Risk of Death in Heart Disease is Associated With Elevated Urinary Globotriaosylceramide

Abstract

BackgroundElevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X‐linked lysosomal disorder that is a risk factor for most types of heart disease.Methods and ResultsWe screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 in whole urine using tandem mass spectrometry, α‐galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb3 levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow‐up of 17 months (hazard ratio=1.59 for increase in Gb3 of 200, 95% CI=1.36 and 1.87, and P<0.0001).ConclusionsIn heart disease patients who do not have Fabry disease or GLA gene mutations, a higher level of urinary Gb3 is positively associated with near‐term mortality. The elevation of urinary Gb3 and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities.Clinical Trial RegistrationURL: clinicaltrials.gov. Unique Identifier: NCT01019629.

Low frequency of Fabry disease in patients with common heart disease

“…30,31 On the other hand, our study demonstrates that analysis of enzyme activity or the amount of substrate in the urine alone lacks the required specificity for large-scale screening. Urinary Gb 3 was elevated in about 15% of patients with heart disease who otherwise did not have GLA mutations, 20 and it is known to be normal in patients with mild mutations and in females, 29 or is falsely elevated for other reasons. 32 α-Galactosidase A activity was not a useful measurement either, because females often have normal enzyme levels 33 and a substantial number (15) of males screened had enzyme activity near or below 2 μmol/L/hr (data not shown), a threshold found to contain patients with Fabry disease.…”

“…20 α-Galactosidase A activity evaluation by tandem mass spectrometry Enzyme analysis was performed as previously described. 20 GLA gene analysis GLA gene variants were searched for in pooled DNA using massively parallel sequencing 21 or in individual genomic DNA samples using the Illumina MiSeq platform (Illumina, Inc.; San Diego, CA).…”

“…20 α-Galactosidase A activity evaluation by tandem mass spectrometry Enzyme analysis was performed as previously described. 20 GLA gene analysis GLA gene variants were searched for in pooled DNA using massively parallel sequencing 21 or in individual genomic DNA samples using the Illumina MiSeq platform (Illumina, Inc.; San Diego, CA). Briefly, the SmartChip MyDesign TE system (WaferGen Bio-systems, Inc., Fremont, CA) was designed to enrich multiple samples for multiple resequencing targets simultaneously using a 4-polymerase chain reaction primer amplification strategy.…”

Cerebrovascular Involvement in Fabry Disease

“…38 Despite this, screening for FD using urinary GL-3 levels is not recommended because these markers have been shown to be increased in patients who do not have FD but have common forms of heart disease, such as coronary artery disease or valvular dysfunction. 43 An FD screening study of patients with stroke reported biologically significant Fabry mutations in 21 male (4.9%) and 7 (2.4%) female patients with stroke, 32 but did not publish details on the type of mutations identified. This study could, therefore, have included intronic mutations and other mutations of undetermined clinical significance.…”

Chronic kidney disease and an uncertain diagnosis of Fabry disease: Approach to a correct diagnosis

“…First, 'urinary Gb3 (in the range of classical males)', measured in whole urine, was suggested to confirm FD nephropathy. Others suggested that urinary and/or plasma Gb3 levels may be significantly increased in other diseases than FD [24,25]. Consequently, there was no agreement, although 4/11 of the panelists were convinced that this criterion, in the context of chronic kidney disease and a GLA variant, is sufficient to confirm FD nephropathy.…”