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Danon disease
A rare X-linked genetic condition due to deficiency of the lysosomal-associated membrane protein 2 (LAMP2) characterized by severe cardiomyopathy and variable degrees of muscle weakness, frequently associated with intellectual deficits (in males).
ORPHA:34587
Classification level: Disorder
- GSD due to LAMP-2 deficiency
- Glycogenosis due to LAMP-2 deficiency
- Lysosomal glycogen storage disease with normal acid maltase activity
- GSD, type 2B
- GSD, type IIb
- Glycogen storage disease, type IIb
- Glycogen storage disease, type 2B
- Glycogen storage disease due to LAMP-2 deficiency
Prevalence: <1 / 1 000 000
Inheritance: X-linked dominant
Age of onset: Childhood
More than 100 families have been described in the literature so far.
The disease classically manifests in males at a median age of 13-14 years. The clinical picture may be severe in both sexes, but onset generally occurs later in females and disease progression tends to be slower in females.
The disease is caused by mutations in the LAMP2 gene, localised to Xq24. The LAMP2 protein is an essential component of the lysosomal membrane and appears to play a role in autophagosome-lysosome fusion and the cellular process of autophagy. Originally the condition was classified as a 'glycogen storage disease' reflecting elevated glycogen visible on histological analysis; however, as the condition is not due to a specific defect in glycogen storage, the name Danon disease is currently preferred.
The main diagnostic method is molecular genetic testing for identification of loss-of-function variants in LAMP2. Histological and/or electron microscopy findings of cytoplasmic vacuoles and increased cellular glycogen levels can be suggestive of the diagnosis. Exclusion of Pompe disease should be done if LAMP2 molecular testing is non-conclusive. Staining of LAMP-2 protein revealing reduced or absence in males heart, muscle, lymphocytes, may also be performed for diagnosis, but is not widely available clinically. Identification of a LAMP2 pathogenic variant in a proband allows cascade testing of other at-risk relatives.
The differential diagnosis should include X-linked myopathy with excessive autophagia (XMEA) and glycogen storage disease type 2.
Antenatal diagnosis of at-risk pregnancies can be done if a known LAMP2 pathogenic variant has been detected in a parent (typically detected in the mother as males with this disease have reduce reproductive fitness).
Genetic counseling is recommended for the X-linked inheritance pattern seen in the disease.
There is no specific treatment for this disease. Symptomatic treatment is required for the cardiac manifestations and patients may require a heart transplant.
Patients are at risk of sudden death due to arrhythmia and/or heart failure during early adulthood. Death or transplant occurs at median ages in males and females of 19-21 years and 34-38 years, respectively.
Last update: January 2024 - Expert reviewer(s): Dr Eric ADLER - Dr Matthew TAYLOR
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