Case Report: A typical triad of Danon disease caused by a LAMP2 splice-donor variant with multilevel functional...

Danon disease is a rare X-linked dominant disorder caused by pathogenic variants in LAMP2, typically presenting with cardiomyopathy, skeletal myopathy, and intellectual disability, and showing a severe course in males. In this study, we report the case of a 29-year-old Han Chinese male with the classic triad, plus macular degeneration and a complex neuromuscular phenotype including axonal-demyelinating sensorimotor polyneuropathy. Whole-exome sequencing identified a hemizygous splice-donor variant in LAMP2 (NM_002294.2:c.928 + 1G > A). A functional analysis in peripheral blood with matched controls experimentally confirmed markedly reduced LAMP2 mRNA levels and decreased LAMP2 protein expression, supporting the variant as a loss-of-function allele. The patient rapidly progressed to end-stage heart failure and died 18 months after diagnosis, highlighting the severe multisystem impact of this variant. This case expands the functional evidence for pathogenic LAMP2 splice-site variants and suggests peripheral nervous system involvement in severe multisystem Danon disease.