NHS Specialised Services Commissioning
Rare Neuromuscular Disorders Group
Congenital Myasthenic Syndromes:
Oxford University Hospitals NHS Trust
Annual Report October 2014
Service Overview
Page 2
Service Objectives, Outcomes and Performance Measures
Page 3
Patient Feedback
Page 5
Financial Update
Page 6
Service Developments
Page 6
Development Plans
Page 7
Service Engagement & Communication
Page 8
Meetings, Presentations and Publications
Page 10
Appendices
Pages 13 to 32
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The Congenital Myasthenic Syndrome (CMS) service at the Oxford Radcliffe
Hospital combines a specialist genetic analysis laboratory with a dedicated
inpatient (funded locally) and outpatient clinical service to offer a
multidisciplinary service for patients across the country.
The core CMS team comprises of:
Clinical team
Dr Jackie Palace
Dr Sandeep Jayawant
Dr Stephanie Robb
Dr Ravi Knight
Dr Pedro M. Rodriguez Cruz
Birute Saul
Hayley Ramjattan
Mary Quirke
Julia Goodgame
Consultant Neurologist (Service Lead)
Consultant Paediatric Neurologist
Consultant Paediatric Neurologist (GOSH)
Consultant Neurophysiologist
CMS Clinical Fellow
CMS Service Co-ordinator
Neuromuscular Physiotherapist
Myasthenia Specialist Nurse
Clinical Service Manager, CMS/NMO
Laboratory team
Weatherall Institute of Molecular Medicine
Prof David Beeson
Dr Wei-Wei Liu
Dr Judy Cossins
Dr Richard Webster
Ms Susan Maxwell
Lead Molecular Geneticist
Molecular Geneticist
Molecular Biologist
Post-Doc Electrophysiologist Medical Researcher
Research Assistant
Oxford University Hospitals Team
Dr Anneke Seller
Dr Tracy Lester
Dr Mike Oldridge
Director of Genetics Laboratories
Principal Clinical Scientist
Clinical Scientist
Service Overview
The service sees around 189 patients each year, both as outpatients and
inpatients, and offers remote advice to Doctors, patients and their carers
around the country regarding the diagnosis and management of CMS
patients. The clinical team review patients primarily in an outpatient setting,
often performing additional investigations, such as QMG scores (Quantitative
Myasthenia Gravis Score), pulmonary function testing (spirometer) and EMGs
(Electromyogram). The outpatient clinics are also attended by a Clinical
Genetics Research Nurse, Julie Phipps, funded by the UK clinical research
network (UKCLRN).
Monthly joint all day clinics with Dr Stephanie Robb and the Oxford clinical
team are now routinely established. Joint clinics alternate between GOSH
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London and Oxford, and allow good practice to be shared between centres.
We had a joint clinic with St Thomas’s Hospital (Dr Heinz Jungbluth) and
King’s College Hospital (Dr Fiona Norwood) in London. Dr Fiona Norwood will
be joining us in October 2014 for a joint clinic here in Oxford.
Both the clinical and laboratory teams offer an advice service to healthcare
professionals around the country and overseas. This involves e-mail,
telephone and letter correspondence regarding numerous patients, including
those seen in clinic who are under local follow-up and patients who are unable
to be seen at the centre due to geographical access issues. In the future we
are planning to establish a Telemed clinic to alleviate geographical access
difficulties to our services. In addition, the clinical and genetic research teams
have an advisory service to the diagnostic genetic laboratory on specific
genes that need testing usually after consultation with the referring clinicians.
This part of the service reduces the gene screening activity and keeps the
costs down. These are referred to as “genetic reviews”.
The Diagnostic Genetics Laboratory at the Churchill Hospital, Oxford provides
specialised genetic screening for patients with suspected CMS or related rare
neuromuscular conditions. There are currently a number of genes screened
for that are associated with CMS: CHRNA1, CHRNB1, CHRND, CHRNE,
CHRNG, RAPSN, COLQ, CHAT, DOK7, GFPT1 and DPAGT1. Each of these
genes encodes proteins involved in maintaining the function of the
neuromuscular junction.
In addition to these screens, further screening for MUSK, AGRN, ALG2 and
ALG14 genes is available on a research basis by Professor Beeson’s group,
based at the Weatherall Institute of Molecular Medicine.
If a mutation in the genetic code is identified, additional tests can also be
undertaken in Professor Beeson’s laboratory to determine the pathogenicity.
These include:
-
Electrophysiology to assess AChR channel kinetics for fast or slow
channel syndromes or reduced conductance syndrome.
AChR cell surface expression to test for AChR deficiency syndromes
AChR clustering assays to test pathogenicity of RAPSN, DOK7, MuSK
and AGRN variants
Exon trapping to test for intronic variants
Reporter assays to test for promoter variants
Expression assays to test CHAT, GFPT1, DPAGT1, MUSK, AGRN,
ALG2, ALG14
Once the screening has been performed, the patients are either reviewed in
outpatient clinic, or alternatively, the details of the case are reviewed by the
clinical team and remote advice offered to the referring clinician.
As our understanding of these conditions increases, it has become apparent
that treatment choice is determined by the underlying pathogenic mechanism
of the CMS subtype the patient has. Some of the treatments used routinely in
some CMS subtypes cause deterioration in other subtypes. Accumulated
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experience has allowed development of a treatment algorithm, which has
been updated due to our increasing knowledge of using Salbutamol or
ephedrine, 2-adrenergic agonists with effects at the neuromuscular junction,
in CMS [Appendix 1]. We have an increasing number of patients with AChRdeficiency and Fast channel syndrome who showed a dramatic improvement
by adding Salbutamol to their previous therapies [Appendix 2].
Service Objectives and Outcomes
The purposes and goals of the service
 Treat effectively [Appendix 1]
 Make a definitive diagnosis (including prenatal diagnosis where
requested) [Appendix 3]
 Provide information for patients, families and their schools and other
health care professions about CMS.
(See later - Page 8: Service Engagement and Communication)
Outcomes
Activity Levels
In addition to seeing 189 patients in the outpatient clinics, the clinical team
also reviewed the genetic results of 311 patients in Sept 2013-Aug2014
period, offering advice on diagnosis and management to the referring
Clinician. We also had 4 CMS inpatients that were admitted electively to the
ward in order to optimise their treatment regime.
DNA samples: the number of DNA samples received by the diagnostic
laboratory has increased a 9.30% compared to last year. This is probably due
to the addition of new glycosylation genes DPAGT1 and GFPT1 to our
screening panel. At the moment we screen a total of 11 genes, but we will
consider including any new CMS related genes we discover.
Activity Levels Recorded [Appendix 4]:




Number of new and follow-up outpatient visits and geographical
information. (Appendix 4a,4b, 4c and 4d)
DNA sample activity – number of patients (Appendix 4e), DNA sample
geographical data (Appendix 4f). Number of exons analysed
(Appendix 4g).
Day cases and inpatient activity is also reported, although is outside of
the NCG funding
Number of remote genetic reviews in Sept 2013-Aug 2014 was 311
(steering specific genetic tests performed dependent on clinical
information). (Appendix 4h)
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
Number of remote consultations from September 2013 – August 2014
was over 50 emails and 40 phone calls.
Performance Indicators




Turnaround time for DNA reporting [Appendix 5]
Clinic Waiting Times
Geographical Distribution
Patient Satisfaction (see later – page 5)
Clinic Waiting Times
Often a delay in patient waiting times is due to patient choice; over 90% of
patients that breached the 6 week waiting times target were initially offered an
appointment within the target. However, in the last year only 6 patients had a
waiting time over 6 weeks.
Geographical Distribution

Geographical data of clinical (Appendix 4c and 4d) genetic tests
(Appendix 4e) and remote reviews (Appendix 4h/i) are shown - We
are reporting Country of residence since NHS England commissioning
region and responsible parties (i.e. CCG and Specialist) are not clear at
present.
As a national referral centre for CMS, Oxford aims to offer equal access to
patients from across the whole of England and Scotland. Some patients cite
transport costs as a limiting factor. For patients living far from Oxford, we try to
offer them the flexibility to schedule their appointments to fit in with leisure
travel plans. In cases where the patients are physically unable to attend
outpatient clinic, remote advice is offered to their local clinician regarding their
diagnosis and management. In the future we are planning to stablish a
Telemed clinic to alleviate geographical access difficulties to our services.
As well as offering a national service, the team also offer advice on
international patients. In the period 2013-2014, 8.62% of our genetic reviews
came from overseas patients, compared to 4.50% last year. This confirms our
efforts in establishing us as a centre of international expertise in CMS
Patient Satisfaction
Feedback from patients, relatives and carers offers important insight into the
quality of service provided. These views are collected in the form of a
questionnaire that is given to the patients and their carers when they attend
an outpatient clinic appointment. Last year, our team developed a new
outpatient questionnaire in order to capture more information about the
performance of the CMS Service measured against the quality indicators and
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to identify any gaps in service provision. We have been using this
questionnaire since April 2013 in all our outpatient clinics.
The results from the period 2013-2014 show the following [Appendix 7]:
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97.53% of patients felt their care was well coordinated
83.87% of patients had an excellent clinical experience regarding
consultations with doctors and physiotherapist.
87.50% of patients felt their queries were dealt with fully when they
contacted the CMS Service for advice.
We updated our patient pre-clinic information booklet in April 2014 to include
new staff members [Appendix 8].
Financial Update
To be presented by the OUH Financial team lead by Carol Ann Gourlay,
Neurosciences Finance Manager.
Service Developments
Charitable Funds Grant – as previously reported
In early 2012 the service was successful in a bid for a grant from the JR
Paediatric Charitable Fund (£300). We purchased a portable DVD player that
is available for our Neurophysiologists to be used to distract children during
EMGs. We did not buy any further toys for the paediatric clinics this year.
Provision of 3,4-Diaminopyridine
We had no supply issues during this period. The NHS Commissioning
document states Firdapse will not be funded; this is meant to allow Physicians
to prescribe the unlicensed cheaper version because there is no licensed
formulation available.
Neuromuscular Physiotherapist
In October 2013, the CMS service appointed a permanent Neuromuscular
Physiotherapist; Hayley Ramjattan. The role of the Physiotherapist is to
support the assessment and management of patients in clinics; using
standardised assessment tools, specialist physiotherapy assessment and
treatment skills, and offer guidance on exercise, activity levels and
participation. The role also extends to care outside of clinics, with links to
community therapists (for example; in respiratory management and
progression of motor development) and supporting coordinated medical input
during hospital admissions (for example; a recent patient admission for spinal
surgery and follow-up orthopaedic care).
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Paediatric and adult physiotherapy outcomes
In 2014 we developed new Outcome Measure Forms [Appendix 9] with the
aim of standardising our clinical measures, especially in paediatric patients.
This is helping us to better monitoring changes in weakness and assessing
response to treatment. This on-going project aims to identify suitable
assessment measures tailored to paediatric CMS and is in collaboration with
specialists at GOSH and Newcastle. We are using the digital dynamometer
acquired last year to measure muscle strength in children where the adult
dynamometer is not appropriate.
Muscle MRI Project
We completed the study of muscle MRI in congenital myasthenia, which was
founded by the Myasthenia Gravis Association. As some forms of congenital
myasthenia show myopathic changes on muscle biopsy, it is possible they
may also demonstrate abnormal appearance on muscle MRI. We included 26
patients with 9 different CMS subtypes and 10 control subjects. The muscle
images were particularly abnormal in GFPT1 and DPAGT1 CMS, although
some subjects with DOK7, slow channel syndrome and RAPSN subtypes also
showed mild extensive or marked changes on muscle MRI. Overall we found
a wide range of MRI appearance from normal to marked abnormality
depending upon subtype. We believe that muscle MRI could have a role in
differentiating CMS subtypes, and monitoring treatment effects in the future.
The study was completed and has been sent to a peer-reviewed journal for
publication.
Current translational research projects
We have been pleasantly surprised by the marked response of some CMS
patients to Salbutamol. At the moment we are studying the molecular
mechanism of Salbutamol at the neuromuscular junction. We believe that this
drug provides a compensatory mechanism to stabilise the motor endplate
structures, improving neuromuscular transmission. A better understanding of it
will help us to provide more efficient treatments. We also have a special
interest in laryngeal and eye muscles. Laryngeal muscles are particularly
affected in DOK7 CMS, with patients suffering from vocal cord palsy and
stridor and needing long-life tracheostomy. Eye muscles are particularly
targeted in myasthenia leading to restricted eye movements and double
vision, which acts as a limiting factor in patient’s daily life. A better
understanding on why these muscles are particularly affected will help us to
develop specific treatments in the future.
Development Plans
Newly identified CMS-associated genes and next generation sequencing
In the last year we have incorporated a number of CMS patients without a
current genetic diagnosis into next generation sequencing techniques. This is
part of a preliminary trial into the use of next generation sequencing (as part of
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the Biomedical Research Centre funding) for the routine screening of genes in
rare Mendelian genetic disorders. At the moment we have found mutations in
two genes not previously known to be related to CMS (GMPPB and
COL13A1) and further studies are currently being undertaken. Last year,
using the same methodology, we were able to identify ALG2 and ALG14 as
two new causative genes for CMS.
New patient Liaison and Project Manager
We aim to appoint a new Healthcare Professional in combination with our
NMO service to help keep updated our website, patient information literature,
and performance outcome questionnaires in the clinics. This person will lead
on analysis of patient services and implement improvement projects where
needed. This will be funded from income obtained within the two services.
Updating CMS booklets
CMS booklets are very important to provide patients and families with
accurate information. This year we plan to update the CMS booklets to include
information about Salbutamol and the CMS subtypes due to mutations within
the N-glycosylation pathway of proteins (DPAGT1, GFPT1, ALG2, ALG14,
GMPPB)
Telemed clinics
We are interested in establishing a Telemed clinic to alleviate geographical
access difficulties of patients to our services. We understand that some of
them need to travel long distances to attend to clinic. Therefore, this would be
a way to monitor patients more easily and for them to save in travel expenses.
Future translational research projects
As stated above, an understanding of the underlying molecular mechanism of
disease due to the different mutations can be fed back to the clinical team to
direct appropriate therapy. Next generation sequencing is revealing a series of
new CMS-associated genes and projects are underway to determine how the
different mutations affect signal transmission at the neuromuscular junction.
Further projects are being undertaken to study the beneficial effects of
salbutamol. At present the precise mechanism through which Salbutamol
improves neuromuscular transmission is not known, but research into the
mechanism may provide a scientific pointer to similar compounds that have
greater efficacy. Professor Beeson has recently been awarded an MRC
Programme Grant to pursue these avenues of translation research.
Service Engagement and Communication
Website
A webpage for the service is hosted on the OUH website and includes: patient
CMS booklet, referral information and pre-referral form, as well as points of
contact for clinicians.
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CMS-DVD
The CMS-DVD content was completed and Myaware (formally MGA) has
approved the funding of 150 copies of the DVD. The information on this DVD
will help patient and families to understand their conditions better. The DVD
artwork has been delayed due the recent change in the logo of Myaware
(formally MGA). A copy of the new artwork is attached (Appendix 10).
Patient Day
The National Congenital Myasthenia patient day is due to take place on
Saturday 25th October at the Holiday Inn in Oxford. .Flyers have been sent to
200 patients. Myaware have been informed of the date and a representative
will be attending (Appendix 11).
Pre-attendance Clinic Information Pack
The content has been approved by the Trust Media and Communications
Department. The information pack is placed on the CMS service webpage.
The information pack is sent to all new patients attending the service prior to
their appointment. This has been updated this year to include new staff
members.
CQUIN
The CQUIN requirement is designed to encourage collaborative learning and
is based on long standing precedent in the highly specialised services (HSS).
The meeting will include discussions of clinical outcomes (Appendix 12),
comparison of centres’ outcomes, identification of where providers need to
adopt new ways of delivering consistent outcomes across all clinical teams.
This meeting is scheduled for the 26th January 2015.
Meetings, Presentations and Publications
Meetings
Dr J Palace, Professor D Beeson, Dr P Rodriquez Cruz, Birute Saul, Hayley Ramjattan
Highly Specialised Services Clinical Outcome
Collaborative Audit Workshop
Newcastle upon Tyne
23rd January 2014
Media communications
Communication on ITV news (Appendix 12)
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http://www.itv.com/news/wales/2014-09-17/the-experimental-drug-thatshelping-a-cardiff-teenager-to-walk-again/
Communication in The Daily Mail (Appendix 2)
http://www.dailymail.co.uk/health/article-2698312/The-asthma-drug-usedbeat-paralysis.html
Oral Presentations
1. P. Rodriguez Cruz: phenotypic overlap of the inherited myasthenia’s and myopathies.
Oxford Neuromuscular Centre annual meeting; Oxford; UK; March 2014.
2. P. Rodriguez Cruz: complex social issues in neuromuscular conditions. Rodriguez Cruz
PM, Palace J, Beeson D. NHS neuromuscular CQUIN meeting. Newcastle; UK; January
2014.
3. P. Rodriguez Cruz: CMS general overview. Myasthenic Kids Weekend. Best Western Moat
House Hotel; Stoke on Trent; UK. June 27-29, 2014.
4. J. Palace: The Muscle Study Group, Lady Margaret Hall, Oxford, UK September 16-18,
2013. Congenital Myasthenic Syndromes.
5. Dr S. Robb: Lecture on the GOSH Practical Neurology Study Days Course; 21 March
2014; Myasthenia in Childhood.
6. Dr S. Jayawant: Myasthenia Study day in Cambridge. 27th June 2014. Recent Advances
in Treatment of Congenital Myasthenia
7. D Beeson. XIII International Congress on Neuromuscular Disease, Nice, France. 6th-10th
July 2014. An emerging subgroup of congenital myasthenic syndromes due to mutations
in the N-linked glycosylation pathway
8. D. Beeson. MRC Translation Neuromuscular Disease Symposium. Institute of Child Health,
March 27th 2014. An update on the Congenital Myasthenic Syndromes.
9. D. Beeson. Annual Meeting of the British Myology Society, Wolfson College Oxford, 11th12th September 2014. The congenital myasthenic syndromes.
Publications
1. Congenital myasthenic syndromes and the neuromuscular junction. Rodríguez Cruz
PM, Palace J, Beeson D. Curr Opin Neurol. 2014 Aug 25. [Epub ahead of print]
2. Congenital myopathies with secondary neuromuscular transmission defects; A case
report and review of the literature. Rodríguez Cruz PM, Sewry C, Beeson D, Jayawant
S, Squier W, McWilliam R, Palace J. Neuromuscul Disord. 2014 Jul 30. pii: S09608966(14)00613-0. doi: 10.1016/j.nmd.2014.07.005. [Epub ahead of print]
3. How common is childhood myasthenia? The UK incidence and prevalence of
autoimmune and congenital myasthenia. Parr JR, Andrew MJ, Finnis M, Beeson D,
Vincent A, Jayawant S. Arch Dis Child. 2014 Jun;99(6):539-42.
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4. Fast-channel congenital myasthenic syndrome with a novel acetylcholine receptor
mutation at the α-ε subunit interface. Webster R, Liu WW, Chaouch A, Lochmüller H,
Beeson D. Neuromuscul Disord. 2014 Feb;24(2):143-7.
5. MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both
IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters. Koneczny
I1, Cossins J, Waters P, Beeson D, Vincent A.
6. DOK7 congenital myasthenic syndrome in childhood: early diagnostic clues in 23
children. Klein A, Pitt MC, McHugh JC, Niks EH, Sewry CA, Phadke R, Feng L, Manzur
AY, Tirupathi S, Devile C, Jayawant S, Finlayson S, Palace J, Muntoni F, Beeson D,
Robb SA. Neuromuscul Disord. 2013 Nov;23(11):883-91.
7. Palace J, Finlayson S. Chapter 19: Inherited Myasthenic Syndromes. Oxford Textbook
of Neuromuscular Disorders (Oxford Textbooks in Clinical Neurology), edited by David
Hilton-Jones and Martin Turner. ISBN: 9780199698073. Due to publish October 2013.
8. Illingworth MA, Main M, Pitt M, Feng L, Sewry CA, Gunny R, Vorstman E, Beeson D,
Manzur A, Muntoni F, Robb SA. RYR1-related congenital myopathy with fatigable
weakness, responding to Pyridostigmine. Neuromuscul Disord. 2014 May 23. pii:
S0960-8966(14)00129-1. doi: 10.1016/j.nmd.2014.05.003. [Epub ahead of print]
9. Heng HS, Lim M, Absoud M, Austin C, Clarke D, Wraige E, Reid C, Robb SA, Jungbluth
H. Outcome of children with acetylcholine receptor (AChR) antibody positive juvenile
myasthenia gravis following thymectomy. Neuromuscul Disord. 2014 Jan;24(1):25-30
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