Background and Aim: Cerebrovascular disease may progress asymptomatically in the early stages of Fabry disease (FD). Our aim was to test whether functional transcranial Doppler (fTCD) could provide useful data in the evaluation of these presymptomatic FD patients. Methods: A cohort of 12 adult FD patients from families with the classical phenotype of the disease was evaluated with fTCD in the posterior cerebral artery. Results: Compared to healthy controls, resting blood velocities were significantly lower in the FD cohort (p = 0.032 for systolic, p = 0.021 for diastolic). FTCD suggested a disturbed neurovascular coupling in the visual cortex of FD patients, with lower gain (p = 0.007) and rate time (p = 0.019). Men had a significantly higher attenuation (p = 0.013) and lower natural frequency (p = 0.046) than the heterozygous women. Conclusion: These data are the first to suggest that patients with FD may develop cortical vascular dysfunction in the territory of the posterior circulation, early in the natural history of the disease. If the present findings are confirmed in larger, prospective studies, fTCD will be useful for assessing stroke risk in as yet asymptomatic FD patients, improving preventive therapeutic management.

Keywords:
Magnetic resonance imaging, Transcranial Doppler, Fabry disease, Neurovascular coupling, Cerebral blood flow, Cerebrovascular disease, Cerebrovascular ultrasound, Magnetic resonance angiography
1.
Rombach SM, Twickler TB, Aerts JM, Linthorst GE, Wijburg FA, Hollak CE: Vasculopathy in patients with Fabry disease: current controversies and research directions. Mol Gen Metab 2010;99:99–108.
2.
Sims K, Politei J, Banikazemi M, Lee P: Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry registry. Stroke 2009;40:788–794.
3.
Fellgiebel A, Muller MJ, Ginsberg L: CNS manifestations of Fabry’s disease. Lancet Neurol 2006;5:791–795.
4.
Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, Walter U, Mix E, Lohr M, Harzer K, Strauss U, Pahnke J, Grossmann A, Benecke R: Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study. Lancet 2005;366:1794–1796.
5.
Barbey F, Brakch N, Linhart A, Jeanrenaud X, Palecek T, Bultas J, Burnier M, Hayoz D: Increased carotid intima-media thickness in the absence of atherosclerotic plaques in an adult population with Fabry disease. Acta Paediatr Suppl 2006;95:63–68.
6.
Moore DF, Altarescu G, Ling GS, Jeffries N, Frei KP, Weibel T, Charria-Ortiz G, Ferri R, Arai AE, Brady RO, Schiffmann R: Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement. Stroke 2002;33:525–531.
7.
Hilz MJ, Kolodny EH, Brys M, Stemper B, Haendl T, Marthol H: Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease. J Neurol 2004;251:564–570.
8.
Burlina AP, Manara R, Caillaud C, Laissy JP, Severino M, Klein I, Burlina A, Lidove O: The pulvinar sign: frequency and clinical correlations in Fabry disease. J Neurol 2008;255:738–744.
9.
Albrecht J, Dellani PR, Muller MJ, Schermuly I, Beck M, Stoeter P, Gerhard A, Fellgiebel A: Voxel-based analyses of diffusion tensor imaging in Fabry disease. J Neurol Neurosurg Psychiatry 2007;78:964–969.
10.
Fellgiebel A, Keller I, Marin D, Muller MJ, Schermuly I, Yakushev I, Albrecht J, Bellhauser H, Kinateder M, Beck M, Stoeter P: Diagnostic utility of different MRI and MR angiography measures in Fabry disease. Neurology 2009;72:63–68.
11.
Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, Hopkin RJ, Bultas J, Lee P, Sims K, Brodie SE, Pastores GM, Strotmann JM, Wilcox WR: Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med 2006;8:539–548.
12.
Schiffmann R: Fabry disease. Pharmacol Ther 2009;122:65–77.
13.
Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, Grabowski G, Packman S, Wilcox WR: Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338–346.
14.
Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, Csiba L, Desvarieux M, Ebrahim S, Fatar M, Hernandez Hernandez R, Jaff M, Kownator S, Prati P, Rundek T, Sitzer M, Schminke U, Tardif JC, Taylor A, Vicaut E, Woo KS, Zannad F, Zureik M: Mannheim Carotid Intima-Media Thickness Consensus (2004–2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim 2004 and Brussels 2006. Cerebrovasc Dis 2007;23:75–80.
15.
Rosset A, Spadola L, Ratib O: Osiri X: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging 2004;17:205–216.
16.
Smith SM, De Stefano N, Jenkinson M, Matthews PM: Normalized accurate measurement of longitudinal brain change. J Comp Assist Tomogr 2001;25:466–475.
17.
Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, Federico A, De Stefano N: Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 2002;17:479–489.
18.
Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS: A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001;14:21–36.
19.
Azevedo E, Santos R, Freitas J, Rosas MJ, Gago M, Garrett C, Rosengarten B: Deep brain stimulation does not change neurovascular coupling in non-motor visual cortex: an autonomic and visual evoked blood flow velocity response study. Parkinsonism Relat Disord 2010;16:600–603.
20.
Rosengarten B, Huwendiek O, Kaps M: Neurovascular coupling in terms of a control system: validation of a second-order linear system model. Ultrasound Med Biol 2001;27:631–635.
21.
Rosengarten B, Aldinger C, Kaufmann A, Kaps M: Comparison of visually evoked peak systolic and end diastolic blood flow velocity using a control system approach. Ultrasound Med Biol 2001;27:1499–1503.
22.
Rosengarten B, Budden C, Osthaus S, Kaps M: Effect of heart rate on regulative features of the cortical activity-flow coupling. Cerebrovasc Dis 2003;16:47–52.
23.
Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA: MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol 1987;149:351–356.
24.
Rosengarten B, Aldinger C, Spiller A, Kaps M: Neurovascular coupling remains unaffected during normal aging. J Neuroimaging 2003;13:43–47.
25.
Hao Q, Wong LK, Lin WH, Leung TW, Kaps M, Rosengarten B: Ethnic influences on neurovascular coupling: a pilot study in Whites and Asians. Stroke 2010;41:383–384.
26.
Rosengarten B, Grebe M, Muller A, Voss RK, Kaps M: Severity of coronary artery disease but not degree of coronary stenosis is correlated to cerebrovascular reactivity. Cerebrovasc Dis 2009;28:290–297.
27.
Buerk DG, Ances BM, Greenberg JH, Detre JA: Temporal dynamics of brain tissue nitric oxide during functional forepaw stimulation in rats. Neuroimage 2003;18:1–9.
28.
Moore DF, Scott LT, Gladwin MT, Altarescu G, Kaneski C, Suzuki K, Pease-Fye M, Ferri R, Brady RO, Herscovitch P, Schiffmann R: Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabry disease: reversal by enzyme replacement therapy. Circulation 2001;104:1506–1512.
29.
Rosengarten B, Dost A, Kaufmann A, Gortner L, Kaps M: Impaired cerebrovascular reactivity in type 1 diabetic children. Diabetes Care 2002;25:408–410.
30.
Rosengarten B, Sperner J, Gorgen-Pauly U, Kaps M: Cerebrovascular reactivity in adolescents with migraine and tension-type headache during headache-free interval and attack. Headache 2003;43:458–463.
31.
Rosengarten B, Paulsen S, Molnar S, Kaschel R, Gallhofer B, Kaps M: Activation-flow coupling differentiates between vascular and Alzheimer type of dementia. J Neurol Sci 2007;257:149–154.
32.
Azevedo E, Castro P, Santos R, Freitas J, Coelho T, Rosengarten B, Panerai R: Autonomic dysfunction affects cerebral neurovascular coupling. Clin Auton Res 2011;21:395–403.
33.
Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, Schiffmann R: Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 1998;50:1746–1749.
34.
Moore DF, Ye F, Schiffmann R, Butman JA: Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry disease. AJNR Am J Neuroradiol 2003;24:1096–1101.
35.
Fellgiebel A, Keller I, Martus P, Ropele S, Yakushev I, Bottcher T, Fazekas F, Rolfs A: Basilar artery diameter is a potential screening tool for Fabry disease in young stroke patients. Cerebrovasc Dis 2011;31:294–299.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.