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Aortic root dilation is an underrecognized cardiac manifestation of Fabry disease

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Fabry disease is one of the most common lysosomal storage disorders, estimated to affect between 1 in 5,000 to 1 in 30,000 people. This X-linked disorder arises from pathogenic variants in the GLA gene, leading to a deficiency in alpha-galactosidase A. Insufficient enzyme activity causes glycosphingolipid deposition in vascular endothelium, smooth muscle, pericytes, cardiomyocytes, and kidney glomerular, interstitial, and tubular cells. Classic Fabry disease primarily affects males, manifesting early in life with angiokeratomas, acroparasthesias, hypohydrosis, corneal whirling, gastrointestinal symptoms, and kidney function impairment. Females more often present with late-onset or atypical forms with variable symptom severity. Both classic and late-onset Fabry disease are frequently associated with cardiac complications, such as hypertrophic cardiomyopathy and arrhythmia, which are a major source of morbidity and mortality, particularly in classic Fabry disease. This retrospective study aims to describe the prevalence of aortic root dilation and its complications in a cohort of Fabry disease patients. We will also describe the average age at diagnosis of aortic root dilation, the rate of aortic root expansion, and correlations between aortic root dilation, therapy, demographics, and genetic variants.

 

Methods:
This retrospective study involves a chart review of 127 Fabry disease patients (114 living and 13 deceased) previously and currently in our clinical care. Measurements of aortic root diameter at the annulus, sinus of Valsalva, sinotubular junction, and ascending aorta are extracted from both magnetic resonance imaging (MRI) and transthoracic echocardiogram (TTE) reports. We use descriptive statistics to determine the prevalences of aortic root dilation and its complications, such as aortic insufficiency, along with the annual rate of change in aortic root diameter and the average age at diagnosis of aortic root dilation. Correlations between aortic root dilation and variables such as age, sex, race, body surface area, blood pressure, genetic variant, and therapy are assessed using chi-squared or Fisher's exact tests. Aortic root dilation is defined as an aortic root diameter measuring above the 95th percentile in normal adults. This is based on recommendations from the American Society of Echocardiography and the American Heart Association.

 

Results:
Preliminary analysis of the Fabry disease cohort identified aortic root dilation in at least 4 patients based on imaging (TTE or MRI) at the level of the annulus, sinus of Valsalva, sinotubular junction, or ascending aorta. Of these, 2 patients had imaging evidence of at least mild aortic insufficiency, a common consequence of aortic root dilation. The average age at first detection of aortic dilation was 57 years. Analysis of the prevalence of aortic root dilation in the full cohort is ongoing.

 

Conclusion:
These preliminary findings in combination with further analysis of our cohort may indicate that aortic root dilation is a more common cardiac manifestation of Fabry disease than previously recognized. Quantitative analyses for the remainder of the cohort are ongoing and will be presented as available.

 

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