Danon Disease
A number sign (#) is used with this entry because of evidence that Danon disease, also known as X-linked vacuolar cardiomyopathy and myopathy, is caused by mutation in the gene encoding lysosome-associated membrane protein-2 (LAMP2; 309060).
DescriptionDanon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease; 232300) with 'normal acid maltase' or alpha-glucosidase (GAA; 606800) (Danon et al., 1981). However, Nishino et al. (2000) stated that Danon disease is not a glycogen storage disease because glycogen is not always increased.
Sugie et al. (2005) classified Danon disease as a form of autophagic vacuolar myopathy, characterized by intracytoplasmic autophagic vacuoles with sarcolemmal features. The characteristic vacuole is believed to be an autolysosome surrounded by secondarily-generated membranes containing sarcolemmal proteins, basal lamina, and acetylcholinesterase activity.
X-linked myopathy with excessive autophagy (XMEA; 310440) is a distinct disorder with similar pathologic features.
Clinical FeaturesAntopol et al. (1940) described 2 brothers who died in the second decade of life with heart failure. Autopsy of 1 patient showed glycogen storage disease limited to the myocardium. Mehrizi and Oppenheimer (1960) reported 2 related patients with heart failure associated with unusual deposition of glycogen in the myocardium.
Danon et al. (1981) reported 2 unrelated males with mental retardation, hypertrophic cardiomyopathy, and proximal muscle weakness. One patient had hepatomegaly. Examination of skeletal muscle biopsies showed features suggestive of a lysosomal glycogen storage disease. However, acid alpha-glucosidase activity was normal, excluding a diagnosis of Pompe disease, or glycogen storage disease type II (GSD II). Both patients died at the age of 17 years. Riggs et al. (1983) described lysosomal storage disease with normal acid maltase activity in 2 brothers. One of the brothers showed muscle weakness at age 3 years. Both patients had Wolff-Parkinson-White electrocardiographic findings.
Bergia et al. (1986) reported a kindred in which 2 sisters gave birth to a total of 3 sons with mental retardation, scapuloperoneal muscular weakness, and hypertrophic cardiomyopathy. Intellectual deterioration began at about age 5 years. Hypertrophic cardiomyopathy manifesting itself in the teens led to death at ages 17 and 21 years in 2 of the patients. On evaluation in their teens, the affected males showed wasting of distal muscle groups, positive Gowers maneuver, and predominant humeroperoneal distribution of muscle weakness. Creatine kinase was elevated as was also lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. A marked myopia was also present. The mother of 2 of the patients, a presumed carrier of the mutant gene, had evidence of cardiomyopathy without elevated serum muscle enzymes.
Tripathy et al. (1988) described an 18-year-old black male who developed manifestations of complete atrioventricular nodal block; endomyocardial biopsy showed membrane-bound glycogen resembling the findings of GSD II. The glycogenosis appeared to be limited to the myocardium because the rest of the physical examination, the histology, and enzyme studies of muscle and skin fibroblasts were normal.
Dworzak et al. (1994) described a Sicilian family in which 3 males and 2 females over 3 generations were affected with lysosomal glycogen storage myopathy with normal acid maltase. Cardiac disease had led to the death of a woman in the first generation and of one of her sons. The proband, his sister, and her son, were alive and had been studied in detail. The index case underwent heart transplant. His 32-year-old sister had atrial fibrillation and mild left ventricular enlargement with systolic dysfunction on echocardiogram. She also had mild intellectual impairment, limb weakness, and mild muscle involvement on muscle biopsy. Dworzak et al. (1994) stated that this was the first case of a female with multisystem involvement.
In skeletal muscle biopsies from 3 patients with Danon disease, Murakami et al. (1995) found intracytoplasmic vacuoles with occasional folds or indentations in the sarcolemma that were connected to the membrane enclosing the vacuoles. Immunohistochemical studies showed that the vacuolar membranes contained acetylcholinesterase and proteins of the sarcolemma and basal lamina.
Sugie et al. (2002) described the clinicopathologic features of 20 affected men and 18 affected women from 13 families with Danon disease confirmed by genetic analysis. All patients had cardiomyopathy. Men were affected before the age of 20 years, whereas most affected women developed cardiomyopathy in adulthood. Eighteen of 20 male patients (90%) and 6 of 18 female patients (33%) had skeletal myopathy; 14 of 20 male patients (70%) and 1 of 18 female patients (6%) had mental retardation. Muscle histology revealed basophilic vacuoles that contained acid phosphatase-positive material within membranes that lacked LAMP2. Heart transplantation was the most effective treatment for the otherwise lethal cardiomyopathy.
Laforet et al. (2004) reported a patient with Danon disease who had features of axonal Charcot-Marie-Tooth disease (see, e.g., CMT2A1; 118210), including pes cavus, distal muscular atrophy of the lower limb, and distal sensory loss. He also developed progressive visual loss due to retinopathy as a young adult.
Lobrinus et al. (2005) reported a Swiss family with Danon disease confirmed by genetic analysis. There were 4 affected males and 2 affected females. The proband developed severe left ventricular cardiomyopathy with ventricular arrhythmia in adolescence. He had diffuse muscular atrophy with mild proximal and axial weakness and markedly increased serum creatine kinase. IQ was 76. Two first cousins had mild muscle involvement, normal intelligence, and cardiac involvement with cardiac symptom onset in adolescence. The mother of the 2 cousins died suddenly at age 40 years from cardiomyopathy. Cardiac muscle biopsy from the proband and 1 cousin showed hypertrophic cardiomyocytes with enlarged and irregular nuclei and vacuolated cytoplasm, as well as absence of LAMP2 protein. Electron microscopy showed that the vacuoles contained degenerating mitochondria, glycogen, small vesicles, and granular debris. Although skeletal muscle biopsies from all 3 patients showed normal morphology and normal glycogen content, all had complete absence of the LAMP2 protein. Cytoplasmic vacuoles could be seen in about 10% of skeletal muscle fibers in the proband and in approximately 1% of fibers in 1 cousin. No vacuoles were observed in the skeletal muscle of the other cousin. There was immunoreactivity to complement components C5b-9 of the membrane attack complex in some of the vacuoles, but not on the fiber surface.
Balmer et al. (2005) reported a mother and son with Danon disease confirmed by genetic analysis. The boy presented at age 2.5 years with mild left ventricular hypertrophy and mild myopathy. His heart disease progressed, resulting in death at age 16 years shortly before planned heart transplantation. His affected mother developed severe dilated cardiomyopathy and died at age 46 years. Postmortem analysis showed fibrosis and necrosis of the myocardium. Balmer et al. (2005) emphasized that cardiac transplantation is the only effective therapeutic option in Danon disease.
Prall et al. (2006) reported the ophthalmic manifestations of genetically proven Danon disease in 4 females and 2 males. The females demonstrated a peripheral pigmentary retinopathy, lens changes, myopia, abnormal electroretinogram, and abnormal visual fields. The males demonstrated a nearly complete loss of pigment in the retinal pigment epithelium. Prall et al. (2006) suggested that retinopathy could potentially be used to identify asymptomatic carriers.
Schorderet et al. (2007) identified diffuse retinal dysfunction, affecting the cones more than the rods, in 2 brothers and their maternal aunt with Danon disease caused by a mutation in LAMP2. Expression of the disease was milder in the aunt, who was an obligate carrier, than in the hemizygous boys, possibly due to lyonization.
Taylor et al. (2007) identified genetically confirmed Danon disease (309060.0012) in and reported long-term follow-up on the family that presented with dilated cardiomyopathy and was linked to the DMD gene (300337) by Towbin et al. (1993). The original female proband and her 3 sons had dilated cardiomyopathy; subsequently, 3 other male relatives developed severe concentric cardiac hypertrophy associated with Wolff-Parkinson-White syndrome. Other features in this family included skeletal myopathy with high serum creatine kinase, mild cognitive impairment in males, and a pigmentary retinopathy in females. Cardiac biopsy specimens showed extensive vacuolar changes in an affected adult male, but the skeletal muscle biopsy in a 13-month-old mutation-carrying male showed no vacuolization by standard histology. Taylor et al. (2007) concluded that X-linked dilated cardiomyopathy may be the presenting sign of Danon syndrome and that the absence of vacuolar myopathy in biopsies from young patients may not exclude Danon disease.
Maron et al. (2009) reported the clinical course and outcome of 7 young patients (6 boys and 1 girl) in whom LAMP2 mutations were previously identified by Arad et al. (2005). Over a mean follow-up period of 8.6 years and by ages 14 to 24 years, the patients developed left ventricular systolic dysfunction and cavity enlargement, with adverse clinical consequences including death from progressive refractory heart failure in 4 patients, sudden death in 1, aborted cardiac arrest in 1, and cardiac transplantation in 1. Left ventricular hypertrophy was particularly marked, with massive ventricular septal thickness in 2 patients of 60 mm and 65 mm at age 23 and 14 years, respectively. In 6 patients, a ventricular preexcitation pattern at study entry was associated with markedly increased R-wave or S-wave voltages and deeply inverted T-waves. Autopsy findings included a combination of histopathologic features that were consistent with lysosomal storage disease, such as clusters of vacuolated myocytes, but also typical of CMH due to sarcomere protein mutations (see, e.g., 192600), such as myocyte disarray, small vessel disease, and myocardial scarring. Maron et al. (2009) noted that 7 female LAMP2 obligate carriers in 2 of the families, aged 19 to 51 years, had remained asymptomatic, underscoring the striking differences in clinical phenotypes and outcomes between female carriers and affected male patients.
Boucek et al. (2011) presented data on 82 patients with Danon disease from 36 families. Men were severely affected with cognitive disabilities (100%), hypertrophic cardiomyopathy (88%), and muscle weakness (80%). Men had a high morbidity and were unlikely to reach the age of 25 years without a cardiac transplantation. Women were less severely affected but reported higher than expected levels of cognitive (47%) and skeletal muscle complaints (50%) and manifesting an equal prevalence of dilated cardiomyopathy and hypertrophic cardiomyopathy. Combining their data with that of 63 other Danon disease case reports in the literature, Boucek et al. (2011) determined that the average ages of first symptom, cardiac transplantation, and death were 12.1, 17.9, and 19.0 years in men and 27.9, 33.7, and 34.6 years in women, respectively. Boucek et al. (2011) concluded that women with Danon disease present with clinical symptoms and events approximately 15 years after men and report a higher proportion of cognitive and skeletal muscle problems than had been recognized.
InheritanceByrne et al. (1986) described a family in which 7 members of 3 generations had cardioskeletal myopathy with accumulation of glycogen in lysosomes but normal acid maltase levels. Cardiomyopathy dominated the clinical picture with death between ages 18 and 40 years. There was no male-to-male transmission, but 3 affected females were as severely affected as the 4 males.
Dworzak et al. (1994) found reports of 12 young boys with mild myopathy, varying degrees of mental retardation, and severe cardiomyopathy, whose skeletal muscle examination showed lysosomal glycogen storage not due to acid maltase deficiency. Only 2 cases were sporadic. All of the 10 other cases had a brother or male relative in the maternal line who was either equally affected or had died from heart disease in the second decade. In most cases females were also affected, but cardiomyopathy was the only reported phenotypic expression. The females generally died in the fourth decade. The pattern suggested X-linked dominant inheritance.
Molecular GeneticsIn 10 unrelated patients with Danon disease, Nishino et al. (2000) identified 10 different mutations in the LAMP2 gene (see, e.g., 309060.0001-309060.0006). All of the mutations resulted in premature termination of the LAMP2 protein. Several patients had previously been reported by Danon et al. (1981), Dworzak et al. (1994), Riggs et al. (1983), and Byrne et al. (1986). Western blot analysis of skeletal muscle biopsies from the patients showed marked deficiency or complete absence of the LAMP2 protein. From these results, and the finding that Lamp2-deficient mice manifest a singular vacuolar cardioskeletal myopathy, Nishino et al. (2000) concluded that primary LAMP2 deficiency is the cause of Danon disease. The authors stated that this was the first example of human cardiomyopathy caused by mutations in a lysosomal structural protein rather than an enzymatic protein.
Charron et al. (2004) analyzed the LAMP2 gene in 50 patients with hypertrophic cardiomyopathy (CMH; see 192600) who were negative for mutations in 9 sarcomeric genes and did not have autosomal dominant inheritance. The authors identified 2 different mutations in the LAMP2 gene (309060.0008 and 309060.0009) in 2 patients, both with skeletal muscle weakness on examination and PAS-positive sarcoplasmic vacuoles on skeletal muscle biopsy by light microscopy, who died at ages 22 and 25 years, respectively. The prevalence of Danon disease was therefore 1% of patients with CMH (2 of 197 patients initially screened with CMH in this study) or 4% of enrolled index cases (2 of 50 index patients who were screened for LAMP2 mutations). Danon disease was responsible for 50% of the cases of CMH with clinical skeletal myopathy (2 of 4 patients); none of the 41 patients with isolated CMH had Danon disease.
In genetic analyses of 24 subjects with increased left ventricular wall thickness and electrocardiogram suggesting ventricular preexcitation, Arad et al. (2005) found 4 LAMP2 mutations (see, e.g., 309060.0010). Clinical features associated with defects in LAMP2 included male sex, severe hypertrophy, early onset (at 8 to 17 years of age), ventricular preexcitation, and asymptomatic elevations of 2 serum proteins. Mutations in heterozygous state appeared to be responsible for unusual heart disease in some females.
In the family ('XLCM-2') that presented with dilated cardiomyopathy and was linked to the DMD gene by Towbin et al. (1993), Taylor et al. (2007) identified a 1-bp deletion in the LAMP2 gene (309060.0012).
Genotype/Phenotype CorrelationsIn a male patient with hypertrophic cardiomyopathy, exercise intolerance, and hyperCKemia consistent with a mild form of Danon disease, Musumeci et al. (2005) identified a missense mutation in the LAMP2 gene (309060.0011). The patient did not have muscle weakness or mental retardation. Musumeci et al. (2005) noted that all previous mutations in the LAMP2 gene causing Danon disease resulted in premature termination of the protein, and stated that this was the first missense mutation reported in the LAMP2 gene.
NomenclatureAlthough this disorder was originally described as a type of glycogen storage disease, Danon et al. (1981) recognized that acid alpha-glucosidase and other enzymes of glycogen metabolism were normal in affected patients. The subsequent identification of the structural lysosome-associated membrane protein-2 gene as responsible for the disorder enabled the proper identification of Danon disease as resulting from a defect of the lysosomal membrane (Nishino et al., 2000). Former designations for this disorder are retained here for historical purposes.