Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7.
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.


CONCLUSIONS
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.


METHODS
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.
Lashley
D
D
Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford OX3 9DS, UK.
Palace
J
J
Jayawant
S
S
Robb
S
S
Beeson
D
D
D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004809:Ephedrine / Q000008:administration & dosage* / Q000009:adverse effects; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics*; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D020294:Myasthenic Syndromes, Congenital / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D017063:Outcome Assessment, Health Care / Q000379:methods; D018579:Patient Selection; D011446:Prospective Studies; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013566:Sympathomimetics / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
C511692:DOK7 protein, human; D009124:Muscle Proteins; D013566:Sympathomimetics; D004809:Ephedrine
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