Psychiatric and cognitive characteristics of individuals with Danon disease (LAMP2 gene mutation)

Abstract

Danon disease (DD) is a rare X-linked disorder caused by loss-of-function mutations in the LAMP2 gene, which encodes lysosome-associated membrane protein. It is characterized by the triad of hypertrophic cardiomyopathy, myopathy, and intellectual disability. Whereas the molecular and pathophysiological mechanisms underlying this disorder have been previously reported and continue to be explored, the cognitive deficits and psychiatric comorbidities manifested in DD remain an understudied topic. We systematically assessed cognitive abilities and psychiatric comorbidities in 13 males and females. Most of the participants in our cohort (n=9; 75%) had an IQ score within the normal range, while only one participant had intellectual disability. Participants' performance on the Cognitive Neuropsychiatric Battery (CNB) showed only mildly impaired cognitive abilities in most modules, except in the executive functioning test, which was low compared to healthy controls. Of note, 69% of the participants met criteria for at least one psychiatric disorder, mainly mood and anxiety disorders, occurring alone or in combination in the same patient. The results of the present study challenge earlier reports suggesting that mental retardation is a core constituent in DD. Of importance, it underscores the need to refer Danon patients to psychiatric assessment.

Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene

“…Danon disease patients with genetically confirmed LAMP2 variants exhibit LAMP2 protein deficiency in many organs, including the cardiac and skeletal muscles, leukocytes and fibroblasts, and, like lamp2 knockout mice, these patients showed involvement of various organs including the liver, lung, and brain. However, these patients also exhibited gastrointestinal, renal and ocular symptoms, as well as intellectual disability and psychiatric disorders such as depression and anxiety (23,24).…”

Review: Danon disease: Review of natural history and recent advances

“…Other central neurological symptoms, such as generalized seizures, autism, psychosis, suicidal ideation and depression were rarely reported . Brain PET and MRI imaging showed either decreased glucose metabolism in the cortex (possibly underlying cognitive involvement ) or involvement of the central nervous system .…”

A family with Danon disease caused by a splice site mutation in LAMP2 that generates a truncated protein

“…Metabolic cardiomyopathy includes Fabry disease, Danon disease, Pompe disease, and Protein Kinase AMP‐Activated Non‐Catalytic Subunit Gamma 2 (PRKAG2) cardiac syndrome. These conditions all cause cardiac hypertrophy resulting from mutations in non‐sarcomeric genes (Yardeni et al., ). The glycogen accumulation disease caused by LAMP2 mutations is an X‐linked condition, characterized by cardiomyopathy, skeletal myopathy, and varying degrees of intellectual disability (Chen et al., ).…”