Klinische und Genotyp-Phänotyp-Korrelation epidemiologischer, bildgebender und neurologischer Befunde bei Patienten mit Morbus Wilson

Zusammenfassung

Der Morbus Wilson, eine autosomal-rezessive Erkrankung des Kupferstoffwechsels, ist durch eine variable klinische Konstellation von hepatischen, neurologischen und psychiatrischen Leitsymptomen gekennzeichnet. Gegenwärtig sind ca. 250 verschiedene Mutationen des ATP 7B-Genes bekannt, die als krankheitsauslösend gelten. Gegenstand der Diskussion ist es, ob eine Genotyp-Phänotyp-Korrelation bezüglich dieser Mutationen vorliegt. Die vorliegende Studie untersucht diese Frage bei 39 Patienten anhand der Genotypeinteilung in homozygot (Gruppe I) bzw. compound heterozygot für die Mutation H1069Q (Gruppe II) und anderer Mutationen (Gruppe III). Betrachtet werden der klinische Verlaufstyp, der neurologische Schweregrad, epidemiologische Aspekte, das Vorliegen einer psychopathologischen Störung, zentrale Latenzen der akustisch evozierten Potenziale (FAEP mit Welle III und Interpeaklatenz III-V) und Befunde des kranialen MRT. Während die psychopathologischen Befunde, Ergebnisse der FAEP und des MRT mit dem klinischen Verlaufstyp korrelieren, lässt sich eine Genotyp-Phänotyp-Korrelation zum Vorliegen der H1069Q-Mutation nicht nachweisen. Das qualitative und quantitative Befundmuster ist ohne signifikante Unterschiede in den vorliegenden 3 Genotypgruppen. Entscheidende Bedeutung für die Ausprägung der Befunde und ihre Reversibilität kommt weiterhin dem Zeitpunkt des Therapiebeginns zur Begrenzung des toxischen Kupfereinflusses zu.

Abstract

Wilson's disease, a rare autosomal recessive disorder of hepatic copper transport, is characterized by a varying pattern of hepatic, neurologic and psychiatric symptoms. Currently, about 250 causative mutations of the ATP 7B gene are known. However, a correlation between genotype and phenotype according to these mutations is not yet clear. To elucidate a possible correlation in this study 39 patients with Wilson's disease were subdivided into three groups according to the underlying mutation in group I for homocygote respectively group II for compound heterocygote mutation in H1069Q and group III for other mutations. Clinical subtype and extent of neurologic disturbance as well as epidemiologic aspects, presence of psychiatric symptoms, results of acustically evoked potentials (Wave III, interpeak latency III-V) and findings of cranial MRI were considered.
While psychopathological symptoms, the results of acustically evoked potentials and cranial MRI show a correlation to the clinical subtype of Wilson's disease there was no genotype-phenotype correlation on the basis of the mutation in H1069Q. The qualitative and quantitative pattern of results do not show any significant differences in the three groups of genotype. Thus, the time of treatment onset still has most influence on the extent of clinical manifestation and reversibility of the toxic copper accumulation.

Literatur

• 1 Maier-Dobersberger T. Morbus Wilson. Diagnosestellung mit konventionellen und molekularbiologischen Methoden.  Dtsch med Wschr. 1999;  124 493-496
• 2 Cuthbert J A. Wilson's disease: A new gene and animal model for an old disease.  J Investig Med. 1995;  43 (4) 323-336
• 3 Cox D W. Molecular advances in Wilson Disease.  Prog Liver Dis. 1996;  14 245-264
• 4 Marsden C D. Wilson's disease.  Q J Med. 1987;  65 959-966
• 5 Stremmel W, Meyerrose K W, Niederau C, Hefter H, Kreuzpainter G, Strohmeyer G. Wilson's disease: clinical presentation, treatment, and survival.  Ann Intern Med. 1991;  115 720-726
• 6 Roberts E A, Cox D W. Wilson disease.  Bailliere's Clinical Gastroenterology. 1998;  12 (2) 237-256
• 7 Jaspert A, Claus D, Lang C, Kolominsky P, Neundörfer B. Klinik, neurologische Diagnostik und Therapie des M. Wilson. In: Huffmann G, Braune H-J, Henn K-H (Hrsg). Extrapyramidalmotorische Erkrankungen. Reinbek: Einhorn 1994: 551-555
• 8 Schlaug G, Hefter H, Engelbrecht V, Kuwert T, Arnold S, Stöcklin G, Seitz R J. Neurological impairment and recovery in Wilson's disease: evidence from PET and MRI.  J Neurol Sci. 1996;  136 129-139
• 9 Roh J K, Lee T G, Wie B A, Lee S B, Park S H, Chang K H. Initial and follow-up brain MRI findings and correlation with the clinical course in Wilson's disease.  Neurology. 1994;  44 1064-1068
• 10 Selwa L M, Vanderzant C W, Brunberg J A, Brewer G J, Drury I, Beydoun A. Correlation of evoked potentials and MRI findings in Wilson's disease.  Neurology. 1993;  43 2059-2064
• 11 Hall H C. La degenerescence hepato-lenticulaire. Maladie de Wilson-Pseudosklerose Masson. Paris 1921: 361
• 12 Bearn A G. A genetical analysis of thirty families with Wilson's disease (hepatolentical degeneration).  Ann Hum Genet. 1960;  24 33-43
• 13 Frydman M, Bonne-Tamir B, Farrer L A, Conneally P M, Magazanik A, Ashbel S, Goldwitch Z. Assignment of the gene for Wilson's disease to chromosome 13: Linkage to the esterase D locus.  Proc Nat Acad Sci USA. 1985;  82 1819-1821
• 14 Bowcock A M, Farrer L A, Hebert J M. et al . Eight closely linked loci place the Wilson disease locus within 13q14-q21.  Am J Hum Genet. 1988;  43 664-674
• 15 Bull P C, Thomas G R, Rommens J M, Forbes J R, Cox D W. The Wilson disease gene is a putative copper transporting P-Type ATPase similar to the Menkes gene.  Nature Genetics. 1993;  5 327-337
• 16 Petruhkin K, Fischer S G, Piratsu M. et al . Mapping, cloning and genetic characterization of the region containing the Wilson's disease gene.  Nature Genetics. 1993;  5 338-343
• 17 Tanzi R E, Petrukhin K, Chernov I. et al . The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.  Nature Genetics. 1993;  5 343-350
• 18 Yamaguchi Y, Heiny M E, Gitlin J D. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease.  Biochem Biophys Res Commun. 1993;  197 271-277
• 19 Payne A S, Kelly E J, Giltlin D. Functional expression of the Wilson's disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation.  Proc Natl Acad Sci. 1998;  95 10 854-10 859
• 20 Shah A B, Chernov I, Zhang H T. et al . Identification and analysis of mutations in the Wilson disease gene (ATP7B): Population frequencies, genotype-phenotype correlation, and functional analyses.  Am J Hum Genet. 1997;  61 317-328
• 21 Gollan J L, Gollan T J. Wilson disease in 1998: genetic, diagnostic and therapeutic aspects.  J Hepatol. 1998;  28 28-36
• 22 Cox D W, Thomas G R, Roberts E A, Walshe J M. The Wilson Disease gene: Clinical implications.  Hepatology. 1994;  20 (4 Pt 2) 267-(Abstract)
• 23 Bachmann H, Lössner J, Biesold D. Untersuchungen zur Wilsonschen Erkrankung in der DDR. Teil I: Genetik und Epidemiologie.  Z ges Inn Med. 1979;  34 744-748
• 24 Scheinberg I H, Sternlieb I. Wilson's disease. In: Smith Jr LH (Hrsg). Major Problems in Internal Medicine, Vol. 23. Philadelphia: Saunders 1984
• 25 DiDonato M, Bibudhendra S. Copper transport and its alteration in Menkes and Wilson diseases.  Biochemica et Biophysica Acta. 1997;  1360 3-16
• 26 Kenney S, Cox D W. The Wilson Disease Database and its contents are Copyright ( 1999 - 2000 University of Alberta. Last updated march 7th 2000. http://www.medgen.med.ualberta.ca/database.html. 
• 27 Ferenci P. Wilson's disease.  Ital J Gastroenterol Hepatol. 1999;  31 416-425
• 28 Czlonkowska A, Rodo M, Gajda J, Ploos van Amstel H K, Juyn J, Houwen R HJ. Verv high frequency of the His1069Gln mutation in Polish Wilson disease patients.  J Neurol. 1997;  244 591-592
• 29 Maier-Dobersberger T, Ferenci P, Polli C. et al . Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction.  Ann Intern Med. 1997;  127 21-26
• 30 Caca K, Ferenci P, Kühn H-J. et al . High prevalence of the H1069Q mutation in Easet German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis.  J Hepatol. 2001;  35 575-581
• 31 Thomas G R, Forbes J R, Roberts E A, Walshe J M, Cox D W. The Wilson disease gene: spectrum of mutations and their consequences.  Nature Genetics. 1995;  9 210-217
• 32 Houwen R H, Juyn J, Hoogenraad T U, Ploos van Amstel J K, Berger R. H714Q mutation in Wilson disease is associated with late neurological presentation.  J Med Genet. 1995;  32 480-482
• 33 Stapelbroek J M, Bollen C W, Ploos van Amstel J K. et al . The H1069Q mutation in in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis.  J Hepatol. 2004;  41 758-763
• 34 Forbes J R, Cox D W. Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant?.  Am J Hum Genet. 1998;  68 1663-1674
• 35 Schiefermeier M, Kolleger H, Madl C, Polli C, Oder W, Kühn H J, Berr F, Ferenci P. The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson's disease.  Brain. 2000;  123 585-590
• 36 Schöls L, Rieß O. Kupferstoffwechselstörungen. In: Rieß O, Schöls L (Hrsg). Neurogenetik. Berlin: Springer 1998: 218-222
• 37 Hefter H, Arendt G, Stremmel W, Freund H J. Motor impairment in Wilson's disease, I: slowness of voluntary limb movements.  Acta Neurol Scand. 1993;  87 133-147
• 38 Hermann W, Barthel H, Hesse S, Grahmann F, Kühn H-J, Wagner A, Villmann T. Comparison of clinical types of Wilson's disease and glucose metabolism in extrapyramidal-motoric brain regions.  J Neurol. 2002;  249 896-901
• 39 Hermann W, Villmann T, Wagner A. Elektrophysiologisches Schädigungsprofil von Patienten mit einem Morbus Wilson.  Der Nervenarzt. 2003;  10 881-887
• 40 Prayer L, Wimberger D, Kramer J, Grimm G, Oder W, Imhof H. Cranial MRI in Wilson's disease.  Neuroradiology. 1990;  32 211-214
• 41 Thuomas K A, Aquilonius S M, Bergström K, Westermark K. Magnetic resonance imaging of the brain in Wilson's disease.  Neuroradiology. 1993;  35 447-452
• 42 Cuthbert A J. Wilson's Disease: A new gene and an animal model for an old disease.  J Investig Med. 1995;  43 (4) 323-336
• 43 Thomas G R, Forbes J R, Roberts E A, Walshe J M, Cox D W. The Wilson disease gene: spectrum of mutations and their consequences.  Nature Genetics. 1995;  9 210-217
• 44 Czlonkowska A, Rodo M, Gajda J, Ploos van Amstel H K, Juyn J, Houwen R. Verv high frequency of the His1069Gln mutation in Polish Wilson disease patients.  J Neurol. 1997;  244 591-592
• 45 Portala K. Psychopathology in Wilson's Disease. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 2001: 1-61
• 46 Nijeholt J L, Korf J. Wilson's disease and monoamines.  Arch Neurol. 1978;  35 617
• 47 Hawkins R A, Mazziotta J C, Phelps M E. Wilson's disease studied with FDG and positron emission tomography.  Neurology. 1987;  37 1707-1711
• 48 Snow B J, Bhatt M, Martin W RW, Li D, Calne D B. The nigrostriatal dopaminergic pathway in Wilson's disease studied with positron emission tomography.  J Neurol Neurosurg Psychiatry. 1991;  54 12-17
• 49 Jeon B, Kim J M, Jeong J M, Kim K M, Chang Y S, Lee M C. Dopamine transporter imaging with [¹²³I]-β-CIT demonstrates presynaptic nigrostriatal dopaminergic damage in Wilson's disease.  J Neurosurg Psychiatry. 1998;  65 60-64
• 50 Oertel W H, Tatsch K, Schwarz J. et al . Decrease of D2 receptors indicated by 123 I-iodobenzamide single-photon emission computed tomography relates to neurological deficit in treated Wilson's disease.  Ann Neurol. 1992;  32 743-748
• 51 Westermark K, Tedroff J, Thoumas K-A. et al . Neurological Wilson's Disease Studied with Magnetic Resonance Imaging and with Positron Emission Tomography Using Dopaminergic Markers.  Movement Disorders. 1995;  10 596-603
• 52 Hermann W, Villmann T, de Groot M, Grahmann F, Wagner A. Kinesiologische Diagnostik bei Morbus Wilson.  Klinische Neurophysiologie. 2000;  2 94-100
• 53 Hermann W, Wagner A, Kühn H-J, Grahmann F, Villmann T. Classification of fine motoric disturbances in Wilson's disease using artifical neural networks.  Acta Neurol Scand. 2005;  111 400-406
• 54 Roach E S, Ford C S, Spudis E V. et al . Wilson's disease: evoked potentials and computed tomography.  J Neurol. 1985;  232 20-23
• 55 Huster D, Hoppert M, Lutsenko S. et al . Defective cellular localisation of mutant ATP 7B in Wilson's disease patients and hepatoma cell lines.  Gastroenterology. 2003;  124 335-345
• 56 Forbes J R, Cox D. Copper-dependent trafficking of Wilson's disease mutant ATP 7B proteins.  Hum Mol Genet. 2000;  9 1927-1935
• 57 Ferenci P, Zollner G, Trauner M. Hepatic transport systems.  J Gastroenterol Hepatol. 2002;  17 105-112