Pathophysiologische Aspekte hirnstruktureller Veränderungen bei Morbus Fabry: Literaturübersicht

Zusammenfassung

Morbus Fabry (M. Fabry) ist eine seltene X-chromosomal vererbte lysosomale Speicherkrankheit, bei der es durch Defizienz des Enzyms α-Galaktosidase A (α-GAL) zur progredienten Akkumulation von Glykosphingolipiden (v. a. Gb3) in Lysosomen verschiedener Organsysteme kommt, wobei insbesondere das vaskuläre Endothel und glatte Muskelzellen betroffen sind. Zerebrale Manifestationen sind häufig verlaufs- und prognosebestimmend. Die vorliegende Arbeit gibt eine systematische Übersicht über die vorliegende Literatur zu den hirnstrukturellen Befunden bei Patienten mit M. Fabry und diskutiert die z. T. noch unklaren pathophysiologischen Aspekte der hirnstrukturellen und zerebrovaskulären Veränderungen. Zerebrovaskuläre Ereignisse (v. a. Hirninfarkt, TIA) treten bei M. Fabry häufig schon in jungen Jahren auf, auch bei heterozygoten Frauen. In der strukturellen kraniellen Bildgebung können schon bei jungen Patienten so genannte „White Matter Lesions” (WML) beobachtet werden. Verschiedene pathophysiologische Aspekte der Entwicklung von zerebraler Angiopathie und WML bei M. Fabry werden im Hinblick auf die aktuelle Studienlage erörtert. Neben den WML stellen Signalanhebungen im Bereich des Pulvinar (T1-Wichtung) sowie ausgeprägte Polichoektasien der großen Gefäße, insbesondere im hinteren Stromgebiet, wegweisende Befunde dar. Durch neuere Methoden kranialer Bildgebung wie der Diffusions-Tensor-Bildgebung lässt sich möglicherweise ein Muster zerebraler Affektion schon vor dem Auftreten von WML bei jungen Fabry-Patienten quantitativ erfassen. Hierdurch könnte auch ein möglicher Einfluss der Enzymersatztherapie auf die Entwicklung der hirnstrukturellen Veränderungen sensitiv bestimmt werden. Es sollte aufgrund der aktuellen Datenlage erwogen werden, ob eine Screening-Untersuchung auf M. Fabry mittels Gb3-Bestimmung im Urin bei jungen Patienten (< 55 Jahre) mit ätiologisch unklarem ischämischen Hirninfarkt sinnvoll ist. In jedem Fall sollte man an M. Fabry als mögliche Schlaganfallursache denken und auf typische klinische Merkmale achten.

Abstract

Fabry Disease (FD) is a rare X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A (α-GAL) enzyme activity. Neutral glycosphingolipides (esp. Gb3) accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. Cerebral manifestations that might be mainly due to progressive cerebrovascular dysfunction, are one major and often life-threatening burden of the disease. We reviewed the present literature concerning brain structural alterations in FD and discuss the possibly relevant underlying pathophysiological aspects of these disturbances. Cerebrovascular events (TIA, stroke) occur in FD at a rather early age. In female FD patients who were considered to be less affected “carriers” for a long time, the prevalence of cerebrovascular events seems to be at last as high as in male patients. In structural imaging white matter lesions (WML) can be found frequently even in young FD patients. In a recent study clinically equally affected men and women with FD showed a comparable severity of WML load. Different pathophysiological aspects of cerebral angiopathy and WML development are discussed against the background of current concepts (e. g. accumulation of Gb3 in vascular endothelium with consecutive cell proliferation and luminal stenosis, acceleration of focal intravasal pressure and disturbances of vascular auto-regulation). Pathological increase of pulvinar signal in T1-weighted MRI has also been described in FD. This finding was assumed to be caused by calcification as a consequence of disturbed local circulation. To enhance our knowledge about the relevant neurobiological processes the authors propose a more sensitive and early detection of brain structural changes in FD. New brain structural MRI methods such as diffusion-tensor imaging could provide a pattern of ultrastructural changes even in young patients without visible WML. This strategy could be as well useful for quantification of possible effects of the enzyme replacement therapy on brain structural alterations in FD. Based on recent data a systematic FD-screening by measuring Gb3 in urine of young patients with cryptogenic stroke should be discussed. Basically in such cases FD should be clinically considered.

Schlüsselwörter

Morbus Fabry - White Matter Lesions (WML) - Hirninfarkt

Key words

Fabry Disease - White Matter Lesions (WML) - stroke

Literatur

• 1 Jansen T BF, Altmeyer P. Angiokeratoma corporis diffusum in Fabry disease: an historical perspective.  Acta Paediatrica Suppl. 2005;  94 95
• 2 Meikle P J, Hopwood J J, Clague A E, Carey W F. Prevalence of lysosomal storage disorders.  Jama. 1999;  281 249-254
• 3 Desnick R JIY, Eng C M. Galactosidase A deficiency: Fabry disease. New York 2001
• 4 Schäfer E, Baron K, Widmer U, Deegan P, Neumann H P, Sunder-Plassmann G, Johansson J O, Whybra C, Ries M, Pastores G M, Mehta A, Beck M, Gal A. Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease.  Hum Mutat. 2005;  25 412
• 5 Morgan S H, Rudge P, Smith S J, Bronstein A M, Kendall B E, Holly E, Young E P, Crawfurd M D, Bannister R. The neurological complications of Anderson-Fabry disease (α-galactosidase A deficiency) - investigation of symptomatic and presymptomatic patients.  Q J Med. 1990;  75 491-507
• 6 Hughes D A, Mehta A B. Vascular complications of Fabry disease: enzyme replacement and other therapies.  Acta Paediatr Suppl. 2005;  94 28-33; discussion 29 - 10
• 7 Mehta A, Ricci R, Widmer U, Dehout F, Garcia De Lorenzo A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M, Beck M. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey.  Eur J Clin Invest. 2004;  34 236-242
• 8 MacDermot K D, Holmes A, Miners A H. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males.  J Med Genet. 2001;  38 750-760
• 9 Grewal R P. Psychiatric disorders in patients with Fabry's disease.  Int J Psychiatry Med. 1993;  23 307-312
• 10 MacDermot K D, Holmes A, Miners A H. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females.  J Med Genet. 2001;  38 769-775
• 11 Kampmann C, Baehner F, Ries M, Beck M. Cardiac involvement in Anderson-Fabry disease.  J Am Soc Nephrol. 2002;  13 Suppl 2 S147-149
• 12 Kampmann C, Wiethoff C M, Perrot A, Beck M, Dietz R, Osterziel K J. The heart in Anderson Fabry disease.  Z Kardiol. 2002;  91 786-795
• 13 Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J, Bruhl K, Gal A, Bunge S, Beck M. Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes.  J Inherit Metab Dis. 2001;  24 715-724
• 14 Whybra C, Wendrich K, Ries M, Gal A, Beck M. Clinical manifestation in female Fabry disease patients.  Contrib Nephrol. 2001;  36 245-250
• 15 Schiffmann R, Murray G J, Treco D, Daniel P, Sellos-Moura M, Myers M, Quirk J M, Zirzow G C, Borowski M, Loveday K, Anderson T, Gillespie F, Oliver K L, Jeffries N O, Doo E, Liang T J, Kreps C, Gunter K, Frei K, Crutchfield K, Selden R F, Brady R O. Infusion of α-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.  Proc Natl Acad Sci U S A. 2000;  97 365-370
• 16 Eng C M, Guffon N, Wilcox W R, Germain D P, Lee P, Waldek S, Caplan L, Linthorst G E, Desnick R J. Safety and efficacy of recombinant human α-galactosidase A - replacement therapy in Fabry's disease.  N Engl J Med. 2001;  345 9-16
• 17 Schiffmann R, Kopp J B, Austin 3rd H A, Sabnis S, Moore D F, Weibel T, Balow J E, Brady R O. Enzyme replacement therapy in Fabry disease: a randomized controlled trial.  Jama. 2001;  285 2743-2749
• 18 Beck M, Ricci R, Widmer U, Dehout F, de Lorenzo A G, Kampmann C, Linhart A, Sunder-Plassmann G, Houge G, Ramaswami U, Gal A, Mehta A. Fabry disease: overall effects of agalsidase alfa treatment.  Eur J Clin Invest. 2004;  34 838-844
• 19 Baehner F, Kampmann C, Whybra C, Miebach E, Wiethoff C M, Beck M. Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study.  J Inherit Metab Dis. 2003;  26 617-627
• 20 MacDermot J, MacDermot K D. Neuropathic pain in Anderson-Fabry disease: pathology and therapeutic options.  Eur J Pharmacol. 2001;  429 121-125
• 21 Grau A J, Schwaninger M, Goebel H H, Beck M. [Fabry's disease: new therapeutic options for this lysosomal storage disorder].  Nervenarzt. 2003;  74 489-496
• 22 Ries M, Ramaswami U, Parini R, Lindblad B, Whybra C, Willers I, Gal A, Beck M. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents.  Eur J Pediatr. 2003;  162 767-772
• 23 Müller J M, Müller K-M, Dascalescu A, Whybra C, Baron K, Scheurich A, Mann K, Beck M, Schmidt L G, Fellgiebel A. Psychiatric ad Neuropsychological Signs and Symptoms in Patients with Fabry Disease: Literature Review.  Fortschr Neurol Psychiat. 2005;  73 687-693
• 24 Dütsch M, Marthol H, Stemper B, Brys M, Haendl T, Hilz M J. Small fiber dysfunction predominates in Fabry neuropathy.  J Clin Neurophysiol. 2002;  19 575-586
• 25 Cable W J, Dvorak A M, Osage J E, Kolodny E H. Fabry disease: significance of ultrastructural localization of lipid inclusions in dermal nerves.  Neurology. 1982;  32 347-353
• 26 Toyooka K, Said G. Nerve biopsy findings in hemizygous and heterozygous patients with Fabry's disease.  J Neurol. 1997;  244 464-468
• 27 Hilz M J, Brys M, Marthol H, Stemper B, Dutsch M. Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy.  Neurology. 2004;  62 1066-1072
• 28 Mehta A, Ginsberg L. Natural history of the cerebrovascular complications of Fabry disease.  Acta Paediatr Suppl. 2005;  94 24-27; discussion 29 - 10
• 29 Rolfs A BT, Zschiesche M, Morris P, Winchester B, Bauer P, Walter U, Mix E, Bottcher T, Löhr M, Harzer K, Strauss U, Pahnke J, Grossmann A, Benecke R. High prevalence of fabry disease in a prospective study of young patients with cryptogenic stroke.  The Lancet. 2005;  in press 366 1794-1796
• 30 Crutchfield K E, Patronas N J, Dombrosia J M, Frei K P, Banerjee T K, Barton N W, Schiffmann R. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease.  Neurology. 1998;  50 1746-1749
• 31 Takanashi J, Barkovich A J, Dillon W P, Sherr E H, Hart K A, Packman S. T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabry disease.  AJNR Am J Neuroradiol. 2003;  24 916-921
• 32 Moore D F, Ye F, Schiffmann R, Butman J A. 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
• 33 Fellgiebel A, Müller M J, Mazanek M, Baron K, Beck M, Stoeter P. White matter lesion severity in male and female patients with Fabry disease.  Neurology. 2005;  65 600-602
• 34 Gupta S, Ries M, Kotsopoulos S, Schiffmann R. The relationship of vascular glycolipid storage to clinical manifestations of fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women.  Medicine (Baltimore). 2005;  84 261-268
• 35 Moore D F, Altarescu G, Barker W C, Patronas N J, Herscovitch P, Schiffmann R. White matter lesions in Fabry disease occur in "prior" selectively hypometabolic and hyperperfused brain regions.  Brain Res Bull. 2003;  62 231-240
• 36 Mitsias P, Levine S R. Cerebrovascular complications of Fabry's disease.  Ann Neurol. 1996;  40 8-17
• 37 Grewal R P. Stroke in Fabry's disease.  J Neurol. 1994;  241 153-156
• 38 Elleder M. Sequelae of storage in Fabry disease - pathology and comparison with other lysosomal storage diseases.  Acta Paediatrica Suppl. 2003;  92 46-53
• 39 Moore D F, Scott L T, Gladwin M T, Altarescu G, Kaneski C, Suzuki K, Pease-Fye M, Ferri R, Brady R O, 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
• 40 Altarescu G, Moore D F, Pursley R, Campia U, Goldstein S, Bryant M, Panza J A, Schiffmann R. Enhanced endothelium-dependent vasodilation in Fabry disease.  Stroke. 2001;  32 1559-1562
• 41 DeGraba T, Azhar S, Dignat-George F, Brown E, Boutiere B, Altarescu G, McCarron R, Schiffmann R. Profile of endothelial and leukocyte activation in Fabry patients.  Ann Neurol. 2000;  47 229-233
• 42 Pantoni L, Garcia J H. Pathogenesis of leukoaraiosis: a review.  Stroke. 1997;  28 652-659
• 43 Bisschops R H, Graaf Y van der, Mali W P, Grond J van der. High total cerebral blood flow is associated with a decrease of white matter lesions.  J Neurol. 2004;  251 1481-1485
• 44 Shibata M, Ohtani R, Ihara M, Tomimoto H. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion.  Stroke. 2004;  35 2598-2603
• 45 Itoh Y, Esaki T, Cook M, Qasba P, Shimoji K, Alroy J, Brady R O, Sokoloff L, Moore D F. Local and global cerebral blood flow and glucose utilization in the α-galactosidase A knockout mouse model of Fabry disease.  J Neurochem. 2001;  79 1217-1224
• 46 Hilz M J, Kolodny E H, 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
• 47 Ritter M, Dittrich R, Droste D W. Microembolus detection in four patients with Fabry's disease: further support for a primarily microangiopathic origin of early cerebrovascular symptoms.  Eur Neurol. 2003;  50 141-145
• 48 Dobrovolny R, Dvorakova L, Ledvinova J, Magage S, Bultas J, Lubanda J C, Elleder M, Karetova D, Pavlikova M, Hrebicek M. Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population.  J Mol Med. 2005;  83 647-654
• 49 Ashton-Prolla P, Tong B, Shabbeer J, Astrin K H, Eng C M, Desnick R J. Fabry disease: twenty-two novel mutations in the α-galactosidase A gene and genotype/phenotype correlations in severely and mildly affected hemizygotes and heterozygotes.  J Investig Med. 2000;  48 227-235
• 50 de Veber G A, Schwarting G A, Kolodny E H, Kowall N W. Fabry disease: immunocytochemical characterization of neuronal involvement.  Ann Neurol. 1992;  31 409-415
• 51 Kaye E M, Kolodny E H, Logigian E L, Ullman M D. Nervous system involvement in Fabry's disease: clinicopathological and biochemical correlation.  Ann Neurol. 1988;  23 505-509
• 52 Rahman A N, Lindenberg R. The Neuropathology of Hereditary Dystopic Lipidosis.  Arch Neurol. 1963;  147 373-385
• 53 Tedeschi G, Bonavita S, Banerjee T K, Virta A, Schiffmann R. Diffuse central neuronal involvement in Fabry disease: a proton MRS imaging study.  Neurology. 1999;  52 1663-1667
• 54 Moore D F, Altarescu G, Ling G S, Jeffries N, Frei K P, Weibel T, Charria-Ortiz G, Ferri R, Arai A E, Brady R O, Schiffmann R. Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement.  Stroke. 2002;  33 525-531
• 55 Jardim L, Vedolin L, Schwartz I V, Burin M G, Cecchin C, Kalakun L, Matte U, Aesse F, Pitta-Pinheiro C, Marconato J, Giugliani R. CNS involvement in Fabry disease: clinical and imaging studies before and after 12 months of enzyme replacement therapy.  J Inherit Metab Dis. 2004;  27 229-240
• 56 Fellgiebel A, Wille P, Müller M J, Winterer G, Scheurich A, Vucurevic G, Schmidt L G, Stoeter P. Ultrastructural hippocampal and white matter alterations in mild cognitive impairment: a diffusion tensor imaging study.  Dement Geriatr Cogn Disord. 2004;  18 101-108
• 57 Prins ND, van Straaten EC, van Dijk EJ, Simom M, van Schijndel RA, Vrooman HA, Koudstaal PJ, Scheltens P, Breteler MM. Measuring progression of cerebral white matter lesions on MRI: visual rating and volumetrics.  Neurology. 2004;  62 1533-1539