Elsevier

Neuromuscular Disorders

Volume 20, Issue 12, December 2010, Pages 833-838
Neuromuscular Disorders

Workshop report
Respiratory management of congenital myasthenic syndromes in childhood: Workshop 8th December 2009, UCL Institute of Neurology, London, UK

https://doi.org/10.1016/j.nmd.2010.08.002Get rights and content

Introduction

A workshop on the respiratory management of congenital myasthenic syndromes (CMS) in childhood was held on 8 December 2009 at the UCL Institute of Neurology, UK. The workshop was sponsored by the Muscular Dystrophy Campaign and attended by 20 participants from 9 centres (8 in UK and 1 in Europe). The aim of the workshop was to review respiratory management of childhood CMS in major UK specialist centres and develop recommendations for standards of care to help anticipate and treat respiratory complications.

The congenital myasthenic syndromes are a heterogeneous group of genetic disorders which result in impaired neuromuscular transmission and fatiguable weakness. Advances in molecular genetic diagnosis have lead to the identification of distinct genotypes [1] which are associated with particular patterns of respiratory decompensation.

Many CMS children present with respiratory difficulties at birth and most are at risk of ventilatory failure with intercurrent respiratory illnesses. However, recurrent, life-threatening episodic apnoea in infancy and childhood (often precipitated by infection or even stress) is a particular feature of the presynaptic CMS caused by mutations in CHAT and postsynaptic CMS due to mutations in RAPSN. Other phenotypes, such as the synaptic CMS due to mutations in COLQ and the slow channel syndromes caused by mutations in the acetylcholine receptor subunits, cause an end plate myopathy which results in progressive respiratory muscle weakness and respiratory failure requiring long term ventilatory support. The fast channel syndromes are associated with recurrent and particularly severe respiratory crises in infancy and childhood. Other genotypes have diverse respiratory presentations, for example the post-synaptic CMS caused by mutations in DOK7 may be associated, in severe cases, with respiratory failure requiring ventilation at birth, or congenital stridor due to vocal cord palsy often necessitating tracheostomy, without any evidence of the limb girdle weakness which develops later. Progressive respiratory failure may occur in childhood or adulthood.

In recent reviews of 46 CMS children seen at two large regional centres [2], [3] we reported the frequency and diversity of respiratory complications in childhood CMS, highlighting the genotype/phenotype correlation which facilitates proactive anticipatory respiratory care. We reported the usefulness of non-invasive ventilation (NIV) for emergency use in children with episodic apnoea, in addition to resuscitation training for all parents and the need to monitor carefully certain genotypes in view of their specific risks. We suggested that all CMS children should be under the care of a specialist respiratory centre and should undergo regular respiratory surveillance. It is important to note that before the identification of CMS in the index cases, several families had suffered the death of one or more children from unexplained respiratory illnesses, very likely to have been associated with undiagnosed CMS.

Significant advances have been made in the respiratory management of most neuromuscular disorders [4], with recommendations for the care of adults, excluding neuromuscular junction disorders [5] and in standards of care documents for childhood disorders such as SMA and Duchenne Muscular Dystrophy [6], [7]. However there are no detailed published guidelines regarding respiratory management in the congenital myasthenic syndromes.

This workshop was convened to share information on the respiratory management of childhood CMS in major UK specialist centres, with the aim of improving awareness and devising recommendations for the monitoring and management of respiratory complications. In view of the rarity of CMS and the absence of randomised controlled trials, these recommendations are, of necessity, based on expert opinion and non-analytic studies of small case series.

Section snippets

Overview of the congenital myasthenic syndromes (Georgina Burke)

Dr. Georgina Burke (Southampton and Oxford, UK) opened the meeting by giving a comprehensive overview of the known genetic mechanisms underlying pre-synaptic, synaptic and post-synaptic congenital myasthenic syndromes. Currently at least 12 genes have been identified in which mutation events result in abnormal neuromuscular transmission and fatigable muscle weakness. Genetic mutation data from 268 CMS patients analysed by the UK National Commissioning Group (NCG) service in Oxford illustrated

Stratification of respiratory risk

This session began with emphasis on the importance of early recognition of CMS symptoms and referral for expert neurophysiological diagnosis. Although susceptibility to bulbar and respiratory decompensation with intercurrent illness occurs in most CMS children and adults, a precise genetic diagnosis is crucial to predict more specific patterns of respiratory involvement associated with individual genotypes. In the UK DNA samples are referred for genetic analysis to the UK NCG service for CMS in

Workshop participants

Rob Bullock, Newcastle, UK; Georgina Burke, Southampton and, Oxford, UK; Michelle Chatwin, London, UK; Debbie Clarke, London, UK; Phil Davies, Glasgow, UK; Jayne Gallagher, Oxford, UK; Iain Horrocks, Glasgow, UK; Jeremy Hull, Oxford, UK; Elspeth Jardine, Glasgow, UK; Heinz Jungbluth, London, UK; David Kilner, London, UK; Maria Kinali, London, UK; Andrea Klein, London, UK and Zurich, Switzerland; Adnan Manzur, London, UK; Robert McWilliam, Glasgow, UK; Francesco Muntoni, London, UK; Stephanie

Acknowledgements

We thank the Muscular Dystrophy Campaign for providing financial support and sponsorship for this workshop. The support of the UCL Neuromuscular MRC Centre is also gratefully acknowledged.

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References (9)

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    Interestingly, type 1 fiber predominance was seen in 14 of 25 CMS patients in the aforementioned report [1], indicating that CMS may well be misdiagnosed as congenital myopathy with type 1 fiber predominance. Most patients with CMS display respiratory difficulties at birth, especially those with a rapsyn deficiency, and infection or stress can trigger recurrent life-threatening respiratory failure in infancy and childhood [4,13]. In the present case, it was initially difficult to suspect CMS as he had not developed severe respiratory failure owing to the absence of infections.

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    Myasthenic crisis causing respiratory failure has been shown to be associated with about 10% mortality.10 Moreover, 3 studies reported the presence of severe and recurrent brief resolved unexplained events (BRUE) as first symptoms in infants, which investigations led to the diagnosis of CMS.6,8,9 Even if the role of polysomnography (PSG) was found to be neither sufficiently distinctive nor predictive of BRUE,11 recent guidelines recommended a systematic PSG in infants who have experienced a BRUE or when there is clinical evidence of sleep-disordered breathing (SDB).12

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    However, it is not clear why in this disorder patients are prone to acute onset severe respiratory crises, as may also be seen in patients with Rapsyn or ChAT mutations. They contrast with the relatively stable disease course of patients with AChR deficiency due to ε-subunit mutations in whom neuromuscular transmission is mediated through residual expression of the fetal form of the AChR [16,20]. εP121L appears to be a relatively common CMS mutation within the white population from the British Isles, possibly arising from an ancient founder mutation.

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On behalf of [all] participants (see end of report).

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