Elevated Cerebral Blood Flow Velocities in Fabry Disease With Reversal After Enzyme Replacement

TLDR

Fabry disease, an X‑linked alpha‑galactosidase A deficiency, is associated with cerebrovascular disease characterized by small‑vessel pathology and posterior‑predominant large‑vessel ectasia. The study aimed to evaluate cerebral blood flow velocities using transcranial Doppler in untreated and enzyme‑treated Fabry patients. Cerebral blood flow velocities were measured by transcranial Doppler, including CO2‑retention breath‑holding tests, in 26 patients enrolled in a 6‑month double‑blind placebo‑controlled enzyme‑replacement trial followed by an 18‑month open‑label follow‑up, with mixed‑effects ANOVA used for analysis. Fabry patients exhibited significantly higher peak, mean, pulsatility, and resistance indices, especially in the middle cerebral M1 and posterior cerebral arteries, and enzyme replacement therapy markedly reduced these velocities and flow acceleration over 18 months.

Abstract

Fabry disease is an X-linked inherited disorder resulting from a deficiency of alpha-galactosidase A. Cerebrovascular disease in Fabry disease includes small-vessel disease and larger-vessel ectasia in a predominantly posterior distribution. We assessed transcranial Doppler (TCD) blood flow velocities in naive and enzyme-treated Fabry patients.TCD was used to noninvasively examine patients with Fabry disease for abnormal cerebral blood flow velocities. TCD measurements were also made during CO2 retention by breathholding to examine cerebrovascular vessel reactivity. Twenty-six patients were enrolled in a 6-month, double-blind, placebo-controlled trial of enzyme replacement therapy consisting of biweekly intravenous alpha-galactosidase A infusions, with a subsequent 18-month follow-up in an open-label trial. Statistical analysis consisted of applying a mixed-effects ANOVA model for correlated outcomes.Peak velocity, mean velocity, pulsatility index, and resistance index were found to be significantly higher in patients compared with control subjects. When the individual vessels were considered, elevated flow velocities were found in the middle cerebral M1 branch and the posterior cerebral artery. Enzyme replacement therapy significantly decreased peak, mean, and end-diastolic velocities and flow acceleration at the 18-month follow-up time point.Patients with Fabry disease have elevated cerebral blood flow velocities. These velocities significantly improved with enzyme replacement therapy.