Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7

Abstract

Background: Mutations in the postsynaptic adaptor protein Dok-7 underlie congenital myasthenic syndrome (CMS) with a characteristic limb girdle pattern of muscle weakness. Patients usually do not respond to or worsen with the standard CMS treatments: cholinesterase inhibitors and 3,4-diaminopyridine. However, anecdotal reports suggest they may improve with ephedrine.

Methods: This was an open prospective follow-up study to determine muscle strength in response to ephedrine in Dok-7 CMS. Patients were first evaluated as inpatients for suitability for a trial of treatment with ephedrine. The response was assessed at 2 and 6 to 8 months follow-up clinic visits using a quantitative myasthenia gravis (severity) score (QMG) and mobility measures.

Results: Ten out of 12 of the cohort with DOK7 mutations tolerated ephedrine. We noted a progressive response to treatment over the 6 to 8 months assessment period with a significant improvement at the final QMG score (p = 0.009). Mobility scores also improved (p = 0.0006). Improvements in the subcomponents of the QMG score that measured proximal muscle function (those muscle groups most severely affected) were most marked, and in some cases were dramatic. All patients reported enhanced activities of daily living at 6-8 months.

Conclusion: Ephedrine appears to be an effective treatment for Dok-7 CMS. It is well-tolerated by most patients and improvement in strength can be profound. Determining the long-term response and the most effective dosing regimen will require further research.

Classification of evidence: This study provides Class IV evidence that ephedrine given at doses between 15 and 90 mg/day improves muscle strength in patients with documented mutations in DOK7.

Figure 1 Quantitative myasthenia gravis (severity) (QMG) scores of patients treated with ephedrine QMG is a severity score with a maximum of 39. Children underwent a limited scale with a maximum of 30 and the total corrected to/39. **p = 0.009 Wilcoxon signed rank test. #One patient started ephedrine treatment when not directly under our supervision.

Figure 2 Change in performance for subcomponents of the quantitative myasthenia gravis (severity) (QMG) scores (A) Change in percentage of the lower limit of normal (minimum required to achieve 0 in the QMG scale). (B) Mean values at baseline and at 6- to 8-month follow-up. Values for patients 1, 2 (arm, leg, and head raise), 3 (head raise), 4 (arm, leg, head raise and grip), and 8 (leg raise) were capped at 100% of the lower limit of normal at the time of measuring.

Figure 3 Individual variability in response to treatment Time (seconds) of individual patients for (A) left arm raised 90 degrees and (B) right legs raised 45 degrees. Data points are mean of right side and left side scores. Values for patients 1, 2, and 4 (arm and leg) and 8 (leg only) were capped at 240 s (arm) and 100 s (legs).

Figure 4 Mobility assessment Individual points show the percentage reduction in time required for patients to carry out the test. Performances are normalized to the baseline record prior to treatment.