DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine

Santos, Mariana; Cruz, Simão; Peres, João; Santos, Luís; Tavares, Purificação; Basto, Jorge Pinto; Salgado, Vasco; Valverde, Ana

doi:10.1016/j.nmd.2017.12.005

Cited by 11 publications

(12 citation statements)

References 20 publications

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“…CMS with DOK7 mutations has been reported to worsen with AChEI treatment, 31 but the patient with DOK7 mutation in our study showed improvements with combination AChEI and albuterol treatment. Patients with DOK7 mutations have also been reported to benefit from fluoxetine treatment 12 . In the follow‐up of our patients with AGRN mutations, we observed diverse therapeutic effects of AChEI, including responsive, nonresponsive, or aggravated effects.…”

Section: Discussionmentioning

confidence: 63%

“…Patients with DOK7 mutations have also been reported to benefit from fluoxetine treatment. 12 In the follow-up of our patients with AGRN mutations, we observed diverse therapeutic effects of AChEI, including responsive, nonresponsive, or aggravated effects. Ephedrine and albuterol are alternative and safe treatment options for many CMS subtypes, although the effects of these two agents were attenuated in patients with AGRN mutations over 5 years in the present study.…”

Section: Discussionmentioning

confidence: 77%

“…11 However, drug effects are not constant in some types of CMS. [12][13] Diminished drug responses have also been observed in some CMS subtypes. 14 Therefore, the continuous observation of these agents is necessary to evaluate their long-term effects.…”

Section: Introductionmentioning

confidence: 99%

“…Based on the molecular defects and the response to NMJ‐modulating drugs, CMS therapies can be divided into three categories: responsive to cholinergic upregulation (e.g., acetylcholinesterase inhibitor [AChEI] and 3,4‐diaminopyridine), responsive to β‐adrenergic agonists (e.g., albuterol and ephedrine), and responsive to open‐channel blockers (e.g., fluoxetine and quinidine) 11 . However, drug effects are not constant in some types of CMS 12–13 . Diminished drug responses have also been observed in some CMS subtypes 14 .…”

Section: Introductionmentioning

confidence: 99%

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Congenital myasthenic syndrome in China: genetic and myopathological characterization

Zhao

Liu

Bian

et al. 2021

Ann Clin Transl Neurol

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Objective We aimed to summarize the clinical, genetic, and myopathological features of a cohort of Chinese patients with congenital myasthenic syndrome, and follow up on therapeutic outcomes. Methods The clinical spectrum, mutational frequency of genes, and pathological diagnostic clues of various subtypes of patients with congenital myasthenic syndrome were summarized. Therapeutic effects were followed up. Results Thirty‐five patients from 29 families were recruited. Ten genes were identified: GFPT1 (27.6%), AGRN (17.2%), CHRNE (17.2%), COLQ (13.8%), GMPPB (6.9%), CHAT, CHRNA1, DOK7, COG7, and SLC25A1 (3.4% each, respectively). Sole limb‐girdle weakness was found in patients with AGRN (1/8) and GFPT1 (7/8) mutations, whereas distal weakness was all observed in patients with AGRN (6/8) mutations. Tubular aggregates were only found in patients with GFPT1 mutations (5/6). The patients with GMPPB mutations (2/2) had decreased alpha‐dystroglycan. Acetylcholinesterase inhibitor therapy resulted in no response or worsened symptoms in patients with COLQ mutations, a diverse response in patients with AGRN mutations, and a good response in patients with other subtypes. Albuterol therapy was effective or harmless in most subtypes. Therapy effects became attenuated with long‐term use in patients with COLQ or AGRN mutations. Interpretation The genetic distribution of congenital myasthenic syndrome in China is distinct from that of other ethnic origins. The appearance of distal weakness, selective limb‐girdle myasthenic syndrome, tubular aggregates, and decreased alpha‐dystroglycan were indicative of the specific subtypes. Based on the follow‐up findings, we suggest cautious evaluation of the long‐term efficacy of therapeutic agents in congenital myasthenic syndrome.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Congenital myasthenic syndrome in China: genetic and myopathological characterization

Zhao

Liu

Bian

et al. 2021

Ann Clin Transl Neurol

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“…The majority of patients receive either AChE inhibitors or β 2 adrenergic receptor agonists as first-line treatment. AChE inhibitors such as pyridostigmine are commonly used in patients with AChR deficiency, most of which are caused by biallelic mutations in the CHRNE gene, while they should be avoided in patients with DOK7 and COLQ defects, where they may be ineffective or may cause clinical worsening [29–31]. DOK7 patients have been enrolled in several case series and open-label trials where they received β 2 adrenergic receptor agonists (ephedrine, salbutamol) as off-label treatment with substantial benefit [32,33].…”

Section: Resultsmentioning

confidence: 99%

Targeted therapies for congenital myasthenic syndromes: systematic review and steps towards a treatabolome

Thompson

Bonne

Missier

et al. 2019

Emerging Topics in Life Sciences

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Despite recent scientific advances, most rare genetic diseases — including most neuromuscular diseases — do not currently have curative gene-based therapies available. However, in some cases, such as vitamin, cofactor or enzyme deficiencies, channelopathies and disorders of the neuromuscular junction, a confirmed genetic diagnosis provides guidance on treatment, with drugs available that may significantly alter the disease course, improve functional ability and extend life expectancy. Nevertheless, many treatable patients remain undiagnosed or do not receive treatment even after genetic diagnosis. The growth of computer-aided genetic analysis systems that enable clinicians to diagnose their undiagnosed patients has not yet been matched by genetics-based decision-support systems for treatment guidance. Generating a ‘treatabolome’ of treatable variants and the evidence for the treatment has the potential to increase treatment rates for treatable conditions. Here, we use the congenital myasthenic syndromes (CMS), a group of clinically and genetically heterogeneous but frequently treatable neuromuscular conditions, to illustrate the steps in the creation of a treatabolome for rare inherited diseases. We perform a systematic review of the evidence for pharmacological treatment of each CMS type, gathering evidence from 207 studies of over 1000 patients and stratifying by genetic defect, as treatment varies depending on the underlying cause. We assess the strength and quality of the evidence and create a dataset that provides the foundation for a computer-aided system to enable clinicians to gain easier access to information about treatable variants and the evidence they need to consider.

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Pregnancy outcomes in patients with congenital myasthenic syndromes

et al. 2022

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Introduction/Aims The congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited disorders that affect neuromuscular junction transmission. Data on pregnancy outcomes in women with CMS are limited due to their infrequency. In this study we explored pregnancy with CMS in a large cohort of women attending a national specialty clinic in England. Methods All women with CMS who had a documented pregnancy were invited to complete a questionnaire assessing clinical status during pregnancy and postpartum, pregnancy outcomes, fetal outcomes, and medication use during pregnancy. Results Among 16 women with CMS (acetylcholine receptor deficiency [CHRNE], slow channel syndrome [CHRNA1], DOK7, RAPSYN and glycosylation [DPAGT1 and GFPT1]), 27 pregnancies were recorded: 26 single pregnancies and 1 twin pregnancy. Symptom worsening was reported in 63% of pregnancies, but recovery to baseline function was seen in all but one patient. Miscarriage and cesarean section occurred in 31% and 33% of the women, respectively. Over half of the patients continued taking their medication during pregnancy, which included pyridostigmine (n = 10), 3,4‐diaminopyridine (n = 9), ephedrine (n = 3), salbutamol (n = 3), and quinidine (n = 1). No fetal malformations were recorded. Discussion Our results show that clinical worsening during pregnancy was common but rarely persistent. The majority of women with CMS can safely plan pregnancy, but close follow‐up is required from their neurology and obstetric teams. Although we identified no safety concerns, continued medication use should be reviewed on a case‐by‐case basis.

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DOK7 myasthenic syndrome with subacute adult onset during pregnancy and partial response to fluoxetine

Cited by 11 publications

References 20 publications

Congenital myasthenic syndrome in China: genetic and myopathological characterization

Congenital myasthenic syndrome in China: genetic and myopathological characterization

Targeted therapies for congenital myasthenic syndromes: systematic review and steps towards a treatabolome

Pregnancy outcomes in patients with congenital myasthenic syndromes

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