CNS involvement in Fabry disease: Clinical and imaging studies before and after 12 months of enzyme replacement therapy

Abstract

We report the clinical and radiological central nervous system (CNS) findings of 8 Fabry disease patients, before (8/8) and after (7/8) 12 months of enzyme replacement therapy (ERT) with agalsidase-alpha. Eight biochemically proven Fabry disease patients (from four families) were included. Patients were evaluated at baseline and at regular intervals during 12 months of ERT. Evaluations included a thorough, standardized neurological examination, and magnetic resonance imaging (MRI) and angiography (MRA). Brain proton magnetic resonance spectroscopy (MRS) was also performed in 5/8 patients. The presence and location of grey- and white-matter lesions, the presence of vascular occlusion or ectasia on MRA and the metabolite ratios on MRS were determined, as well as their relation to age, symptoms and neurological examination. Neurological examination showed few abnormalities in these patients: scores varied (on a 0-100 scale) from zero to 5, at baseline and in the 12th month of ERT. The most consistent findings on MRI were asymmetric, widespread patterns of deep white-matter (WM) lesions, hyperintense on T2 and FLAIR-weighted images, found in 4/8 patients at baseline, predominantly in frontal and parietal lobes. These lesions did not correlate with other clinical variables, although there was a trend towards an association of the lesions with age and hearing loss. The youngest patient with MRI lesions was 24 years old. After 12 months of ERT, MRI was normal in 3/7, showed the same WM lesions in 2/7, and showed worsening of WM lesions in 2/7 patients (from the same family). Abnormal MRS metabolite ratios were detected at baseline in 4/5 patients. While neurological examination remained almost normal during the 12 months of ERT, new small-vessel CNS involvement still appeared in 2/7 patients. We do not know why ERT was not able to prevent this in these two related male patients. This could be due either to their older ages (46 and 36 years), or to a more pathogenic mutation. We conclude that MRI was more sensitive than neurological examination in detecting CNS involvement and progression in Fabry disease in the time interval studied.

White matter lesions in Fabry disease before and after enzyme replacement therapy: a 2-year follow-up

“…NE, as previously reported 9 , generated a score which varied from zero (normal examination) to 100 (NE completely abnormal). For the purposes of the present analysis, we have only analyzed NE scores resulting from CNS involvement (NE CNS score; range: 0 to 85).…”

“…However, the design of this previous study did not follow each lesion individually, and for this reason it would not be able to detect a disappearance of any lesion at all. As a matter of fact, few other studies on the natural history of CNS impact of FD have been published to date 2,[17][18][19] , and we have already discussed this topic 9 .…”

“…Mean age of the group at the beginning of the investigation was 32 years (range: 24-46 years). Clinical, biochemical and molecular characteristics of these patients have already been published 9 , and some data were shown in Table 1. The following investigations (described bellow) started immediately before inclusion of these individuals in the protocol with agalsidase-alpha, 0.2 mg/kg qo week, and continued at regular intervals during a period of 24 months.…”

“…The effect of ERT on CNS involvement is still not clear. We have previously reported the clinical and radiological CNS findings of 8 FD patients during their first 12 months of ERT with agalsidase-alpha 9 . MRI results in that study were either neutral or even negative.…”

Fabry Disease: Treatment and diagnosis

“…Cardiac complications are diverse, and includes concentric hypertrophic miocardiopathy, diastolic dysfunction, and valvular or conduction defects (22). Magnetic resonance imaging frequently reveals white matter lesions (23), and cerebrovascular events, such as, transient ischemic attack or stroke occur, sometimes before the development of renal or cardiac events (24).…”