NHS Specialised Services Commissioning
Rare Neuromuscular Disorders Group
Congenital Myasthenic Syndromes:
Oxford University Hospitals NHS Trust
Annual Report October 2015
Service Overview
Page 2
Service Objectives, Outcomes and Performance Measures
Page 4
Patient Feedback
Page 6
Financial Update
Page 6
Service Developments
Page 7
Development Plans
Page 8
Service Engagement & Communication
Page 9
Service problems
Page 10
Meetings, Presentations and Publications
Page 10
Appendices
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The Congenital Myasthenic Syndrome (CMS) service at The John 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 Pinki Munot
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 Paediatric Neurologist (GOSH)
Consultant Neurophysiologist
CMS Clinical Fellow
CMS Service Co-ordinator
Neuromuscular Physiotherapist
Myasthenia Specialist Nurse
Neurological Clinical Services Manager
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 201 patients each year as outpatients and 4 as
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).
Monthly joint all day clinics with Dr Stephanie Robb and the Oxford clinical
team are now routinely established. Joint clinics alternate between GOSH
London and Oxford, and allow good practice to be shared between centres.
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The CMS Service held a Joint Paediatric clinic with St Thomas’s Hospital (Dr
Heinz Jungbluth) on the 9th July and an Adult Clinic at King’s College Hospital
(Dr Fiona Norwood) in London on the 4th September.
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 or severity of
illness.
The CMS Service have established Telemed appointments within our clinics,
where we contact patients who are unable to attend clinic. 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 within Professor Beeson’s research 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:
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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.
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In addition, whole screen exome and whole screen genome screening is
performed via Professor Beeson’s group in selected cases of CMS, where the
genetic cause remains unidentified and the diagnosis of CMS is undoubted.
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
experience has allowed development of a treatment algorithm, which was
updated last year due to our increasing knowledge of using Salbutamol or
ephedrine, 2-adrenergic agonists with effects at the neuromuscular junction,
in CMS [Appendix 1]. As we reported last year, we have an increasing
number of patients with AChR-deficiency and Fast channel syndrome who
showed a dramatic improvement by adding Salbutamol to their previous
therapies. This year, we finalised our observational study on a number of
patients with severe AChR-deficiency, which has been recently published in
the journal Neurology demonstrating an important beneficial therapeutic step
in treatment [Appendix 2].
Service Objectives and Outcomes
The purposes and goals of the service
 Make a definitive diagnosis (including prenatal diagnosis where
requested) [Appendix 3]
 Treat effectively [Appendix 1]
 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 201 patients in the outpatient clinics, the clinical team
also reviewed the genetic results of 430 patients in Sept 2014-Aug 2015
period, offering advice on diagnosis and management to the referring
Clinician. We also had 4 CMS inpatients (7 occupied bed days) 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 decreased by 13.5% compared to last year. This is probably
due to sample numbers returning to more stable numbers after the addition of
new glycosylation genes, DPAGT1 and GFPT1, to our screening panel last
year. At the moment we screen a total of 11 genes, but we regularly expand
this to include any new CMS related genes discovered.
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Activity Levels Recorded [Appendix 4]:
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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 this is
actually outside of the Highly Specialised Funding
Number of remote genetic reviews in April 2014 - April 2015 was 433
(steering specific genetic tests performed dependent on clinical
information). The 30% increase in genetic reviews this year was due to
updating old genetic results from previous years. We expect to return to
the usual numbers next year. (Appendix 4h)
Number of remote consultations from September 2014 – August 2015
was over 40 phone calls and 400 emails. This represents a great
increase in our email communication with patients and other medical
professionals from far and wide. We are making a big effort to provide
an accessible service at the push of a button.
Number of Telemed appointments from March 2015 to August 2015
was 11. This service was implemented in March 2015.
Performance Indicators
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Turnaround time for DNA reporting [Appendix 5]
Clinic Waiting Times
Geographical Distribution
Patient Satisfaction (see later – page 6)
Geographical Distribution

Geographical data of outpatient activity (Appendix 4c and 4d) genetic
tests (Appendix 4f) and remote reviews (Appendix 4i) 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 and we have set up a Telemed service from
March 2015.
As well as offering a national service, the team also offer advice on
international patients. In the period April 2014 – April 2015, 8.23% of our
genetic reviews came from overseas patients, compared to 8.62% last year.
This confirms our efforts in establishing us as a centre of international
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expertise in CMS. We are receiving more enquiries regarding from EU
countries using the S2 EU Cross-border Healthcare Directive referral process
(3 pending patients).
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. We give our patients a feedback
questionnaire in order to capture more information about the performance of
the CMS Service measured against the quality indicators and to identify any
gaps in service provision. We have been using this questionnaire since April
2013 in all our outpatient clinics. This information is collated on to our
database and any negative feedback is disseminated to the CMS team for
positive action and steps
“EXTREMELEY HOT IN WAITING ROOM!”
When the above comment was received, the CMS Service Co-Ordinator
spoke with the Estates Department at the Hospital and portable air
conditioning units are now in the clinic rooms when the weather is hot. This
ensures our patients are in a cool room when we see them, and thus reducing
their fatigue levels.
The results from the period 2014-2015 (April 2014 – August 2015) show the
following [Appendix 7]:
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98.25% of patients felt their care was well coordinated
99.11% of patients had an excellent or good clinical experience
regarding consultations with doctors and physiotherapist.
93.33% of patients felt their queries were dealt with fully when they
contacted the CMS Service for advice.
The CMS Service updated our patient pre-clinic information booklet in March
2015, 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.
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Service Developments
Charitable Funds Grant – as previously reported
In June 2015 the service was successful in a bid for a grant from the JR
Charitable Fund for £107 to purchase a play mat that can be used in the clinic
room for young babies/children to be assessed on.
Neuromuscular Physiotherapist
The CMS service has a dedicated 0.2 wte Neuromuscular Physiotherapist,
who attends both the adult and paediatric clinics. The role of the
Neuromuscular 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. This support has been well
received by the CMS cohort, where advice on exercise progression is often
discussed in clinic. There is the potential to audit patient activity levels within
our CMS cohort in the future, to evaluate patient participation levels in
exercise with this additional physiotherapy support.
The role of the physiotherapist also extends to care outside of clinics, with
links to community therapists (for example; in supporting respiratory
management and progression of motor development) and supporting
coordinated medical input during hospital admissions.
Telemed clinics
The Telemed clinics were set up in March 2015 as some patients were finding
it difficult to attend clinic due to geographical access issues. The CMS
coordinator liaises with the patient a convenient time for the team to call the
patient from the CMS clinic. After the telephone consultation, a letter is
dictated and sent to their doctor. We have used this method in eleven patients
so far and this has proven successful. Therefore, this is a way to monitor
patients more easily and for them to save in travel expenses, as some
patients have difficulty affording the cost of travel. This also stops patients
from being lost to follow-up.
Current translational research projects
As reported, several forms of CMS show a marked beneficial response to
Salbutamol or ephedrine. 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.
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Development
Newly identified CMS-associated genes and next generation sequencing
The CMS Service continue to incorporate 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
the Biomedical Research Centre funding) for the routine screening of genes in
rare Mendelian genetic disorders. 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. Previously, using the same
methodology, we were able to identify DPAGT1, ALG2 and ALG14 as
causative genes for CMS.
Given the number of new CMS-associated genes that are being identified Drs
Michael Oldridge and Tracy Lester are actively exploring generating a Next
Generation Sequencing CMS panel to be used in the screening. This would
be designed to detect the more common CMS, variants in the genes
described above, and the more unusual CMS such as AGRN and MUSK that
are currently screened for in the research laboratory.
New patient Liaison and Project Nurse
The CMS Service 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, in association with our Myasthenia &
NMO Nurses. This will be funded from income obtained within the two
services.
Updating CMS booklets
The new CMS booklets have been updated with the new relevant information
regarding recently identified CMS and therapy. Myaware is currently editing
the booklets ready for printing and dispatching. A view of the new look logo
can be found in Appendix 10.
Myasthenia Nurse
Our Myasthenia Nurse is increasingly included in educating our patients and
families regarding their diagnosis and treatments, and providing support out of
the clinic.
Future translational research projects
As stated above, an understanding of the underlying molecular mechanism of
disease due to the different mutations is 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
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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. We are also screening for small molecules that can increase
levels of the DOK7 protein as an alternative therapeutic strategy.
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. The website has recently been updated with the contact
information for the CMS Team.
CMS-DVD
The CMS-DVD content was completed and myaware (formally MGA) has
provided 150 copies of the DVD. We have been giving the CMS-DVD to newly
diagnosed patients (and parents) and sending them to school when requested
by the parents of patients with CMS. The information on this DVD will help
patient and families to understand their conditions better (Appendix 11).
Patient Day
The CMS Patient Day took place on the 25th of October 2014 in Oxford. A
total of 49 patients and their family members attended. The agenda consisted
of overviews, presentations, and breakout sessions where patients interacted
with each other and the CMS team (Appendix 12). Patients completed a
questionnaire feedback with a positive outcome (Appendix 13). The National
Congenital Myasthenia Patient Day is due to take place in the Spring of 2016
in Oxford. Myaware have been informed and representatives will be attending.
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 14),
comparison of centres’ outcomes, and identification of where providers need
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to adopt new ways of delivering consistent outcomes across all clinical teams.
This meeting took place on the 26th January 2015 in Newcastle.
Service Problems
Provision of 3,4-Diaminopyridine
The CMS Service 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.
Provision of Salbutamol
There is a current problem with the manufacturing of Salbutamol modified
release capsules (Ventmax®). The manufacturer Chiese has discontinued the
product. There are no current issues with the supply of Salbutamol tablets or
liquid formulation, which are manufactured by GSK. All our patients who
contacted us regarding this issue, we wrote to their GPs and local consultants
to re-prescribe salbutamol with the new formulation. This has so far proved
successful. We are awaiting an update from the manufacturers regarding
Ventmax.
Meetings, Presentations and Publications
Meetings
Dr J Palace, Professor D Beeson, Dr P Rodriquez Cruz, Birute Saul, Hayley Ramjattan, Julia
Goodgame, Dr. Tracy Lester, Dr Mike Oldridge
Highly Specialised Services Clinical Outcome
Collaborative Audit Workshop
Newcastle upon Tyne
26th January 2015
Oral Presentations
1.
D. Beeson: Annual Meeting of the British Myology Society, Wolfson College Oxford,
11th-12th September 2014. The congenital myasthenic syndromes.
2.
D.Beeson UCL Update in Neuromuscular Disorders Course on 6 May 'Update on the
molecular basis of congenital myasthenic syndromes’
3.
S. Robb: UCL Update in Neuromuscular Disorders Course on 6 May 'CMS
Presentations and Management'.
4.
P Rodriguez Cruz: meeting the expectations of patients in the working diagnosis of
neuromuscular disorders. NHS neuromuscular CQUIN meeting. Newcastle; UK;
January 2015.
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5.
J Palace: Talk at the Norwegian Neuromuscular Diseases Interest Group for
Norwegian Neurologists in Oslo: 11th March 2015
6.
P Rodriguez Cruz: limb-girdle syndrome and glycosylation defects. Oxford University
Hospital Neurology Grand Round. Oxford; UK: July 2015.
Publications
1. Salbutamol and ephedrine in the treatment of severe AChR deficiency syndromes.
Rodríguez Cruz PM, Palace J, Ramjattan H, Jayawant S, Robb SA, Beeson D.
Neurology. 2015, Aug 21. pii: 10.1212/WNL.0000000000001952. [Epub ahead of print].
2. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic
disorders with dystroglycanopathies. Belaya K, Rodríguez Cruz PM, Liu WW, Maxwell
S, McGowan S, Farrugia ME, Petty R, Walls TJ, Sedghi M, Basiri K, Yue WW, Sarkozy
A, Bertoli M, Pitt M, Kennett R, Schaefer A, Bushby K, Parton M, Lochmüller H, Palace
J, Muntoni F, Beeson D. Brain. 2015 Sep;138(Pt 9):2493-504. doi:
10.1093/brain/awv185. Epub 2015 Jun 30
3. Factors influencing success of clinical genome sequencing across a broad spectrum of
disorders. Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A,
Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento
C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall
R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger
L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R,
Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D,
Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck
J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Németh AH, Nesbit
MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N,
Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L,
Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A,
Silverman E, Simmons A, Sørensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson
I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty
L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D,
Donnelly P, McVean G. Nat Genet. 2015 Jul;47(7):717-26. doi: 10.1038/ng.3304. Epub
2015 May 18.
4. Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine
Receptors in the Diagnosis of Seronegative Myasthenia Gravis.Rodríguez Cruz PM, AlHajjar M, Huda S, Jacobson L, Woodhall M, Jayawant S, Buckley C, Hilton-Jones
D, Beeson D, Vincent A, Leite MI, Palace J.JAMA Neurol. 2015 Jun;72(6):642-9. doi:
10.1001/jamaneurol.2015.0203.
5. Congenital myasthenic syndrome caused by mutations in DPAGT. Klein A, Robb S,
Rushing E, Liu WW, Belaya K, Beeson D. Neuromuscul Disord. 2015 Mar;25(3):253-6.
doi: 10.1016/j.nmd.2014.11.013. Epub 2014 Nov 26.
6. Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases
characterized by defects in the neuromuscular junction. Arimura S, Okada T, Tezuka T,
Chiyo T, Kasahara Y, Yoshimura T, Motomura M, Yoshida N,Beeson D, Takeda S,
Yamanashi Y. Science. 2014 Sep 19;345(6203):1505-8. doi: 10.1126/science.1250744
7. Inherited disorders of the neuromuscular junction: an update. Rodríguez Cruz PM,
Palace J, Beeson D.J Neurol. 2014 Nov;261(11):2234-43. doi: 10.1007/s00415-0147520-7. Epub 2014 Oct 11. Review
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8. Collagen Q--a potential target for autoantibodies in myasthenia gravis. Zoltowska
Katarzyna M, Belaya K, Leite M, Patrick W, Vincent A, Beeson D. J Neurol Sci. 2015
Jan 15;348(1-2):241-4. doi: 10.1016/j.jns.2014.12.015. Epub 2014 Dec 18.
9. A severe congenital myasthenic syndrome with 'dropped head' caused by novel MUSK
mutations. Giarrana ML, Joset P, Sticht H, Robb S, Steindl K, Rauch A, Klein A. Muscle
Nerve. 2015 Apr 21. doi: 10.1002/mus.24687.
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