Neue Erkenntnisse bei der seronegativen generalisierten Myasthenia gravis

Zusammenfassung

Die generalisierte Myasthenia gravis (MG) ist eine Autoimmunerkrankung, die in 80-90% der Fälle durch pathogenetische Autoantikörper (AK) gegen nikotinerge Azetylcholinrezeptoren (AChR) gekennzeichnet ist. Bei einem Teil der Patienten mit AChR-AK-negativer generalisierter MG (so genannte seronegative MG) sind Autoantikörper gegen die muskelspezifische Rezeptor-Tyrosinkinase (MuSK) nachweisbar, die eine Rolle in der Anordnung der AChR während der Synapsenbildung spielt. Allerdings wird seit kurzem diskutiert, ob MuSK-AK lediglich ein Epiphänomen darstellen oder die Pathogenese hinreichend erklären können.

Eine MuSK-AK-positive MG ist häufiger bei Frauen. Die bulbäre und Atemhilfsmuskulatur ist häufig betroffen. MuSK-AK-positive Patienten scheinen weniger gut auf eine medikamentöse immunsuppressive Therapie anzusprechen als AChR-AK-positive. Eine gute Wirksamkeit wird durch Plasmapherese erzielt. Pathologische Thymusbefunde sind bei MuSK-AK-positiven Fällen deutlich seltener als bei AChR-AK-positiven. Bislang ist noch ungeklärt, ob die Thymektomie den Krankheitsverlauf bei MuSK-AK-positiven Patienten beeinflusst.

Weiterhin kann eine autoimmunvermittelte seronegative MG durch kongenitale Myasthenieformen mit späterem Manifestationsbeginn (Rapsyn-Mutationen, »slow-channel«-Syndrom durch AChR-Mutationen) vorgetäuscht werden.

Summary

Generalized Myasthenia gravis (MG) is an autoimmunmediated disorder, characterized in 80-90% by pathogenetic autoantibodies (Ab) against the nicotinergic acetylcholine receptor (AChR). In some patients with AChR-Ab-negative generalized MG (so-called seronegative MG) antibodies against the muscle-specific receptor tyrosin kinase (MuSK) were detected. MuSK plays a role in the clustering of AChR during synaptogenesis. It is not clear whether MuSK-Ab can sufficiently explain pathogenesis or whether they are just an epiphenomenon. MuSK-Ab-positive MG occurs more often in women. Bulbar and respiratory muscles are often involved. AChR-Abpositive patients seem to respond better to immunosuppressive therapy than MuSK-Ab-positive patients. Patients show short-time benefit after plasmapheresis. Pathological thymus findings are rarer in MuSK-Ab-positive than in AChR-Ab-positive cases. Therefore a favourable influence of thymectomy on the course of the disease seems to be less probable.

Additionally, congenital myasthenic syndromes with late onset (e.g. by rapsyn mutations, slow-channel syndrome by AChR mutation) can mimic an autoimmune mediated seronegative MG.

Schlüsselwörter

Myasthenia gravis generalisata - kongenitale Myasthenie-Syndrome - muskelspezifische Rezeptor-Tyrosinkinase - Rapsyn-Mutationen - »slow-channel«-Syndrom

Keywords

Myasthenia gravis generalisata - congenital myasthenic syndrome - muscle-specific tyrosine kinase - rapsyn-mutation - “slow-channel”-syndrome

• Literatur

• 1 Abicht A, Lochmüller H. What’s in the serum of seronegtive MG and LEMS? MuSK et al. Neurology 2002; 59: 1672-3.
• 2 American Association of Electrodiagnostic Medicine Quality Assurance Committee. Literature review of the usefulness of repetitive nerve stimulation and single fiber EMG in the electrodiagnostic evaluation of patients with suspected myasthenia gravis or Lambert Eaton myasthenic syndrome. Muscle Nerve 2001; 24: 1239-47.
• 3 Andrews PI, Massey JM, Sanders DB. Acetylcholine receptor antibodies in juvenile myasthenia gravis. Neurology 1993; 43: 977-82.
• 4 Anlar B, Ozdirim E, Renda Y, Yalaz K, Aysun S, Topcu M. et al. Myasthenia gravis in childhood. Acta Paediatr 1996; 85: 838-42.
• 5 Blaes F, Beeson D, Plested P. et al. IgG from “seronegative” myasthenia gravis patients binds to a muscle cell line,TE671, but not to human acetylcholine receptor. Ann Neurol 2000; 47: 504-10.
• 6 Birmanns B, Brenner T, Abramsky O, Steiner I. Seronegative myasthenia gravis: clinical features, response to therapy and synthesis of acetylcholine receptor antibodies in vitro. J Neurol Sci 1991; 102: 184-9.
• 7 Buckel A, Beeson D, James M, Vincent A. Cloning of the cDNA encoding human rapsyn and mapping the RAPSYN gene locus to chromosome 11p11.2-p11.1. Genomics 1996; 35: 613-6.
• 8 Bufler J, Pitz R, Czep M, Wick M, Franke C. Purified IgG from seropositive and seronegative patients with myasthenia gravis reversibly blocks currents through nicotinic acetylcholine receptor channels. Ann Neurol 1998; 43: 458-64.
• 9 Burke G, Cossins J, Maxwell S, Owens G, Vincent A, Robb S. et al. Rapsyn mutations in hereditary myasthenia. Distinct earlyand lateonset phenotypes. Neurology 2003; 61: 826-8.
• 10 Chauplannaz G, Brady B. Hereditary myasthenic syndromes with late onset. Value of electrophysiological tests. Rev Neurol (Paris) 1994; 150: 142-8.
• 11 Croxen R, Newland C, Beeson D, Oosterhuis H, Chauplannaz G, Vincent A. et al. Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome. Hum Mol Genet 1997; 06: 767-74.
• 12 Croxen R, Hatton C, Shelley C, Brydson M, Chauplannaz G, Oosterhuis H. et al. Recessive inheritance and variable penetrance of slowchannel congenital myasthenic syndromes. Neurology 2002; 59: 162-68.
• 13 Engel AG, Lambert EH, Mulder D, Torres C, Sahashi K, Bertorini T. et al. A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholineinduced ion channel. Ann Neurol 1982; 11: 553-69.
• 14 Engel AG, Ohno K, Milone M, Wang H-L, Nakano S, Bouzat C. et al. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet 1996; 05: 1217-27.
• 15 Evoli A, Bartoccioni F, Batocchi AP, Scuderi F, Tonali P. Anti-AchR-negative myasthenia gravis: clinical and immunological features. Clin Invest Med 1989; 12: 104-9.
• 16 Evoli A, Batocchi AP, Lo MMonaco, Servidei S, Padua L, Majolini L, Tonali P. Clinical heterogeneity of seronegative myasthenia gravis. Neuromusc Disord 1996; 06: 155-61.
• 17 Evoli A, Tonali PA, Padua L, Lo MMonaco, Scuderi F, Batocchi AP, Marino M, Bartoccioni E. Clinical correlates with anti-MuSK antibodies in generalized myasthenia gravis. Brain 2003; 126: 1-8.
• 18 Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review). Report of the quality standards subcommittee of the American academy of neurology. Neurology 2000; 55: 7-15.
• 19 Guillermo GR, Tellez-Zenteno JF, Weder-Cisneros N, Mimenza A, Estanol B, Remes-Troche JM. et al. Response of thymectomy: Clinial and pathological characteristics among seronegative and seropositive myasthenia gravis patients. Acta Neurol Scand 2004; 109: 217-21.
• 20 Hain B, Hanisch F, Deschauer M. »Seronegative« Myasthenie mit Antikörpern gegen die muskelspezifische Tyrosin-Kinase. Nervenarzt 2004; 75: 362-7.
• 21 Hoch W. Formation of the neuromuscular junction. Agrin and its unusual receptors. Eur J Biochem 1999; 265: 1-10.
• 22 Hoch W, McConville J, Helms S, Newsom-Davies J, Melms A, Vincent A. Auto-Antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nature Medicine 2001; 07: 365-8.
• 23 Lin W, Burgess RW, Dominguez B, Pfaff SL, Sanes JR, Lee K-F. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 2001; 410: 1057-64.
• 24 Lindström J. An essay for antibody to human acetylcholine receptor in serum from patients with myasthenia gravis. Clin Immunol Immunopathol 1977; 07: 36-43.
• 25 Liyanage Y, Hoch W, Beeson D, Vincent A. The agrin/muscle-specific kinase pathway: New targets for autoimmune and genetic disorders at the neuromuscular junction. Muscle Nerve 2002; 25: 4-16.
• 26 Maselli RA, Dunne V, Pascual-Pascual SI, Bowe C, Agius M, Frank R, Wollmann RL. Rapsyn mutations in myasthenic syndrome due to impaired receptor clustering. Muscle Nerve 2003; 28: 293-301.
• 27 McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsome-Davies J. et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravies. Ann Neurol 2004; 55: 580-84.
• 28 Melber D. Maternal-fetal transmission of myasthenia gravis without acetylcholine receptor antibodies [letter]. N Engl J Med 1988; 319: 996.
• 29 Mossman S, Vincent A, Newsom-Davis J. Myasthenia gravis without acetylcholine-receptor antibody: a distinct disease entitiy. Lancet 1986; 01: 116-9.
• 30 Müller JS, Mildner G, Müller-Felber W, Schara U, Krampfl K, Petersen B. et al. Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients. Neurology 2003; 60: 1805-10.
• 31 Oh SJ. Electrophysiological characteristics in seronegative myasthenia gravis. Ann N Y Acad Sci 1993; 681: 584-7.
• 32 Ohno K, Engel AG, Shen X-M, Selcen D, Brengman J, Harper CM. et al. Rapsyn mutations in humans cause endplate acetylcholine-receptor deficiency and myasthenic syndrome. Am J Hum Genet 2002; 70: 875-85.
• 33 Ohta K, Fujinami A, Saida T, Nishimura M, Kuno S, Ohta M. Frequency of anti-AChR epsilon subunit-specific antibodies in myasthenia gravis. Autoimmunity 2003; 36: 151-4.
• 34 Palace J, Vincent A, Beeson D. Myasthenia gravis: Diagnostic and management dilemmas. Curr Opin Neurol 2001; 14: 583-9.
• 35 Plested CP, Tang T, Spreadbury I, Littleton ET, Kishore U, Vincent A. AChR phosphorylation and indirect inhibition of AChR function in seronegative MG. Neurology 2002; 59: 1682-8.
• 36 Sanders DB, Howard JF, Massey JM, Mihovilovic M, Olanow CW, Roses AD, Stewart CJ. Seronegative Myasthenia gravis. Ann Neurol 1987; 22: 126.
• 37 Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A. Clinical aspects of MuSK antibody positive seronegative MG. Neurology 2003; 60: 1978-80.
• 38 Sander A, Hesser BA, Witzemann V. MuSK induces in vivo acetylcholine receptor clusters in a ligand-independent manner. J Cell Biol 2001; 155: 1287-96.
• 39 Sanes J, Lichtman J. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Neurosci Rev 2001; 02: 791-803.
• 40 Scuderi F, Marino M, Colonna L, Mannella F, Evoli A, Provenzano C, Bartoccioni E. Antip110 autoantibodies identify a subtype of “seronegative” myasthenia gravis with prominent oculobulbar involvement. Lab Invest 2002; 82: 1139-46.
• 41 Soliven BC, Lange DJ, Penn AS, Younger D, Jaretzki A, Lovelace RE, Rowland LP. Seronegative myasthenia gravis. Neurology 1988; 38: 5147.
• 42 Spring PJ, Spies JM. Myasthenia gravis. Options and timing of immunomodulatory treatment. BioDrugs 2001; 15: 173-83.
• 43 Tsujihata M, Yoshimura T, Satoh A. et al. Diagnostic significance of IgG, C3, and C9 at the limb motor end-plate in minimal myasthenia gravis. Neurology 1989; 39: 1359-63.
• 44 Verma PK, Oger J-F. Seronegative generalized myasthenia gravis: low frequency of thymic pathology. Neurology 1992; 42: 586-9.
• 45 Vincent A, Newsom-Davis J. Acetylcholin receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985; 48: 1246-52.
• 46 Vincent A, Bowen J, Newsom-Davis J, McConville J. Seronegative generalised myasthenia gravis : clinical features, antibodies, and their targets. Lancet Neurology 2003; 02: 99-106.
• 47 Willcox N, Schluep M, Ritter MA, NewsomDavis J. The thymus in seronegative myasthenia gravis patients. J Neurol 1991; 238: 256-61.
• 48 Yasaki E, Prioleau C, Barbier J, Richard P, Andreux F, Leroy JP. et al. Electrophysiological and morphological characterization of a case of autosomal recessive congenital myasthenic syndrome with acetylcholine receptor deficiency due to a N88K rapsyn homozygous mutation. Neuromuscul Disord 2004; 14: 24-32.
• 49 Zhou L, McConville J, Chaudry V, Adams RN, Skolasky RL, Vincent A. et al. Clinical comparism of muscle-specific tyrosine kinase (MuSK) antibody-positive and –negative myasthenic patients. Muscle Nerve 2004; 30 (01) 55-60.
• 50 Lindstrom J. Is “seronegative” MG explained by autoantibodies to MuSK?. Neurolgy 2004; 62: 1920.
• 51 Ohta K, Shigemoto S, Kubo S, Maruyama N, Abe Y, Ueda N. et al. MuSK antibodies in AchR Ab-seropositive MG vs. AchR Ab seronegative MG. Neurology 2004; 62: 2132.
• 52 Selcen D, Fukuda T, Shen X-M, Engel AG. Are MuSK antibodies the primary caue of myasthenic symptoms?. Neurology 2004; 62: 1939.