Danon Disease 

Updated: Feb 09, 2016
Author: Keith K Vaux, MD; Chief Editor: Maria Descartes, MD 

Overview

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.[3]

Pathophysiology

Various genetic causes result in HCM as an isolated finding. In Danon disease, however, although HCM is a major feature, other organ systems are also involved; the disease 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.[4]

Lysosomal-associated membrane protein-2 (LAMP2) is a heavily glycosylated protein found inside the lysosomal membrane.[5] 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.[4] The excessive intrasarcomeric glycogen is mostly responsible for the severe myocardial hypertrophy and is possibly responsible for pre-excitation.

A study by Hashem et al using induced pluripotent stem cell–derived cardiomyocytes indicated that LAMP2 protein deficiency in Danon disease results in autophagic flux impairment, which in turn causes excessive oxidative stress and, subsequently, cardiomyocyte apoptosis.[6]

In a study that included two girls, aged 10 and 13 years, Hedberg Oldfors et al found evidence that early onset HCM in Danon disease, in contrast to the late-onset cases that can occur, may result from an uneven distribution of LAMP2 protein in cardiac muscle, with the protein lacking in some large portions of the muscle, while its expression is preserved in other large myocardial areas.[7]

Epidemiology

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.[8]

Charron et al examined 197 independent index cases with HCM.[9] 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.[10, 5] 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.[5] 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.[8, 1, 11]

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.[10, 5]

Likewise, reviews of multiple case reports or series do not mention the patients' races other than white.[2, 12, 13, 4, 14, 9]

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.[15]

Female patients have a relatively low incidence of skeletal myopathy and mental retardation.[5] 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, 12, 4, 11]

Lacoste-Collin et al reported a new diagnosis of Danon disease in a 41-year-old man.[14]

Van der Kooi et al reported several males from the same family with the proband who presented at age 46 years.[16] 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).[5] 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).

 

Presentation

History

Danon disease usually manifests with the clinical triad of cardiomyopathy, skeletal myopathy, and mental retardation.[5] 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.[13] 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, 13, 9, 1, 11]

    • Female patients most typically present more with symptoms of dilated cardiomyopathy and CHF.[13, 5]

  • 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.[5]

    • Most male patients have mental retardation or a learning disorder.[5, 11, 17]

    • Some male patients present with neurologic symptoms in infancy, including difficulties in walking and delay in achieving developmental milestones.[2, 14]

    • Spinazzi reported 3 patients that had cardioembolic strokes. All 3 patients had a history of atrial fibrillation.[18]

Physical

See the list below:

  • Cardiac findings

    • Heart murmurs can be noted upon examination. However, cardiac findings may be normal.[2, 12]

    • 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.[5]

    • Peripheral neuropathy and maculopathy were reported in one patient with Danon syndrome.[19]

    • Cerebellar and cranial-nerve problems have not been reported.

  • Ophthalmologic findings

    • Males

      • Moderate loss of central visual acuity

      • Depigmentation of the peripheral retina[11]

      • Decreased visual acuity with diffuse choriocapillary atrophy[14]

    • Females[17]

      • 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, 12, 5]

Causes

The transmission of Danon disease is often X-linked dominant; however, spontaneous mutations have been documented.[1] Phenotypic expression varies.[9]

 

DDx

Diagnostic Considerations

These include the following:

  • 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

Differential Diagnoses

 

Workup

Laboratory Studies

Serum creatine kinase (CK) levels are elevated in male patients at 2-3 times the normal value, even if clinical myopathy is mild.[1, 2, 5, 9, 11, 13, 14, 17, 20]

levels of brain natriuretic peptide (heart failure peptide) may be elevated when patients have a dilated form of the disease with symptoms of congestive heart failure (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, 5, 9, 11, 13, 20]

Majer et al found a mosaic mutation pattern in the asymptomatic mother of two brothers with a novel Danon disease mutation, suggesting, according to the authors, that the existence of such mosaicism in other women could mean that there is an underdiagnosed population of Danon disease carriers. The brothers had an Alu-mediated tandem duplication of exons 4 and 5, with LAMP2 being undetectable in their peripheral blood leukocytes. In the mother, however, the percentage of granulocytes with a deficiency of LAMP2 did not match the random pattern of X-chromosome inactivation in her leukocytes. Genetic analysis determined that the exon duplication was mosaically distributed in the mother’s somatic cells, accounting for the LAMP2/X-chromosome mismatch. Majer and colleagues suggested that LAMP2 flow cytometry could, owing to its sensitivity, be an effective pedigree screening tool in such cases.[21]

Imaging Studies

See the list below:

  • Echocardiography[2, 5, 9, 12, 13]

    • Findings are abnormal in all patients with Danon disease (echocardiographic findings are shown in the three images below).

      Echocardiogram of a patient with Danon disease and 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 th 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 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.
    • 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.[22]

    • MRI of the brain may reveal areas of involvement including hyperintensities of supratentorial white matter and cortical atrophy.[14, 19, 23]

Other Tests

See the list below:

  • Molecular genetics studies

    • Mutations in the LAMP2 gene were found in many patients with Danon disease.[10, 14, 5, 9, 1, 11, 24, 25, 26, 27]

    • The LAMP2 gene is on chromosome Xq24 and contains 9 coding exons, with 2 alternate last exons: 9a and 9b.[28, 5, 9, 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.[29, 30]

    • Mutations in LAMP2 have included single or multiple base-pair deletions, additions, and substitutions that result in frameshift or nonsense mutations.[10, 14, 5, 9, 1, 11, 24]

    • In addition, intronic mutations that produce skipping of one or more entire exons has been reported.

  • Electrocardiography[2, 12, 13, 5, 9]

    • 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:

      • Prolonged QRS complex

      • Atrioventricular block, including third-degree block

      • Left bundle-branch block

      • Bradycardia

      • Intra-atrial re-entrant tachycardia

      • Ventricular tachycardia

  • 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

See the list below:

  • 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

See the list below:

  • 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, 13] LAMP2 is absent on immunofluorescence or Western blots, whereas antibody stains for dystrophin and lysosomal-associated membrane protein-1 (LAMP1) are usually positive.[10, 5, 24]

  • Electron microscopy reveals autophagic vacuoles and excess glycogen. The glycogen is both membrane bound and free between myofibrils.[2, 12, 13, 5]

  • 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.[13, 31, 20]

  • Autopsy or explant specimens examined at the time of transplantation reveal cardiomegaly with ventricular hypertrophy and biatrial and biventricular dilatation.[13, 20] Interstitial fibrosis is often prominent, whereas myocardial vacuoles may not contain abundant PAS-positive material as commonly as is seen in biopsy material (examples of this fibrosis are shown in the 2 images below).

    Horizontal ventricular sections of the heart from 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 interst 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).
 

Treatment

Medical Care

Patients with Danon disease require frequent follow-up, with particular attention to the potential for atrial or ventricular arrhythmias and congestive heart failure (CHF). As is recommended in patients with hypertrophic cardiomyopathy (HCM), a ventricular septal thickness more than 30 mm is considered a risk factor for a life-threatening event, particularly in this group of patients who often have a poor prognosis for survival beyond their teenage years.[32]

An implantable cardioverter-defibrillator (ICD) may be indicated. However, in Maron’s study, all 7 patients had ICDs and 5 had lethal arrhythmias that did not convert with ICD therapy.[15] However, not all of those patients died from the arrhythmia. In addition, 4 of those 7 actually died of CHF. CHF must be treated according to the hemodynamic cause for the symptoms. For example, patients with HCM have a relatively restrictive physiology with diastolic dysfunction and should be treated accordingly (ie, improving ventricular filling, improved heart rate control, sinus rhythm maintenance, improved diastolic relaxation); whereas, those with a dilated form of cardiomyopathy tend to have a systolic dysfunction problem that may require different treatment (ie, improved afterload reduction and increased contractility).

Surgical Care

Several surgical interventions should be considered in patients with Danon disease. The proper timing of any of these interventions is not known; however, the risk of sudden death in teenage male patients appears to be substantial. This risk may influence decisions about the timing of surgical interventions.

  • Implantable loop recorder (ILR)

  • This device is implanted under the skin to record any arrhythmias that may happen when cardiovascular symptoms occur.

    • The usual indication is an assessment of severe symptoms that occur too infrequently to be recorded by using conventional, external event recorders.

    • The battery in one device (Reveal Plus; Medtronic, Minneapolis, MN) lasts for 14 months. It can be automatically activated when the programmed parameters of the device are satisfied. It can also be activated when the patient has symptoms. An activator that the patient carries is placed over the device, and a button is pushed to activate the ILR.

  • ICD placement

    • After Danon disease and severe hypertrophic changes of the heart are diagnosed, placement of an ICD should be considered. For patients who have the dilated form of cardiomyopathy, ICDs may be indicated because of the degree of their dysfunction and their history of arrhythmias.

    • Recommendations from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trial apply to these patients.[33]

    • Furthermore, if the degree of CHF has progressed to New York Heart Association class III or IV with maximal medical therapy (eg, beta-blockers, afterload reduction, spironolactone, diuretics), placement of a biventricular pacing system, usually a biventricular ICD, should be considered.[34]

  • Cardiac transplantation

  • Several reports mention patients with Danon disease who underwent cardiac transplantation.[20, 14, 11, 24, 15]

    • Cardiac transplant should be considered as long-term treatment because the life expectancy is short.[19] Consideration of cardiac transplantation is necessary because of the limited life expectancy of teenaged male patients, who have a high incidence of sudden death. Maron et al even recommend consideration of early transplant.[15]

    • In addition, female patients may need a cardiac transplant because they are not expected to live past their fifth decade.

    • Cardiac transplantation is a reasonable treatment for Danon disease despite the presence of muscular problems because the neurologic disability or problems are mild.

Consultations

Because of the severe nature of this disease and the short life expectancy in male patients, extensive counseling and education with the patient and family is important. When an ICD or cardiac transplantation is contemplated, psychiatric counseling may be needed. Dealing with these issues may be particularly challenging if the patient has clinically significant mental retardation.

Consultation with a neurologist is recommended to assess the degree of skeletal myopathy and cognitive deficiencies.

Genetic consultation regarding molecular testing and genetic counseling is important.

Diet

For the most part, no dietary restrictions are necessary for Danon disease. However, when the patient has symptoms of CHF, sodium restriction may be beneficial. Caffeine can potentially aggravate any underlying tachyarrhythmia.

Activity

Competitive athletic activity should be restricted for individuals with Danon disease and cardiomyopathy as recommended in the 36th Bethesda Conference: Eligibility Recommendations for Competitive Athletes With Cardiovascular Abnormalities.[35] Exceptions include activities classified as I-A, which include low-intensity sports with low static and low dynamic components, such as billiards, bowling, or golf.

As for noncompetitive activity, leisurely activities (eg, using an exercise bike or treadmill, playing doubles tennis, cycling at low intensity) are permitted in patients with HCM. The premise is that patients engaging in low-intensity activities are more apt than others to respond to the onset of warning symptoms.[36]

From a neurologic standpoint, male patients with Danon disease may exercise the skeletal muscles. However, they should avoid excessive fatigue, which could cause muscle injury.[37]

 

Medication

Medication Summary

No cardiac medications resolve the problem of hypertrophic cardiomyopathy (HCM), particularly in Danon disease. However, standard medications for congestive heart failure (CHF) and arrhythmias should be used as they are in other patients with these conditions. For Danon disease with HCM, no medical treatment is indicated unless the patient has symptoms of CHF or angina. On the contrary, patients with dilated cardiomyopathy should be given anti-CHF medications.

No medications are known to resolve or ease the neuromuscular symptoms of Danon disease.

To the authors' knowledge, no reports have demonstrated successful experience with any of the antiarrhythmic agents used in Danon disease. However, treatment of supraventricular tachycardia (SVT) should begin with beta-blockers. Digoxin and verapamil should be avoided when evidence suggests the presence of Wolff-Parkinson-White syndrome. Although ablation may be indicated, other antiarrhythmic medications (eg, propafenone, disopyramide, amiodarone, sotalol) may be helpful to control SVT if ablation is not possible or desired. The beneficial effects or adverse effects of these medications, when used in Danon disease, have not been established.

Diuretic agents

Class Summary

These drugs are indicated for CHF due to systolic or diastolic dysfunction.

Furosemide (Lasix)

Loop diuretic that increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Increases renal blood flow without increasing filtration rate. Onset of action generally within 1-h. Increases potassium, sodium, calcium, and magnesium excretion.

Dose must be individualized to patient. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after previous dose, until desired diuresis occurs. In infants, titrate with 1-mg/kg/dose increments until satisfactory effect achieved.

Diuretics have major clinical uses in managing disorders involving abnormal fluid retention (edema) or in treating hypertension; diuretic action decreases blood volume.

PO administration less potent diuretic effect than IV administration.

Spironolactone (Aldactone)

Potassium-sparing diuretic. Indicated for management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.

Beta blockers

Class Summary

These agents are indicated for the management of dilated cardiomyopathy.

Carvedilol (Coreg)

Used only for patients with dilated cardiomyopathy and CHF. Nonselective beta- and alpha-adrenergic blocker. Also has antioxidant properties. Does not appear to have intrinsic sympathomimetic activity. May reduce cardiac output and decrease peripheral vascular resistance.

Metoprolol (Lopressor)

Indicated for dilated cardiomyopathy. Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions.

ACE inhibitors

Class Summary

These agents reduce afterload in dilated cardiomyopathy and/or CHF.

Enalapril (Vasotec)

Prevents conversion of angiotensin I to angiotensin II (potent vasoconstrictor), increasing levels of plasma renin and reducing aldosterone secretion. Helps control blood pressure and proteinuria. Decreases pulmonary-to-systemic flow ratio in catheterization laboratory and increases systemic blood flow in patients with relatively low pulmonary vascular resistance. Favorable clinical effect when administered over a long period. Helps prevent potassium loss in distal tubules. Body conserves potassium; therefore, less PO potassium supplementation needed.

Patients who develop a cough, angioedema, bronchospasm, or other hypersensitivity reactions after starting ACE inhibitors should receive an angiotensin-receptor blocker.

Captopril (Capoten)

Prevents conversion of angiotensin I to angiotensin II (potent vasoconstrictor), lowering aldosterone secretion. Rapidly absorbed, but bioavailability significantly reduced with food intake. Peak concentration in 1 h; has short half-life. Cleared by kidney. Can be started at low dose and uptitrated prn and as patient tolerates.

Impaired renal function requires reduced dosage. Absorbed well PO. Give at least 1 h before meals. If added to water, use within 15 min.

Accepted as essential part of any antifailure therapy; provides symptomatic improvement and prolongs survival.

 

Follow-up

Further Outpatient Care

See the list below:

  • Most of the cardiac care for patients with Danon disease can be provided in an outpatient setting.

    • This care should include routine echocardiography to monitor the progression of hypertrophy and to detect changes suggestive of decreased left ventricular function and evolution to dilated cardiomyopathy.

    • Holter monitoring should be followed up every 6-12 months depending on the patient's symptoms and degree of hypertrophy, as determined with echocardiography.

  • Male patients with Danon disease may require physical therapy for range-of-motion exercises and should be seen as needed by a pediatric neurologist. No medications cure or ameliorate the neuromuscular symptoms of Danon disease.

Further Inpatient Care

See the list below:

  • Inpatient care is needed for patients with Danon disease who present with life-threatening arrhythmias or clinically significant congestive heart failure (CHF).

  • When the patient develops CHF due to the dilated form of the disease, inpatient medical care may be indicated to administer intravenous inotropic agents and diuretics.

  • When arrhythmias are noted, inpatient telemetry is helpful. Implantation of an implantable cardioverter-defibrillator (ICD) or pacemaker often necessitates an overnight admission with telemetry.

  • Inpatient care is usually not required to manage the neurologic symptoms of Danon disease.

Deterrence/Prevention

See the list below:

  • Currently, no treatment prevents the onset of Danon disease. Early and repeated echocardiographic surveillance of young male relatives of anyone with Danon disease should be performed. Identification of a specific mutation in LAMP2 in a family may allow relatives to consider presymptomatic DNA testing after thorough genetic counseling.

  • Holter monitoring should also be performed when Danon disease is diagnosed.

  • An ICD should be implanted when clinically significant septal thickening of more than 30 mm is noted on echocardiography, when a poor increase in blood pressure is noted during exercise testing, when ventricular tachycardia is noted on Holter monitoring, or if the patient has a family history of sudden death, as is recommended for patients with hypertrophic cardiomyopathy (HCM).[38] The data are insufficient to make a specific recommendation about ICDs in patients with Danon disease alone.

  • From a neurologic perspective, range-of-motion exercises help to prevent joint contractures as the skeletal muscles weaken.

Complications

See the list below:

  • Potential complications for this disease include syncope or sudden death before placement of an ICD.

  • As with other forms of dilated cardiomyopathy, low-flow states can pose a risk of intracardiac thrombus formation with the potential for stroke.

  • The onset of CHF symptoms can be abrupt and should initiate a discussion about and workup for cardiac transplantation.

Prognosis

See the list below:

  • Patients with Danon disease have a poor life expectancy.

    • The prognosis for male patients is poor. Most male patients die before their third decade from either a sudden cardiac arrhythmia or CHF.[5]

    • Female patients live to their fifth decade.[5] Death can be the result of a cardiac arrhythmia or CHF.

  • Male patients have mild weakness of the skeletal muscle with slow or no deterioration over time.

    • These patients also are likely to have a learning disorder or mild mental retardation.[5, 11, 17]

    • Previously reported cases have not documented any deterioration in mental capacity over time.

  • See Mortality/Morbidity.

Patient Education

See the list below:

  • The Hypertrophic Cardiomyopathy Association may have materials that can help patients and families understand the cardiac aspect of this disease, although Danon disease is not specifically mentioned.

  • The following Web sites may have information of interest regarding Danon syndrome:

    • Danon Disease Organization

    • National Institutes of Health Office of Rare Diseases and Genetic and Rare Diseases Information center

    • UpToDate Patient Information

    • The National Information Centre for Metabolic Diseases