Cardiovascular Gaucher Disease Type 3c Associated With Homozygous Asp448His GBA1 Variant: First Case Series From...

Cardiac involvement in Gaucher disease (GD) is an uncommon feature, most often associated with the homozygous Asp448His (D409H) variant in GBA1 and typically presents with valvular and pericardial calcifications or myocardial infiltration. To date, approximately 132 individuals with this cardiovascular phenotype (GDIIIc) have been reported, with limited representation from the Middle East. This study reports the first cohort from Kuwait, involving five individuals from three unrelated Middle Eastern families, all with molecularly confirmed homozygous Asp448His variants. All individuals demonstrated early-onset cardiac valvular disease requiring surgical intervention, in addition to organomegaly, skeletal manifestations, and neurological symptoms. Despite corrective surgeries, four individuals died, with only one adult female currently alive and stable. Remarkably, this surviving patient is the first reported individual with GDIIIc to have successfully conceived and delivered a healthy child prior to her diagnosis, initiation of enzyme replacement therapy, or cardiac surgery. She later developed a broad spectrum of neuropsychiatric symptoms, including phobias, hallucinations, obsessive thoughts, anxiety, and delusions of persecution, as well as resting tremors and dysphagia. Brain MRI revealed granular ependymitis and cerebral microbleeds-neuroradiological features not previously described in GDIIIc-making her case uniquely informative. These findings broaden the phenotypic spectrum of GDIIIc and highlight the importance of recognizing cardiac and neuropsychiatric manifestations in individuals with the Asp448His variant. Early identification and multidisciplinary management may improve outcomes in this ultra-rare but severe disease.