Danon disease: a novel LAMP2 mutation affecting the pre-mRNA splicing and causing aberrant transcripts and partial...

Area of Science:

• Genetics
• Molecular Biology
• Cardiology

Background:

• Danon disease is a rare genetic disorder caused by mutations in the LAMP2 gene, leading to lysosome-associated membrane protein-2 deficiency.
• It primarily affects the heart and skeletal muscle, often presenting with hypertrophic cardiomyopathy and muscle weakness.
• Early diagnosis and understanding the molecular defect are crucial for patient management and genetic counseling.

Observation:

• A novel hemizygous mutation in the LAMP2 gene was identified in an Italian patient with Danon disease.
• The patient exhibited hypertrophic cardiomyopathy, elevated creatine kinase levels, and mild cognitive impairment, but no significant muscle weakness.
• Muscle biopsy showed autophagic vacuoles and glycogen storage, with reduced LAMP-2 protein expression.

Findings:

• The identified mutation affects the splice site of intron 8, leading to aberrant LAMP-2 transcripts with exon skipping and deletions.
• This results in severely reduced levels of functional LAMP-2 protein across all isoforms.
• Low levels of normal LAMP-2B transcript were also detected, suggesting a complex molecular mechanism.

Implications:

• This case underscores the importance of investigating LAMP2 gene mutations in patients with unexplained hypertrophic cardiomyopathy and neurological symptoms.
• Understanding the specific molecular defect is vital for accurate diagnosis, prognosis, and genetic counseling.
• Early detection and management, including potential heart transplantation, can improve outcomes for individuals with Danon disease.