Ephedrine therapy in eight patients with congenital myasthenic syndrome due to DOK7 mutations

Dept. of Pediatric Neurology, University of Essen, Germany.
Neuromuscular Disorders (Impact Factor: 2.64). 10/2009; 19(12):828-32. DOI: 10.1016/j.nmd.2009.09.008
Source: PubMed


In congenital myasthenic syndrome with DOK7 mutations ephedrine was reported to be beneficial in single patients. We carried out a small, open and prospective cohort study in eight European patients manifesting from birth to 12 years. Five patients showed limb-girdle and facial weakness, three a floppy infant syndrome with bulbar symptoms and/or respiratory distress. Ephedrine was started with 25 mg/day and slowly increased to 75-100 mg/day. Within weeks after starting therapy an improvement was observed in all patients and clinical follow-up disclosed positive effects more pronounced on proximal muscle weakness and strength using MRC scale. Effects on facial weakness were less pronounced. Vital capacity measurements and repetitive stimulation tests did not improve in the same way as clinical symptoms did. These investigations are appropriate to confirm the diagnosis in case of pathological results, but they might not be appropriate means to monitor patients under ephedrine therapy.

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    • "Many forms of CMS also present low levels of AChR at the NMJ. Although the underlying mechanisms for that might differ between distinct mutations, the finding that sympathomimetic substances, such as ephedrine and salbutamol, can significantly improve these patients' symptoms (Edgeworth, 1930; Schara et al., 2009; Lashley et al., 2010; Liewluck et al., 2011; Finlayson et al., 2013), suggests an involvement of catecholamines in AChR turnover. Since ephedrine and salbutamol both can activate β2-ARs and thus affect cAMP production, this could point to a possible role of cAMP in stabilizing AChR and/or leading to higher AChR expression. "
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    ABSTRACT: Autonomic regulation processes in striated muscles are largely mediated by cAMP/PKA-signaling. In order to achieve specificity of signaling its spatial-temporal compartmentation plays a critical role. We discuss here how specificity of cAMP/PKA-signaling can be achieved in skeletal muscle by spatio-temporal compartmentation. While a microdomain containing PKA type I in the region of the neuromuscular junction (NMJ) is important for postsynaptic, activity-dependent stabilization of the nicotinic acetylcholine receptor (AChR), PKA type I and II microdomains in the sarcomeric part of skeletal muscle are likely to play different roles, including the regulation of muscle homeostasis. These microdomains are due to specific A-kinase anchoring proteins, like rapsyn and myospryn. Importantly, recent evidence indicates that compartmentation of the cAMP/PKA-dependent signaling pathway and pharmacological activation of cAMP production are aberrant in different skeletal muscles disorders. Thus, we discuss here their potential as targets for palliative treatment of certain forms of dystrophy and myasthenia. Under physiological conditions, the neuropeptide, α-calcitonin-related peptide, as well as catecholamines are the most-mentioned natural triggers for activating cAMP/PKA signaling in skeletal muscle. While the precise domains and functions of these first messengers are still under investigation, agonists of β2-adrenoceptors clearly exhibit anabolic activity under normal conditions and reduce protein degradation during atrophic periods. Past and recent studies suggest direct sympathetic innervation of skeletal muscle fibers. In summary, the organization and roles of cAMP-dependent signaling in skeletal muscle are increasingly understood, revealing crucial functions in processes like nerve-muscle interaction and muscle trophicity.
    Frontiers in Physiology 10/2013; 4:290. DOI:10.3389/fphys.2013.00290 · 3.53 Impact Factor
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    • "Ephedrine has been shown to be helpful, with patients reporting an improvement over a 1–24 month period [5] [6]. However, ephedrine has both a and b-adrenergic effects and concern remains regarding central and cardiac adverse effects, particularly with long term use in children. "
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    ABSTRACT: Congenital myasthenic syndromes due to DOK7 mutations cause fatigable limb girdle weakness. Treatment with ephedrine improves muscle strength. Salbutamol, a β(2)-adrenergic receptor agonist with fewer side effects and more readily available, has been effective in adult and anecdotal childhood cases. This study reports the effects of salbutamol on motor function in childhood DOK7 congenital myasthenic syndrome. Nine children (age range 5.9-15.1years) were treated with oral salbutamol, 2-4mg TDS. The effect on timed tests of motor function, pre- and up to 28months post-treatment, was audited retrospectively. All 9 reported functional benefit within 1month, with progressive improvement to a plateau at 12-18months. Within the first month, all 3 non-ambulant children resumed walking with assistance. Although improvements were seen in some timed tests (timed 10m, arm raise time, 6min walk time) this did not fully reflect the observed functional benefits in daily living activities. No major side effects were reported. We conclude that oral salbutamol treatment significantly improves strength in children with DOK7 congenital myasthenic syndrome and is well tolerated. Outcome measures need to be refined further, both to accurately reflect functional abilities in children and to document progress and treatment response.
    Neuromuscular Disorders 12/2012; 23(2). DOI:10.1016/j.nmd.2012.11.004 · 2.64 Impact Factor
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