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Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation
Journal of the Neurological Sciences 331 (2013) 155–157
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation Paulo J. Lorenzoni a, Rosana H. Scola a,⁎, Cláudia S.K. Kay a, Luciane Filla a, Anna P.P. Miranda a, João M.R. Pinheiro a, Amina Chaouch b, Hanns Lochmüller b, Lineu C. Werneck a a b
Neurology Division, Internal Medicine Department, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
a r t i c l e
i n f o
Article history: Received 27 March 2013 Received in revised form 3 May 2013 Accepted 10 May 2013 Available online 19 June 2013 Keywords: Congenital myasthenic syndromes DOK7 mutation Salbutamol Albuterol Treatment Limb-girdle congenital myasthenic syndrome
a b s t r a c t Introduction: Salbutamol is a selective B2-adrenergic agonist, which has previously been described to be associated with partial improvement of myasthenia gravis and congenital myasthenic syndromes (CMS). In this study, we analyzed the effect of salbutamol in five patients with Dok-7 CMS. Methods: We studied 5 patients (2 male and 3 female), with a mean age of 27 ± 11.06 years, who harbored c.1124_1127dupTGCC, p.G64R and/or p.S45L mutations in DOK7 gene. Salbutamol was given at a dose of 2 mg three times daily (6 mg/day) to all patients. The response was assessed by QMG score at baseline, 3, 6, 9 and 12 months; ADL-MG score and 6 minute walk test at baseline and after 12 months during follow-up clinic visits. Side effect profile of salbutamol was also evaluated. Results: We noted an increasingly positive response as measured by the QMG score after 3 months of salbutamol treatment. Improvement in specific subcomponents of the QMG score such as leg outstretched in 45° supine was most marked. In ADL-MG scores and 6 minute walk test, comparison between baseline and after 12 months revealed a clear beneficial response. Salbutamol was well tolerated in all patients. Conclusions: Salbutamol is an effective treatment in Dok-7 CMS. This study provides class IV evidence that salbutamol given at a dose 6 mg/day improves function as measured by the QMG score, ADL-MG score and 6 minute walk test. © 2013 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
Congenital myasthenic syndromes (CMS) are heterogeneous genetic diseases which often require different therapeutic regimens depending on the underlying genetic defect [1]. In CMS related to Dok-7 deficiency (Dok-7 CMS), treatment is usually not effective with cholinesterase inhibitors, and the response to 3,4-diaminopyridine is limited [1–3]. Ephedrine can be used in the treatment of Dok-7 CMS, but medical access to ephedrine is limited or impossible in some countries [1–5]. Salbutamol, or albuterol, is a selective β2-adrenergic agonist, which has been associated with improvement of Dok-7 CMS [6–8]. However, additional prospective studies are warranted to determine the most effective long-term response. In this study, we analyzed the effect of salbutamol in patients with Dok-7 CMS.
This was a small open label prospective study to determine the clinical response to salbutamol in patients with Dok-7 CMS. The sample population consisted of 5 patients (2 male and 3 female), with a mean age of 27 ± 11.06 years, who harbored c.1124_ 1127dupTGCC, p.G64R and/or p.S45L mutations in DOK7 gene (Table 1). The diagnosis of Dok-7 CMS was established by a combination of clinical features, electrophysiological study and molecular analysis (four patients were previously described) [9]. The patients (or their parents) were informed of the possible benefits and risks of salbutamol therapy. Salbutamol was prescribed at a dose of 2 mg three times daily (total of 6 mg/daily) for a period of 12 months. All patients previously used cholinesterase inhibitors (pyridostigmine) with little benefit except in one who reported some improvement in muscle strength in daily activities. In this study, one patient (case 1) was on dual therapy with concomitant use of pyridostigmine at a dose of 60 mg four times daily (total of 240 mg/daily). This treatment combination was allowed as long as there was no adjustment in dose or treatment during the study period. The 3,4-diaminopyridine was not used by any patients. Tolerance to salbutamol was also evaluated. Treatment response was assessed in follow-up clinic visits by: (1) quantitative myasthenia gravis (QMG) score at baseline, 3 months, 6 months, 9 months and 12 months; (2) myasthenia gravis activities
Abbreviations: ADL-MG, myasthenia gravis activities of daily living; CMS, congenital myasthenic syndromes; Dok-7 CMS, CMS related to Dok-7 deficiency; QMG, quantitative myasthenia gravis; 6MWT, 6 minute walk test. ⁎ Corresponding author at: Neuromuscular Disorders Service, Neurology Division, Internal Medicine Department, Hospital de Clínicas, Universidade Federal do Paraná, Rua General Carneiro 181, 80060-900, Curitiba, PR, Brazil. Tel.: + 55 41 33601800; fax: + 55 41 32643606. E-mail address: [email protected] (R.H. Scola). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.05.017
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P.J. Lorenzoni et al. / Journal of the Neurological Sciences 331 (2013) 155–157
Table 1 Characteristics of patients with congenital myastenic syndrome due to DOK7 mutations. Case
DOK7 mutation
Gender
Age at onset (years)
Age at salbutamol (years)
1.
c.1124_1127dupTGCC homozygous p.G64R/c.1124_1127dupTGCC p.G64R/c.1124_1127dupTGCC p.S45L/c.1124_1127dupTGCC c.1124_1127dupTGCC homozygous
F
5
24
M F F M
Birth 1 6 9
25 23 17 46
2. 3. 4. 5.
F = female; M = male.
of daily living (ADL-MG) scale at baseline and after 12 months; and (3) 6 minute walk test (6MWT) at baseline and after 12 months [10,11]. QMG is a severity score with a maximum of 39 [10]. ADL-MG is a severity score with a maximum of 24 [10,11]. Written informed consent was obtained from all patients participating in this study.
Fig. 1. Quantitative myasthenia gravis (QMG) scores of patients treated with salbutamol. The lines indicate the median value. QMG is a severity score with a maximum of 39.
They were observed only in the initial phase of treatment with salbutamol.
3. Results
4. Discussion
QMG scores at baseline, 3 months, 6 months, 9 months and 12 months revealed a clear beneficial response to salbutamol treatment (Table 2). Fig. 1 displays the range of QMG score from baseline to 12 months. Of note, the QMG score measuring maximum effort with either leg outstretched in 45° showed the most marked improvement between baseline (right: mean, 1.2 ± 0.83; left: mean, 1.2 ± 0.44) and 12 months (right: mean, 0.6 ± 0.54; left: mean, 0.6 ± 0.54). We noted an increasingly positive response to salbutamol treatment as ascertained by the QMG score at first evaluation then at 3 months and up to 6–9 months, after which symptoms seem to plateau. In ADL-MG scores, comparison between baseline and 12 months revealed a beneficial response to salbutamol treatment (Table 2). Fig. 2 displays the range of ADL-MG scores from baseline to 12 months. All patients reported enhanced activities of daily living after 12 months. A similar positive trend was recorded using the 6MWT at baseline and 12 months (Table 2). All patients improved, but one patient showed a very strong increase in walking distance from 63 m to 353 m (case 1). Fig. 3 shows the range of 6MWT from baseline to 12 months. Salbutamol was well tolerated in all patients and treatment was continued over the total duration of the study. It is worth mentioning that some minor side effects were reported when salbutamol was first instigated. These included tremor, occasional palpitations and headache but these did not necessitate withdrawal of the medication.
The dose of salbutamol that we prescribed was well tolerated and patients showed clear benefit on a smaller dose compared to what was previously reported in the literature [6]. Two studies on the use of salbutamol in Dok-7 CMS demonstrated similar results within the first few days of therapy [6,7]. In both studies, the positive effect of salbutamol was more pronounced in the limb-girdle muscles than in other muscle groups, which is similar to our findings [6,7]. The marked improvement in proximal muscle strength may be related to the fact that Dok-7 CMS patients have predominant proximal limb weakness. In some instances the patient perception of the beneficial treatment response in their daily activities was greater than the objective measurement scores. We believe that outcome measures may not fully reflect functional benefit specifically in Dok-7 CMS. Indeed, a similar finding was reported in studies assessing response to ephedrine [2,4]. The improvement in muscle function in this study was similar to the one reported with ephedrine use and is thought to be due to β2 adrenergic effects [2,4,5]. However, the exact pathomechanism accounting for the beneficial effect of salbutamol remains not known. Although there are two other published studies related to treatment with salbutamol in patients with CMS, it is difficult to make any direct comparison between them because different methods were used in
Table 2 The assessments in follow-up clinic visits. Measurement
Baseline
QMG score Mean ± SD 14.2 ± 5.40 Median (range) 15 (7–21)
3 months
6 months
9 months 12 months
11.2 ± 2.77 11.0 ± 2.12 9.0 ± 1.41 9.8 ± 1.09 12 (8–15) 11 (9–14) 10 (7–10) 10 (8–11)
ADL-MG score Mean ± SD 3.6 ± 2.07 Median (range) 4 (1–6)
1.8 ± 0.83 2 (1–3)
6MWT (meters) Mean ± SD 261 ± 145.66 Median (range) 250 (63–470)
359 ± 74.27 345 (281–482)
QMG = quantitative myasthenia gravis; ADL-MG = myasthenia gravis activities of daily living; 6MWT = 6 minute walk test; SD = standard deviation.
Fig. 2. Myasthenia gravis activities of daily living (ADL-MG) scores of patients treated with salbutamol at baseline and after 12 months. ADL-MG is a severity score with a maximum of 24.
P.J. Lorenzoni et al. / Journal of the Neurological Sciences 331 (2013) 155–157
157
Conflict of interest None. Acknowledgments We are grateful to A. Abicht and V. Mihaylova (Friedrich-BaurInstitute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany), and J. Müller (Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK) for their collaboration in the genetic analysis. H. Lochmüller is supported by a grant from the Medical Research Council UK (reference G1002274, grant ID 98482). References
Fig. 3. 6 minute walk test (6MWT) of patients treated with salbutamol at baseline and after 12 months. Values are in meters.
the evaluation [4–7]. To date, there are no standardized outcome measures for the assessment of CMS patients [4–7]. In this study, we used well-established quantitative outcome measures used in myasthenia gravis that have previously been shown to be useful in the assessment of Dok-7 CMS [2,4,6,7,10,11]. However, others have proposed alternative outcome measures [4–7]. This is mainly to account for the difference in clinical manifestations between myasthenia gravis and Dok-7 CMS. In this prospective open label study, salbutamol was well tolerated in all patients and treatment resulted in improvement in proximal weakness as well as in activities of daily living. Despite the small size of our cohort, which arguably prevents any randomized controlled trials, we provide more evidence to support the use of salbutamol treatment in Dok-7 CMS [6,7].
[1] Lorenzoni PJ, Scola RH, Kay CS, Werneck LC. Congenital myasthenic syndrome: a brief review. Pediatr Neurol 2012;46:141–8. [2] Palace J, Lashley D, Newsom-Davis J, Cossins J, Maxwell S, Kennett R, et al. Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain 2007;130: 1507–15. [3] Ammar AB, Petit F, Alexandri N, Gaudon K, Bauche S, Rouche A, et al. Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7. J Neurol 2010;257:754–66. [4] Lashley D, Palace J, Jayawant S, Robb S, Beeson D. Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7. Neurology 2010;74: 1517–23. [5] Schara U, Barisic N, Deschauer M, Lindberg C, Straub V, Strilgl-Pill N, et al. Ephedrine therapy in eight patients with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord 2009;19:828–32. [6] Liewluck T, Selcen D, Engel AG. Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia. Muscle Nerve 2011;44: 789–94. [7] Burke G, Hiscock A, Klein A, Niks EH, Main M, Manzur AY, et al. Salbutamol benefits children with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord 2013;23:170–5. [8] Selcen D, Milone M, Shen XM, Harper CM, Stans AA, Wieben ED, et al. Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann Neurol 2008;64:71–87. [9] Mihaylova V, Scola RH, Gervini B, Lorenzoni PJ, Kay CSK, Werneck LC, et al. Molecular characterisation of congenital myasthenic syndromes in Southern Brazil. J Neurol Neurosurg Psychiatry 2010;81:973–7. [10] Jaretzki III A, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 2000;55:16–23. [11] Wolfe G, Herbelin L, Nations S, Foster B, Bryan W, Barohn R. Myasthenia gravis activities of daily living profile. Neurology 1999;52:1487–9.
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation Paulo J. Lorenzoni a, Rosana H. Scola a,⁎, Cláudia S.K. Kay a, Luciane Filla a, Anna P.P. Miranda a, João M.R. Pinheiro a, Amina Chaouch b, Hanns Lochmüller b, Lineu C. Werneck a a b
Neurology Division, Internal Medicine Department, Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
a r t i c l e
i n f o
Article history: Received 27 March 2013 Received in revised form 3 May 2013 Accepted 10 May 2013 Available online 19 June 2013 Keywords: Congenital myasthenic syndromes DOK7 mutation Salbutamol Albuterol Treatment Limb-girdle congenital myasthenic syndrome
a b s t r a c t Introduction: Salbutamol is a selective B2-adrenergic agonist, which has previously been described to be associated with partial improvement of myasthenia gravis and congenital myasthenic syndromes (CMS). In this study, we analyzed the effect of salbutamol in five patients with Dok-7 CMS. Methods: We studied 5 patients (2 male and 3 female), with a mean age of 27 ± 11.06 years, who harbored c.1124_1127dupTGCC, p.G64R and/or p.S45L mutations in DOK7 gene. Salbutamol was given at a dose of 2 mg three times daily (6 mg/day) to all patients. The response was assessed by QMG score at baseline, 3, 6, 9 and 12 months; ADL-MG score and 6 minute walk test at baseline and after 12 months during follow-up clinic visits. Side effect profile of salbutamol was also evaluated. Results: We noted an increasingly positive response as measured by the QMG score after 3 months of salbutamol treatment. Improvement in specific subcomponents of the QMG score such as leg outstretched in 45° supine was most marked. In ADL-MG scores and 6 minute walk test, comparison between baseline and after 12 months revealed a clear beneficial response. Salbutamol was well tolerated in all patients. Conclusions: Salbutamol is an effective treatment in Dok-7 CMS. This study provides class IV evidence that salbutamol given at a dose 6 mg/day improves function as measured by the QMG score, ADL-MG score and 6 minute walk test. © 2013 Elsevier B.V. All rights reserved.
1. Introduction
2. Methods
Congenital myasthenic syndromes (CMS) are heterogeneous genetic diseases which often require different therapeutic regimens depending on the underlying genetic defect [1]. In CMS related to Dok-7 deficiency (Dok-7 CMS), treatment is usually not effective with cholinesterase inhibitors, and the response to 3,4-diaminopyridine is limited [1–3]. Ephedrine can be used in the treatment of Dok-7 CMS, but medical access to ephedrine is limited or impossible in some countries [1–5]. Salbutamol, or albuterol, is a selective β2-adrenergic agonist, which has been associated with improvement of Dok-7 CMS [6–8]. However, additional prospective studies are warranted to determine the most effective long-term response. In this study, we analyzed the effect of salbutamol in patients with Dok-7 CMS.
This was a small open label prospective study to determine the clinical response to salbutamol in patients with Dok-7 CMS. The sample population consisted of 5 patients (2 male and 3 female), with a mean age of 27 ± 11.06 years, who harbored c.1124_ 1127dupTGCC, p.G64R and/or p.S45L mutations in DOK7 gene (Table 1). The diagnosis of Dok-7 CMS was established by a combination of clinical features, electrophysiological study and molecular analysis (four patients were previously described) [9]. The patients (or their parents) were informed of the possible benefits and risks of salbutamol therapy. Salbutamol was prescribed at a dose of 2 mg three times daily (total of 6 mg/daily) for a period of 12 months. All patients previously used cholinesterase inhibitors (pyridostigmine) with little benefit except in one who reported some improvement in muscle strength in daily activities. In this study, one patient (case 1) was on dual therapy with concomitant use of pyridostigmine at a dose of 60 mg four times daily (total of 240 mg/daily). This treatment combination was allowed as long as there was no adjustment in dose or treatment during the study period. The 3,4-diaminopyridine was not used by any patients. Tolerance to salbutamol was also evaluated. Treatment response was assessed in follow-up clinic visits by: (1) quantitative myasthenia gravis (QMG) score at baseline, 3 months, 6 months, 9 months and 12 months; (2) myasthenia gravis activities
Abbreviations: ADL-MG, myasthenia gravis activities of daily living; CMS, congenital myasthenic syndromes; Dok-7 CMS, CMS related to Dok-7 deficiency; QMG, quantitative myasthenia gravis; 6MWT, 6 minute walk test. ⁎ Corresponding author at: Neuromuscular Disorders Service, Neurology Division, Internal Medicine Department, Hospital de Clínicas, Universidade Federal do Paraná, Rua General Carneiro 181, 80060-900, Curitiba, PR, Brazil. Tel.: + 55 41 33601800; fax: + 55 41 32643606. E-mail address: [email protected] (R.H. Scola). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.05.017
156
P.J. Lorenzoni et al. / Journal of the Neurological Sciences 331 (2013) 155–157
Table 1 Characteristics of patients with congenital myastenic syndrome due to DOK7 mutations. Case
DOK7 mutation
Gender
Age at onset (years)
Age at salbutamol (years)
1.
c.1124_1127dupTGCC homozygous p.G64R/c.1124_1127dupTGCC p.G64R/c.1124_1127dupTGCC p.S45L/c.1124_1127dupTGCC c.1124_1127dupTGCC homozygous
F
5
24
M F F M
Birth 1 6 9
25 23 17 46
2. 3. 4. 5.
F = female; M = male.
of daily living (ADL-MG) scale at baseline and after 12 months; and (3) 6 minute walk test (6MWT) at baseline and after 12 months [10,11]. QMG is a severity score with a maximum of 39 [10]. ADL-MG is a severity score with a maximum of 24 [10,11]. Written informed consent was obtained from all patients participating in this study.
Fig. 1. Quantitative myasthenia gravis (QMG) scores of patients treated with salbutamol. The lines indicate the median value. QMG is a severity score with a maximum of 39.
They were observed only in the initial phase of treatment with salbutamol.
3. Results
4. Discussion
QMG scores at baseline, 3 months, 6 months, 9 months and 12 months revealed a clear beneficial response to salbutamol treatment (Table 2). Fig. 1 displays the range of QMG score from baseline to 12 months. Of note, the QMG score measuring maximum effort with either leg outstretched in 45° showed the most marked improvement between baseline (right: mean, 1.2 ± 0.83; left: mean, 1.2 ± 0.44) and 12 months (right: mean, 0.6 ± 0.54; left: mean, 0.6 ± 0.54). We noted an increasingly positive response to salbutamol treatment as ascertained by the QMG score at first evaluation then at 3 months and up to 6–9 months, after which symptoms seem to plateau. In ADL-MG scores, comparison between baseline and 12 months revealed a beneficial response to salbutamol treatment (Table 2). Fig. 2 displays the range of ADL-MG scores from baseline to 12 months. All patients reported enhanced activities of daily living after 12 months. A similar positive trend was recorded using the 6MWT at baseline and 12 months (Table 2). All patients improved, but one patient showed a very strong increase in walking distance from 63 m to 353 m (case 1). Fig. 3 shows the range of 6MWT from baseline to 12 months. Salbutamol was well tolerated in all patients and treatment was continued over the total duration of the study. It is worth mentioning that some minor side effects were reported when salbutamol was first instigated. These included tremor, occasional palpitations and headache but these did not necessitate withdrawal of the medication.
The dose of salbutamol that we prescribed was well tolerated and patients showed clear benefit on a smaller dose compared to what was previously reported in the literature [6]. Two studies on the use of salbutamol in Dok-7 CMS demonstrated similar results within the first few days of therapy [6,7]. In both studies, the positive effect of salbutamol was more pronounced in the limb-girdle muscles than in other muscle groups, which is similar to our findings [6,7]. The marked improvement in proximal muscle strength may be related to the fact that Dok-7 CMS patients have predominant proximal limb weakness. In some instances the patient perception of the beneficial treatment response in their daily activities was greater than the objective measurement scores. We believe that outcome measures may not fully reflect functional benefit specifically in Dok-7 CMS. Indeed, a similar finding was reported in studies assessing response to ephedrine [2,4]. The improvement in muscle function in this study was similar to the one reported with ephedrine use and is thought to be due to β2 adrenergic effects [2,4,5]. However, the exact pathomechanism accounting for the beneficial effect of salbutamol remains not known. Although there are two other published studies related to treatment with salbutamol in patients with CMS, it is difficult to make any direct comparison between them because different methods were used in
Table 2 The assessments in follow-up clinic visits. Measurement
Baseline
QMG score Mean ± SD 14.2 ± 5.40 Median (range) 15 (7–21)
3 months
6 months
9 months 12 months
11.2 ± 2.77 11.0 ± 2.12 9.0 ± 1.41 9.8 ± 1.09 12 (8–15) 11 (9–14) 10 (7–10) 10 (8–11)
ADL-MG score Mean ± SD 3.6 ± 2.07 Median (range) 4 (1–6)
1.8 ± 0.83 2 (1–3)
6MWT (meters) Mean ± SD 261 ± 145.66 Median (range) 250 (63–470)
359 ± 74.27 345 (281–482)
QMG = quantitative myasthenia gravis; ADL-MG = myasthenia gravis activities of daily living; 6MWT = 6 minute walk test; SD = standard deviation.
Fig. 2. Myasthenia gravis activities of daily living (ADL-MG) scores of patients treated with salbutamol at baseline and after 12 months. ADL-MG is a severity score with a maximum of 24.
P.J. Lorenzoni et al. / Journal of the Neurological Sciences 331 (2013) 155–157
157
Conflict of interest None. Acknowledgments We are grateful to A. Abicht and V. Mihaylova (Friedrich-BaurInstitute, Department of Neurology, Ludwig-Maximilians-University, Munich, Germany), and J. Müller (Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, UK) for their collaboration in the genetic analysis. H. Lochmüller is supported by a grant from the Medical Research Council UK (reference G1002274, grant ID 98482). References
Fig. 3. 6 minute walk test (6MWT) of patients treated with salbutamol at baseline and after 12 months. Values are in meters.
the evaluation [4–7]. To date, there are no standardized outcome measures for the assessment of CMS patients [4–7]. In this study, we used well-established quantitative outcome measures used in myasthenia gravis that have previously been shown to be useful in the assessment of Dok-7 CMS [2,4,6,7,10,11]. However, others have proposed alternative outcome measures [4–7]. This is mainly to account for the difference in clinical manifestations between myasthenia gravis and Dok-7 CMS. In this prospective open label study, salbutamol was well tolerated in all patients and treatment resulted in improvement in proximal weakness as well as in activities of daily living. Despite the small size of our cohort, which arguably prevents any randomized controlled trials, we provide more evidence to support the use of salbutamol treatment in Dok-7 CMS [6,7].
[1] Lorenzoni PJ, Scola RH, Kay CS, Werneck LC. Congenital myasthenic syndrome: a brief review. Pediatr Neurol 2012;46:141–8. [2] Palace J, Lashley D, Newsom-Davis J, Cossins J, Maxwell S, Kennett R, et al. Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain 2007;130: 1507–15. [3] Ammar AB, Petit F, Alexandri N, Gaudon K, Bauche S, Rouche A, et al. Phenotype genotype analysis in 15 patients presenting a congenital myasthenic syndrome due to mutations in DOK7. J Neurol 2010;257:754–66. [4] Lashley D, Palace J, Jayawant S, Robb S, Beeson D. Ephedrine treatment in congenital myasthenic syndrome due to mutations in DOK7. Neurology 2010;74: 1517–23. [5] Schara U, Barisic N, Deschauer M, Lindberg C, Straub V, Strilgl-Pill N, et al. Ephedrine therapy in eight patients with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord 2009;19:828–32. [6] Liewluck T, Selcen D, Engel AG. Beneficial effects of albuterol in congenital endplate acetylcholinesterase deficiency and Dok-7 myasthenia. Muscle Nerve 2011;44: 789–94. [7] Burke G, Hiscock A, Klein A, Niks EH, Main M, Manzur AY, et al. Salbutamol benefits children with congenital myasthenic syndrome due to DOK7 mutations. Neuromuscul Disord 2013;23:170–5. [8] Selcen D, Milone M, Shen XM, Harper CM, Stans AA, Wieben ED, et al. Dok-7 myasthenia: phenotypic and molecular genetic studies in 16 patients. Ann Neurol 2008;64:71–87. [9] Mihaylova V, Scola RH, Gervini B, Lorenzoni PJ, Kay CSK, Werneck LC, et al. Molecular characterisation of congenital myasthenic syndromes in Southern Brazil. J Neurol Neurosurg Psychiatry 2010;81:973–7. [10] Jaretzki III A, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, et al. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology 2000;55:16–23. [11] Wolfe G, Herbelin L, Nations S, Foster B, Bryan W, Barohn R. Myasthenia gravis activities of daily living profile. Neurology 1999;52:1487–9.