SESSION TITLE: Genetic and Developmental Disorders Posters
SESSION TYPE: Original Investigation Poster
PRESENTED ON: Wednesday, October 28, 2015 at 01:30 PM - 02:30 PM
PURPOSE: An association between alpha-1 antitrypsin (A1AT) deficiency and arterial aneurysms, in particular aortic and cerebral aneurysms, has been suggested by case reports and mostly underpowered studies. We performed a single-center study to evaluate further the relationship between A1AT levels and cerebral aneurysm.
METHODS: We studied a series of 97 patients (58 females, 39 males) diagnosed with cerebral aneurysms (ruptured or unruptured): 38 Caucasian, 39 African-American, 14 Hispanic, 6 unclassified. Diagnosis was by magnetic resonance angiogram (MRA) and/or CT angiogram. Blood samples were obtained at the time of diagnosis and all underwent isoelectric focusing (IEF) for determination of A1AT phenotype. We also measured alpha-1 antichymotrypsin (A1AC) as an indicator of an acute-phase reaction (both A1AT and A1AC are acute-phase serum proteins).
RESULTS: Overall, 11/97 cerebral aneurysm patients (~11%) had an atypical A1AT allele by IEF. We found a wide range of concentrations of A1AT (78-284 mg/dL) and A1AC (17-83 mg/dL) and, in general, there was a close correlation between the two values (R2 ~0.85). However, there were notable exceptions: of the 5 PIMZ patients, one showed an elevated level of A1AC (evidence of an acute phase masking A1AT deficiency) while the four others had levels of A1AC and A1AT in the low normal range. Three samples were typed as PIMF and three had an atypical banding pattern on IEF that could not be classified; they also had A1AT levels in the low normal range. Whole-gene sequence determination by next-generation sequencing is underway to identify the putative mutations.
CONCLUSIONS: The accumulation of potentially pathogenic mutations (PI*Z, PI*F, and other atypicals) in this ethnically heterogeneous group that has only the occurrence of cerebral aneurysms in common, is remarkable. Our results suggest that mutations of A1AT may contribute to the development of cerebral aneurysms in some patients. Additional larger studies are warranted.
CLINICAL IMPLICATIONS: In individuals with A1AT deficiency, testing by MRA (non-invasive) and, if necessary, diagnostic cerebral angiogram (with contrast) is indicated to ascertain risk of cerebral aneurysm, a condition with very high mortality and morbidity. Likewise, testing for A1AT deficiency should be considered in patients diagnosed with or at risk of cerebral aneurysm.
DISCLOSURE: Friedrich Kueppers: Consultant fee, speaker bureau, advisory committee, etc.: Consultant fee regarding next-generation sequencing Christopher Sanders: University grant monies: Funding for the sequencing of a selection of the samples included in this study was provided by Temple University The following authors have nothing to disclose: Farah Sultan, Michael Weaver
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