Antibodies against Muscle-Specific Kinase in Juvenile Myasthenia Gravis

Sir,

Myasthenia gravis is an antibody-mediated disorder of the motor endplate. Antibodies against the acetylcholine receptor (AChRAb) are found in 60 - 80 % of adult-onset, and fewer of juvenile myasthenic patients [[1], [2]]. Recently, antibodies against the muscle-specific receptor tyrosine kinase (MuSK) have been shown in 17/24 of AChR-Ab-negative myasthenia patients [[3]]. MuSK is a tyrosine kinase localised to the postsynaptic surface of the neuromuscular junction, and is involved in the development and maintenance of the molecular architecture of the postsynaptic membrane as an agrin receptor [[4]]. MuSK antibodies inhibit the function of the molecule in cultured myotubes and may play a role in the pathogenesis of AChR-Ab-negative MG.

Because a higher proportion of childhood and juvenile myasthenia cases are seronegative for AChRAbs, we investigated the presence of MuSK antibodies in this age group.

Of 40 juvenile myasthenia patients followed up in our clinic, 27 were tested at least twice for AChRAb with at least a one year interval between tests. The clinical diagnosis of myasthenia was confirmed by pharmacological tests in all patients. Congenital myasthenic syndromes were ruled out by the age of onset, the absence of a family history, and the response to immunomodulatory treatment or thymectomy. AChRAb were tested with a commercial radioreceptor assay kit using manufacturers' instructions (IBL Hamburg, Germany) where titers < 0.2 nmol/mL are negative. Patients who were AchRAb-negative on all occasions (n = 8, 29 %) were tested for antibodies to MuSK in the Institute of Molecular Medicine, John Radcliffe Hospital, UK (Table [1]). All cases had ptosis and extraocular muscle weakness increasing during the day. Three patients also had a history of mild generalised weakness. These were assayed by immunoprecipitation of ¹²⁵I-labelled human and rat MuSK (McConville and Vincent, in preparation). The results of this assay are in complete agreement with those published by Hoch et al [[3]]. All sera were negative for MuSK antibodies.

Table 1 Features of the patients Case Sex Age of onset Symptom AchRAb titer (nmol/L) Treatment State when tested 1 F 5 bilateral ptosis, mild generalised weakness 0.1 AChE, steroid Clinical remission 2 F 12 unilateral ptosis, extraocular and mild generalised weakness 0.04 AChE, steroid Clinical remission 3 F 11 ptosis, diplopia 0.16 AChE, thymectomy (thymic hyperplasia) Post-thymectomy, drug-free remission 4 M 3 unilateral ptosis, diplopia, generalised weakness 0.2 AChE, steroid Remission Vitiligo 5 M 3 ptosis, mild generalised weakness 0.2 AChE, steroid Clinical remission 6 M 6 ptosis, strabismus 0 AChE, steroid Minimal ptosis, no meds 7 M 3 ptosis 0.03 steroids Clinical remission 8 M 12 ptosis 0.1 steroids Clinical remission AChE: anticholinesterase drugs

The absence of MuSK antibodies in our series contrasts with the findings of two positive childhood-onset cases reported earlier [[3]]. Possible reasons may include clinical differences: while the cases included in the series by Hoch et al [[3]] had moderate or severe disease, our patients, including those with a history of generalized weakness, had mild symptoms restricted to extraocular muscles when blood samples were obtained. As in AChRAbs, seronegative patients for MuSK antibodies may be more frequent among less severely affected patients [[5]]. Treatment is another factor influencing anti-MuSK positivity: in Hoch et al's series, 4/7 anti-muSK negative patients, but only 2/17 positive patients had received immunosuppressive treatment. Three of our patients were receiving steroids, and one had undergone thymectomy. The definition of serogroups among myasthenic patients may also affect the results. Anti-muSK antibodies are not found in AChR-Ab-positive patients. Because AChR-Abs can develop later during the course of myasthenia, some of these childhood cases who will become anti-AChR positive in the future may not be candidates for anti-MuSK positivity [[5]]. On the other hand, 20 % of all myasthenia patients are negative for either antibody and may have an immune response against other antigens of the neuromuscular junction.

Our results indicate that children with ocular or mild generalised myasthenia are less likely to have anti-MuSK antibodies. Future studies should be conducted in cases with more severe disease and bulbar symptoms, and on serum samples obtained before treatment.

References

• 1 Andrews P I, Massey J M, Sanders D B. Acetylcholine receptor antibodies in juvenile myasthenia gravis.  Neurology. 1993;  43 977-982
• 2 Anlar B, Özdirim E, Renda Y, Yalaz K, Aysun S, Topcu M, Topaloglu H. Myasthenia gravis in childhood.  Acta Pediatr. 1996;  85 838-842
• 3 Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies.  Nat Med. 2001;  7 365-368
• 4 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
• 5 Sanders D B, Andrews I, Howrad J F, Massey J M. Seronegative myasthenia gravis.  Neurology. 1997;  48 (Suppl 5) S40-S45