Danon Disease: LAMP2 Gene Deletion/Duplication

Condition Description

Danon Disease is anX-linked disorder that can affect cardiac muscle, skeletal muscle, and mentalretardation. Affected individuals have also been described with hypertrophiccardiomyopathy, proximal muscle weakness, hepatomegaly, peripheral pigmentaryretinopathy, and elevated creatine kinase. Presentation can be variable evenwithin a family. Affected individuals usually die in their teens or twentiesdue to heart failure; heart transplantation has been shown to be an effectivetreatment. Females have been reported to display symptoms of Danon disease, aswell. Symptoms reported in affected females include skeletal myopathy, atrialfibrillation, mild left ventricular enlargement with systolic dysfunction onechocardiogram, pigmentary retinopathy, mild intellectual impairment, mentalretardation, and death from cardiac disease. While cardiomyopathy in affectedmales occurs before the age of 20, most affected females develop cardiomyopathyin adulthood.

Mutations in the LAMP2 gene (Xq24) have been associatedwith Danon disease. One study reported that the prevalence of Danon disease was1% of patients with hypertrophic cardiomyopathy (2 of 197 patients). In thisstudy, Danon disease was responsible for 50% of the cases of hypertrophiccardiomyopathy (CMH) with clinical skeletal myopathy (2 of 4 patients); none ofthe 41 patients with isolated CMH had Danon disease. In another study, geneticanalyses of 24 subjects with increased left ventricular wall thickness andelectrocardiogram suggesting ventricular preexcitation found 4 LAMP2 mutations. Clinical featuresassociated with defects in LAMP2included male sex, severe hypertrophy, early onset (at 8 to 17 years of age),ventricular preexcitation, and asymptomatic elevations of two serum proteins.Mutations in heterozygous state appeared to be responsible for unusual heartdisease in some females.

Although this disorderwas originally described as a variant of glycogen storage disease II due toaccumulation of glycogen in muscle and lysosomes seen in some patients, acidalpha-glucosidase and other enzymes of glycogen metabolism are normal. Glycogen,however, is not always increased in affected individuals. The subsequentidentification of the structural lysosome-associated membrane protein-2 gene asresponsible for the disorder enabled the proper identification of Danon diseaseas resulting from a defect of the lysosomal membrane.

Click here for the OMIM summary on this condition.

Genes (1)

Indications

This test is indicated for:

  • Confirmation of a clinical/biochemical diagnosis of Danon disease in individuals who have tested negative for sequence analysis
  • Carrier testing in adult females with a family history of Danon disease who have tested negative for sequence analysis

Methodology

DNA isolated from peripheral blood is hybridized to a CGH array to detect deletions and duplications. The targeted CGH array has overlapping probes which cover the entire genomic region.

Detection

Detection is limited to duplications and deletions. The CGH array will not detect point or intronic mutations. Results of molecular analysis must be interpreted in the context of the patient's clinical and/or biochemical phenotype.

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (eglgc@egl-eurofins.com).
Submit only 1 of the following specimen types
Whole Blood (EDTA)
WBP

Requirements
EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.
DNA, Isolated
DNA

Requirements
Microtainer
3µg
Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Sequencing analysis of the LAMP2 gene is available and is required before deletion/duplication analysis.
  • X-Linked Intellectual Disability panels are available for 30, 60, and 90+ genes.
  • Prenataltesting is available to adult females who are confirmed carriers ofmutations. Please contact the laboratory genetic counselor to discussappropriate testing prior to collecting a prenatal specimen.

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