one large study.⁵

Charron et al examined 197 independent index cases with HCM.⁶ Genomic sequencing for the LAMP2 gene revealed mutations in 2 of 197 (1%) patients with HCM.

In another study, 75 patients with possible HCM underwent genetic analysis, 6 had LAMP2 mutations.¹

International

Reports from several countries describe Danon disease in patients of several nationalities.^7,4 However, the incidence of Danon disease appears to be too low to allow investigators to estimate its frequency in a given population.

Mortality/Morbidity

The prognosis for Danon disease in male patients is poor. Sugie et al reviewed the clinical features of 38 patients with genetically confirmed Danon disease.⁴ The mean age at death was 19 years (± 6 y) in male patients compared with 40 years (± 7 y) in female patients. See Prognosis.

Race

Reports of Danon disease have been published in several countries around the world.

Although HCM has been reported in different races and although several reports mentioned that multiple races were included in patient populations, no studies have described a racial distribution; some studies describe Danon disease only in whites.^5,1,8

Reports of 2 small studies described patients from different ethnicities, including Japanese, Italian, Spanish, black, and Greek patients. Some patients were included in both reports.^7,4

Likewise, reviews of multiple case reports or series do not mention the patients' races other than white.^{2,9,10,3,11,6}

Sex

The disease is inherited as an X-linked dominant trait, although spontaneous mutations have been reported in several families.¹

Males are usually more severely affected than females, particularly in degree of cardiomyopathy and age of death. This difference is at least partially explained by a gene-dosage effect.¹ Male individuals have only one X chromosome with the LAMP2 mutation, and most female individuals have one X chromosome with the mutation and one normal X chromosome; therefore, the effect is most pronounced in males. Maron et al reported 7 patients with LAMP2 mutations who have severe HCM, including one a female diagnosed at age 11 years with maximal LV thickness of 30 mm.¹²

Female patients have a relatively low incidence of skeletal myopathy and mental retardation.⁴ In addition, the female patients tend to have dilated cardiomyopathy rather than HCM.

Age

The age of presentation is somewhat variable. The greatest factor that affects the age at presentation is the patient's sex. The age at presentation can range from infancy to the second decade in males but is less well defined in females. Male patients typically present in their teens and rarely survive beyond their 20s.^2,9,3,8

Lacoste-Collin et al reported a new diagnosis of Danon disease in a 41-year-old man.¹¹

Van der Kooi et al reported several males from the same family with the proband who presented at age 46 years.¹³ Other male siblings had symptoms beginning in the mid 40s and are still alive in their 60s. Interestingly, a female sibling died suddenly at age 13 years.

In a series by Sugie et al, the age at presentation in males ranged from 10 months to 19 years (17 ± 7 y), with a mean age of death at 19 years (± 6 y).⁴ Female patients have a relatively mild form of the disease and often survive into their 30s and 40s. For female patients, the mean age at presentation was 38 years (± 12 y) with a mean age at death of 40 years (± 7 y).

Clinical

History

Danon disease usually manifests with the clinical triad of cardiomyopathy, skeletal myopathy, and mental retardation.⁴ The skeletal myopathy and mental retardation 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.¹⁰ 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
  • Male patients may present with palpitations or documented arrhythmias, syncope, chest pain, or cardiac arrest.^2,10,6,1,8
  • Female patients most typically present more with symptoms of dilated cardiomyopathy and CHF.^10,4
• 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 mental retardation or a learning disorder.^4,8,14
• Some male patients present with neurologic symptoms in infancy, including difficulties in walking and delay in achieving developmental milestones.^2,11
• Spinazzi reported 3 patients that had cardioembolic strokes. All 3 patients had a history of atrial fibrillation.¹⁵

Physical

• Cardiac findings
  • Heart murmurs can be noted upon examination. However, cardiac findings may be normal.^2,9
  • 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 knee caps) 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.¹⁶
  • Cerebellar and cranial-nerve problems have not been reported.
• Ophthalmologic findings
  • Males
    • Moderate loss of central visual acuity
    • Depigmentation of the peripheral retina⁸
    • Decreased visual acuity with diffuse choriocapillary atrophy¹¹
  • Females¹⁴
    • 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.^2,9,4

Causes

The transmission of Danon disease is often X-linked dominant; however, spontaneous mutations have been documented.¹ Phenotypic expression varies.⁶

• Search for CME/CE on This Topic »

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