Determinants of white matter hyperintensity burden in patients with Fabry disease

Abstract

Objective: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD).Methods: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p , 0.05 for all analyses.Results: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 6 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2. Cerebrovascular disease, including stroke, is a significant source of morbidity in patients with Fabry disease (FD), an X-linked lysosomal storage disorder characterized by reduced activity of the enzyme a-galactosidase A.1 Burden of MRI-detectable white matter hyperintensity (WMH) has been linked to risk of stroke, 2 poor poststroke outcome, 3 and functional disability in aging adults 4 ; however, there are no systematic studies of WMH in patients with FD. Previously, nonquantitative studies have documented WMH lesions in adults with FD, 5,6 pediatric patients, 7 and the Fabry Outcome Survey registry participants. 8 A comparison of CT and MRI findings in patients with FD suggested the potential utility of a rating scale in this population. 9 The recently published Stroke in Young Fabry Patients (SIFAP1) study 10 showed detailed neuroimaging MRI characteristics including WMH assessed using a validated ordinal scale 11,12 ; however, it failed to identify any FD-specific MRI characteristics.

Enzyme replacement therapy and white matter hyperintensity progression in Fabry disease

“…Nevertheless, 8% had a previous stroke, which is a similar proportion to previous studies. 10 Contrary to previous studies, 8 , 10 we found no association between history of stroke and WMH progression in FD. Furthermore, we found no association between hypertension, smoking, or diabetes and WMH progression in FD.…”

“…Furthermore, prior ERT exposure has been associated with reduced WMH volume in 31- to 40-year-old patients on cross-sectional analysis. 10 Other previous studies evaluating the rate of WMH progression while on ERT have reported conflicting results. 3 , 5 , 30 – 32 While a randomized controlled trial would be needed to test definitively the relationship between ERT and WMH progression, such a trial might not be achievable given the widespread use of ERT in clinical practice and the lack of clinical equipoise regarding the efficacy of ERT in treating cardiac or renal complications of FD.…”

“…To check whether ERT influences the rate of WMH progression in young participants, as has been suggested in previous studies, 8 , 10 we performed post hoc analysis 3. Eighty-one of the 149 included participants were younger than 40 years at baseline; using this subgroup, we performed multiple linear regression with WMH change rate as the dependent variable and the above participant characteristics as independent variables, not including statin use or diabetes history (because no patients younger than 40 years had diabetes).…”

“… 2 White matter hyperintensities (WMH) on MRI are thought to represent cerebral microangiopathic changes and have a reported prevalence of 42% to 81% in FD. 3 – 9 WMH have been associated with left ventricular hypertrophy, 8 cardiomyopathy, 10 previous stroke, 8 , 10 and conventional vascular risk factors 6 in patients with FD and with an increased risk of death, 11 dementia, 12 stroke, 13 and cognitive decline 14 , 15 in the general population. A better understanding of factors influencing WMH progression in patients with FD could therefore provide insight into preventing these sequelae.…”

Parkinson’s Disease and Fabry Disease: Clinical, Biochemical and Neuroimaging Analysis of Three Pedigrees

“…Anderson-Fabry Disease (FD) is a rare X-linked lysosomal storage disorder caused by deficient activity of the enzyme ␣-galactosidase A (␣-GAL A), resulting in progressive and diffuse lysosomal accumulation of neutral glycosphingolipids, especially globotriaosylceramide (Gb3) in vascular endothelium, kidneys, heart, brain, skin, cornea and other tissues leading to multiorgan damage [1]. Transient ischemic attacks (TIAs), strokes [2] and brain white matter lesions (WML) [3] are common central nervous system (CNS) manifestations. In recent years there has been growing body of evidence supporting a link between the pathogenesis of PD and lysosomal dysfunction, namely in Gaucher disease (GD) and FD.…”