Danon Disease Workup

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

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Imaging Studies

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  • 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]
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Other Tests

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  • 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:
  • 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]
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Procedures

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  • 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.
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Histologic Findings

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  • 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).
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