Danon Disease Due to a Novel LAMP2 Microduplication

Area of Science:

• Genetics
• Molecular Biology
• Cardiology

Background:

• Danon disease is a rare X-linked disorder affecting the heart, muscles, brain, and eyes.
• It is typically caused by mutations in the LAMP2 gene, often point mutations.
• Small gene rearrangements are a less common cause, with only a few cases reported.

Purpose of the Study:

• To describe the clinical, pathological, and molecular characteristics of a patient with Danon disease due to a LAMP2 microduplication.
• To identify potential diagnostic challenges associated with this rare genetic disorder.
• To emphasize the importance of specific diagnostic techniques beyond standard gene sequencing.

Main Methods:

• Clinical evaluation of a male proband and his affected mother.
• Pathological examination of endomyocardial and quadriceps muscle biopsies.
• Molecular analysis including LAMP2 gene sequencing, multiplex ligation-dependent probe amplification (MLPA) for deletion/duplication testing, and RT-PCR.
• Immunostaining of banked myocardial tissue.

Main Results:

• The proband presented with hypertrophic cardiomyopathy and elevated creatine kinase.
• Muscle biopsy showed characteristic autophagic vacuoles, but endomyocardial biopsy was nonspecific.
• LAMP2 immunostaining was negative, yet LAMP2 sequencing was normal.
• MLPA revealed a 1.5kb microduplication encompassing LAMP2 exons 4 and 5, confirmed by RT-PCR to cause a frameshift.
• The proband's mother was confirmed to have Danon disease retrospectively.

Conclusions:

• This is the second reported case of pathogenic LAMP2 microduplication causing Danon disease.
• Standard LAMP2 sequencing may miss microduplications, necessitating tissue immunostaining and MLPA for accurate diagnosis.
• Myocardial pathology findings can mimic other conditions like myocarditis, posing a diagnostic challenge.