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ABSTRACT & COMMENTARY
By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Anti-titin antibodies are common in late-onset myasthenia gravis and have a high predictive value for the presence of thymoma in early-onset myasthenia gravis.
Source: Szczudlik P, et al. Antititin antibody in early- and late-onset myasthenia gravis. Acta Neurol Scand 2014:130:229-233.
In addition to autoantibodies directed against the acetylcholine receptor (AchR) and the receptor-associated protein muscle-specific tyrosine kinase (MuSK) patients with myasthenia gravis (MG) demonstrate a host of other antibodies. Anti-striated muscle antibodies, present in 30% of MG and reported in 80% of those with thymoma, are associated with late onset and more severe disease, and react with epitopes on muscle proteins including titin, ryanodine receptor, and the voltage-gated potassium channel Kv1.4. Antibodies to titin may be helpful in predicting disease prognosis, but prior reports have offered contradictory results.
Antibodies to titin were measured among a cohort of 295 consecutive MG patients, 188 women and 107 men, ages 12-89 years, seen at the Department of Neurology, Medical University of Warsaw, Poland, between May 2009 and May 2012. Diagnosis was based on the presence of fluctuating weakness affecting oculobulbar, respiratory, or limb muscles, and was confirmed by radioimmunoassay antibody (AchR or MuSK) or electrodiagnostic testing. Congenital MG patients were excluded. Symptom severity was measured using the Myasthenia Gravis Functional Assessment (MGFA) scale, and a complete history of treatments received, frequency of myasthenic crises and remissions, and clinical outcomes were noted. Statistical analysis included the Shapiro-Wilk and Wilcoxon rank-sum tests, and Chi-squared and Fisher’s exact tests, with P < 0.05 considered significant.
Early-onset MG, defined as onset ≤ 50 years, occurred in 56% (n = 164) of patients and was predominantly female, with 44% (n = 131) experiencing late-onset MG (after age 50), consisting predominantly of men. Peak onset of MG occurred in the third decade in patients with early MG and in the seventh decade in late MG. AChR and MuSK antibodies were present in 92% (n = 271) and 1% (n = 3) of all patients, respectively, with 27% (n = 81) of all MG patients demonstrating anti-titin positivity, all of whom had seropositive MG. Twenty-six patients had thymoma. Early-onset patients were anti-titin positive in 6%, compared to 54% of late-onset MG, but thymoma was present in all early-onset, male, anti-titin positive patients. Anti-titin positivity was significantly associated with bulbar symptoms in early-onset MG, but not late-onset MG, but it did not significantly differ among ocular MG patients across age groups. Neither risk of crisis, use of immunosuppressive medication, nor more severe MGFA class of MG correlated with anti-titin antibodies. Anti-titin antibodies have a high predictive value for thymoma in early-onset MG, but cannot predict disease severity.
Among the 6-12% of MG patients who are seronegative for both AChR and MuSK antibodies, a variable proportion (2-50%) have antibodies against low-density lipoprotein receptor-related protein 4 (LRP4), which disrupts AChR aggregation by inhibiting the interaction of agrin-LRP4-MuSK. Approximately 10-15% seronegative MG will have antibodies directed against agrin, an extracellular matrix protein that is a ligand of LRP4, activates MuSK, and is essential for AchR aggregation, whereas almost 20% will have antibodies directed against cortactin, a protein concentrated at the neuromuscular junction that regulates actin polymerization and promotes AchR clustering downstream from agrin/MuSK. Cortactin antibodies are found in fewer than 5% of seropositive MG patients. Further investigations will surely disclose additional antibodies in most, if not all, cases of hitherto seronegative MG.