Practice Essentials
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]
Signs and symptoms of Danon disease
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.
Cardiac findings
Heart murmurs can be noted upon examination. [2, 7] With advanced disease, signs of congestive heart failure (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]
Ophthalmologic findings
In males, these include moderate loss of central visual acuity, depigmentation of the peripheral retina, [8] and decreased visual acuity with diffuse choriocapillary atrophy. [9]
In females, findings include peripheral pigmentary retinopathy, lamellar opacities in the lens, and nonspecific changes on electroretinography.
Workup in Danon disease
Laboratory studies include the following:
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Brain natriuretic peptide (heart failure peptide) levels - May be elevated when patients have a dilated form of the disease with symptoms of CHF
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Liver enzyme levels - Persistently elevated, although liver dysfunction does not seem to occur
Imaging studies include the following:
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Echocardiography - Findings are abnormal in all patients with Danon disease
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Magnetic resonance imaging (MRI) - Cardiac MRI may be useful for assessing hypertrophy and function and for detecting possible areas of poor gadolinium uptake that indicate scarring, [14] while MRI of the brain may reveal areas of involvement, including hyperintensities of supratentorial white matter and cortical atrophy [9, 15, 16]
Other tests include the following:
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Molecular genetics studies
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Electrocardiography
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Holter monitoring
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Event recording
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Electroencephalography (EEG)
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Electromyography (EMG)
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Biopsy of skeletal muscle
Management of Danon disease
Medical care
Patients with Danon disease require frequent follow-up, with particular attention to the potential for atrial or ventricular arrhythmias and CHF. CHF must be treated according to the hemodynamic cause of the symptoms.
Surgical care
Several surgical interventions should be considered in patients with Danon disease. These include the following:
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Implantable loop recorder (ILR) - This device is implanted under the skin to record any arrhythmias that may happen when cardiovascular symptoms occur
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Implantable cardioverter-defibrillator (ICD)
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Cardiac transplantation
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 intellectual disability, and elevated hepatic enzyme levels. [17]
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. [18] The excessive intrasarcomeric glycogen is mostly responsible for the severe myocardial hypertrophy and is possibly responsible for preexcitation.
In a multicenter study of patients with Danon disease, Darden et al found that in those with preexcitation, fasciculoventricular and extranodal pathways were highly prevalent, as diagnosed through electrophysiologic studies (EPS). The investigators suggested that in patients with preexcitation and Danon disease, EPS be employed to determine whether a fasciculoventricular pathway or a potentially malignant extranodal accessory pathway is present. [19]
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. [20]
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. [21]
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. [22]
Charron et al examined 197 independent index cases with HCM. [10] 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. [23, 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. [22, 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. [23, 4]
Likewise, reviews of multiple case reports or series do not mention the patients' races other than white. [2, 7, 11, 17, 9, 10]
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. [24]
Female patients have a relatively low incidence of skeletal myopathy and intellectual disability. [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, 7, 17, 8]
Lacoste-Collin et al reported a new diagnosis of Danon disease in a 41-year-old man. [9]
Van der Kooi et al reported several males from the same family with the proband who presented at age 46 years. [25] 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).
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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.
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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.
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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.
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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.
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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).
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Electron photomicrograph shows autophagic vacuoles with glycogen in a heart removed during cardiac transplantation (uranyl acetate and Reynolds lead citrate; original magnification X20,000).
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Electron photomicrograph shows increased amounts of intermyofibrillar glycogen in the myocardium (uranyl acetate and Reynolds lead citrate; original magnification, X13,000).
