Multisystemic LAMP-2 defect in Danon disease

Danon disease is an X-linked dominant disorder due to mutations in the LAMP2 gene, presenting with hypertrophic cardiomyopathy, skeletal myopathy and mental retardation. To investigate the effects of LAMP2 gene mutations on protein expression in different tissues, we screened LAMP2 gene mutations and LAMP-2 protein deficiency in the skeletal muscle of 9 unrelated patients with hypertrophic cardiomyopathy and vacuolar myopathy. We identified 3 novel families with unreported LAMP2 gene null mutations and LAMP-2 protein deficiency in skeletal and myocardial muscle, leukocytes and fibroblasts. LAMP-2 protein deficiency was detectable in various tissues indicating that the biochemical diagnosis can be obtained on leukocytes and might be used for screening in male patients, and that the multiorgan protein deficiency would explain the multisystem clinical involvement. In our female patient, muscle histopathology and LAMP-2 protein analysis was inconclusive, indicating that the diagnosis in females can be obtained only by mutation identification.