Neuromuscular Disorders 35 (2024) 42–52

Contents lists available at ScienceDirect

Neuromuscular Disorders
journal homepage: www.elsevier.com/locate/nmd

The myotubular and centronuclear myopathy patient registry:

a multifunctional tool for translational research
Joanne Bullivant a, Anando Sen a, Jess Page a, Robert J. Graham b, Heinz Jungbluth c,d,
Ulrike Schara-Schmidt e, Orla Lynch f, Carsten Bönnemann g, Aart den Hollander h,
Anne Lennox i, Dionne Moat a, Claudia Saegert f, Kimberly Amburgey j, Ana Buj-Bello k,l,
James J. Dowling j, Chiara Marini-Bettolo a,∗
a
The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS
Foundation Trust, Newcastle upon Tyne, UK
b
Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, United States
c
Department of Paediatric Neurology – Neuromuscular Service, Evelina Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London, United
Kingdom
d
Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine (FoLSM), King’s College London, London,
United Kingdom
e
Department of Pediatric Neurology, Developmental Neurology and Social Pediatrics, University of Duisburg-Essen, Essen, Germany
f
Independent Patient Representative
g
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
h
ZNM – Zusammen Stark! E.v., Stuttgart, Germany
i
Myotubular Trust, London, United Kingdom
j
Division of Neurology, Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada
k
Genethon, Evry 91000, France
l
Université Paris-Saclay, Univ Evry, Inserm, Genethon, Integrare research unit UMR_S951, Evry 91000, France

a r t i c l e i n f o a b s t r a c t

Article history: The Myotubular and Centronuclear Myopathy Registry is an international research database containing
Received 5 May 2023 key longitudinal data on a diverse and growing cohort of individuals affected by this group of rare
Revised 15 September 2023
and ultra-rare neuromuscular conditions. It can inform and support all areas of translational research
Accepted 23 October 2023
including epidemiological and natural history studies, clinical trial feasibility planning, recruitment for
clinical trials or other research studies, stand-alone clinical studies, standards of care development, and
Keywords: provision of real-world evidence data. For ten years, it has also served as a valuable communications
Myotubular tool and provided a link between the scientific and patient communities. With the anticipated advent
Centronuclear of disease-modifying therapies for these conditions, the registry is a key resource for the generation
Myopathy
of post-authorisation data for regulatory decision-making, real world evidence, and patient-reported
Registry
outcome measures. In this paper we present some key data from the current 444 registered individuals
Translational
with the following genotype split: MTM1 n=270, DNM2 n=42, BIN1 n=4, TTN n=4, RYR1 n=12,
other n=4, unknown n=108. The data presented are consistent with the current literature and the
common understanding of a strong genotype/phenotype correlations in CNM, most notably the data
supports the current knowledge that XLMTM is typically the most severe form of CNM. Additionally,
we outline the ways in which the registry supports research, and, more generally, the importance of
continuous investment and development to maintain the relevance of registries for all stakeholders.
Further information on the registry and contact details are available on the registry website at
www.mtmcnmregistry.org.
© 2023 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY-NC license
(http://creativecommons.org/licenses/by-nc/4.0/)

∗
Corresponding author.
E-mail address: chiara.marini-bettolo@newcastle.ac.uk (C. Marini-Bettolo).

https://doi.org/10.1016/j.nmd.2023.10.014
0960-8966/© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/)
J. Bullivant, A. Sen, J. Page et al.
1. Introduction
Centronuclear myopathies (CNM) are a group of non-dystrophic
congenital neuromuscular conditions characterised by the presence
of centrally located nuclei in muscle fibres. CNM is an umbrella
term used to describe a heterogenous group of individually rare
congenital myopathies most commonly caused by pathogenic
variants in the myotubularin (MTM1), dynamin 2 (DNM2),
amphiphysin II (BIN1), skeletal muscle ryanodine receptor (RYR1)
or titin (TTN) genes. A rare disease is defined in Europe as a
condition which affects less than 1 in 2,0 0 0 people, and in the
United States as a condition which affects fewer than 20 0,0 0 0
Americans [1,2]. The most common, and typically most severe,
form of CNM is caused by pathogenic variants in the MTM1 gene
and is commonly referred to as X-linked myotubular myopathy
(XLMTM), with an estimated incidence of 1 in 50,0 0 0-10 0,0 0 0
male births [3]. XLMTM symptoms are usually present at birth,
whilst, with notable exceptions, the other autosomal-dominant
(DNM2) and autosomal-recessive (TTN, RYR1, BIN1) forms of CNM
generally have a later onset and milder phenotype [4]. Typical time
from symptom onset to diagnosis varies between subtypes with
the shortest seen in male MTM1 patients and longest in female
MTM1 carriers [5].
Although there is no cure for CNM, several treatments are
currently under pre-clinical development or under investigation
in clinical trials. The treatment at the most advanced stage
of development is a gene replacement therapy for XLMTM
(ASPIRO, sponsored by Astellas Gene Therapies, NCT03199469) [6].
Due to the lack of available treatment options, management of
the condition is largely supportive and conservative depending
on disease severity, with a primary focus on optimising care
and improving quality of life. Current supportive management
approaches include assisted ventilation, assisted feeding, and
regular physiotherapy to preserve muscle power, function and
range of movement [4]. There is case level data supporting the off-
label use of some medications, such as pyridostigmine [7].
While CNM is an overarching histopathological categorisation,
definitive subtype diagnosis is confirmed by genetic testing.
Clinical features, histopathological findings on muscle biopsy and
muscle magnetic resonance imaging (MRI) can further inform and
support the diagnosis. The clinical presentation of CNM varies
depending on the genotype, and unique pathogenic variants cause
significant phenotypic differences [8]. At the more severe end
of the clinical spectrum, XLMTM patients commonly experience
profound hypotonia, external ophthalmoplegia, and respiratory
failure [4]. Respiratory failure often results in death in infancy
or in early childhood. Among those who survive, there is
usually prolonged ventilatory dependence and delayed gross motor
milestones [9]. Numerous medical comorbidities have also been
reported in older patients with XLMTM, involving haematologic,
gastrointestinal, hepatic, and ophthalmic complications [10]. Most
patients with the autosomal-dominant form of CNM are more
mildly affected than those with the X-linked or autosomal-
recessive forms [4], with the notable exception of cases with de
novo dominant DNM2 mutations that may be disproportionately
severe [11,12].
Female carriers of XLMTM, historically, were thought to be
mostly asymptomatic, but there is increasing evidence to suggest
that symptoms in carriers are quite common [13,14]. In carrier
females, symptoms can involve severe, generalized weakness
presenting in infancy as seen in affected males (particularly in
the presence of X-chromosomal abnormalities or with extreme
skewing of X-inactivation), or mild (often asymmetric) weakness
manifesting in adulthood. The most severely affected females may
be wheelchair dependant and experience significant respiratory
decline ultimately resulting in ventilatory support [15].
43
Neuromuscular Disorders 35 (2024) 42–52
Identifying sufficient participants for research with these
conditions can be challenging due to their rarity, variability of
presentation, underdiagnosis, and dispersed patient populations;
the significant burden of involvement in research or clinical trials
on patients and their families is also a barrier. The Myotubular and
Centronuclear Myopathy Patient Registry (henceforth referred to as
“the Registry”) is an international longitudinal research database
for people with a confirmed diagnosis of XLMTM or CNM. It was
established in 2013 by the Myotubular Trust and transferred to
the John Walton Muscular Dystrophy Research Centre at Newcastle
University in the UK during 2015-2016, for continued management
and curation. The Registry accepts registrations of living and
deceased patients, as well as manifesting and non-manifesting
female carriers of XLMTM. It collects genetic and longitudinal data
from both patients and clinicians, on individuals affected by this
group of rare and ultra-rare conditions and makes them available
in a deidentified form for the research community to use. By using
these data and the Registry infrastructure, the Registry can support
translational research in several ways: (a) providing de-identified
data reports in response to a research question, (b) providing
data to inform clinical trial feasibility studies, (c) supporting
recruitment by informing eligible participants about clinical trials
or other studies, (d) circulating research updates to the patient
community, (e) providing data collection services for standalone
studies by other groups, (f) providing data on patient-reported
outcome measures, natural history and real world evidence data to
regulators, and (g) informing standard of care development. As a
result, the Registry helps to further understand the natural history
of disease in the CNM population, characterise their epidemiology,
facilitate clinical trial planning and recruitment, avoid data silos
and duplication of effort, keep the patient community informed,
and contribute to the development of standards of care.
2. Methods
The Registry is an international longitudinal research database
for children and adults with a clinical diagnosis of CNM
or XLMTM, or female carriers of XLMTM. Registration is
voluntary and initiated by the participants via a secure online
password-protected portal (www.mtmcnmregistry.org.). Data are
collected directly from patients and families as shown in Fig. 1,
supplemented by data requested from the patient’s treating doctor
as shown in Fig. 2. All data collected are encrypted and stored on
a secure cloud server in compliance with GDPR and the UK Data
Protection Act 2018. A clinical diagnosis of CNM is sufficient for
enrolment; however, registrations are not marked as genetically
confirmed until the participant or their doctors have provided
a genetic confirmation document. Participants are subsequently
excluded if their genetic report confirms a diagnosis of a condition
other than a CNM. Individuals without genetic resolution but with
a histopathological diagnosis of CNM are continued in the Registry.
Automated emails prompt participants to check and update
their records every six months to ensure the data remain accurate
and current. Fig. 3 shows a steady growth in registry participation
over the years, typically with an influx of registrations seen
following attendance at a patient or family conference. The spike
in quarter 4 of 2021 followed a large-scale communications
effort regarding a move to a new software platform. To promote
accessibility of participation the Registry is available in ten
languages: English, German, French, Spanish, Italian, Polish, Hindi,
Dutch, Brazilian Portuguese, and Arabic.
The Registry holds ethical approval from the National Health
Service (NHS) Health Research Authority (North East – Tyne
& Wear South Research Ethics Committee) and is overseen
by the Principal Investigator and Registry Project Manager. A
multidisciplinary expert steering committee advises on strategic
J. Bullivant, A. Sen, J. Page et al. Neuromuscular Disorders 35 (2024) 42–52

Fig. 1. Data collected from patients or families in the Registry

Shaded boxes signify data collected from each cohort. The individual questions can be viewed in full at https://mtmcnmregistry.org/about/registration-process/index.en.html

direction and opportunities, monitors data usage and grant
proposals, and helps to raise awareness of the Registry. Comprised
of clinical and research expertise, as well as a strong patient
representation, the steering committee is responsible for reviewing
and voting on requests to use Registry data (data enquiries) to
ensure the usage is appropriate, ethically approved, and in-line
with Registry objectives and remit.
For data enquiries, the third party requests a data report to
include pre-agreed variables and data analyses, which will only
contain aggregate or deidentified data. These data reports can

44
J. Bullivant, A. Sen, J. Page et al.
Fig. 2. Data collected from clinicians in the Registry
Shaded boxes signify data collected from clinicians for each cohort.
Fig. 3. Registry recruitment history from May 2016 to January 2023 (includes all
previous participants who consented to join the new platform and set up an online
registration).
be one-off or at intervals for an agreed period. For recruitment
enquiries, the Registry team can circulate details of a clinical
trial or other research study to the Registry cohort, or sub-cohort
depending on inclusion criteria, on behalf of the third party.
More recently we have seen the use of the Registry expanding
beyond these functions, to provide data collection services for
external groups as described later in this paper. Once approved
by the steering committee, enquiries are usually associated with
a fee to support Registry sustainability and cover the cost of
conducting the required work. The operating costs of the Registry
are predominantly funded by grants from patient organisations
and industry, supplemented by income generated from enquiries
as described above.
The Registry strives to work closely and collaboratively with
multiple stakeholders, including patient organisations to increase
patient enrolment and engagement, and other registries in this
disease space to minimise confusion or data duplication. The
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Neuromuscular Disorders 35 (2024) 42–52
Fig. 4. Genetic report status
Registry is part of the TREAT-NMD Global Registry Network which
is recognised as a leading source of data for trial planning and
recruitment at an international level and will comply with the
network’s standard neuromuscular core dataset when it comes into
force [16]. In 2023, the Registry will make its first deidentified data
transfer to the Rare Disease Cures Accelerator-Data and Analytics
Platform (RDCA-DAP) from the Critical Path Institute [17]. This
initiative aims to maximise data utility and accelerate therapy
development across rare diseases by integrating patient-level
datasets from diverse sources including clinical trials, longitudinal
observational studies, patient registries and real-world data, and
standardising them in a regulatory grade format.
2.1. Genetic confirmations
Upon registration participants are asked the status of their
genetic report. As shown in Fig. 4, of the 444 analysed for this
J. Bullivant, A. Sen, J. Page et al.
paper: 192 (43%) said they had a copy and would upload it, 118
(27%) said they did not have a copy, but that it should be available
from their doctor, and 105 (24%) did not answer this question. The
remaining 6% were either waiting for their results, had not had a
genetic test, or reported that no mutation had been found.
Of the 310 participants who indicated that they have a copy
of their report or that one is available in principle, we obtained
a copy of the genetic confirmation in 204 (66%) patients, and
these are then marked as validated registrations. Obtaining copies
of genetic confirmations is an ongoing priority in daily registry
operations, as well as following up with those who have not
yet fully completed the questionnaire, so this metric is steadily
improving.
2.2. Data presentation
For conciseness we present eleven major attributes (sex,
diagnosis, genotype, availability of genetic report, last known
age or age at death, deceased status, country of current
residence, best motor function, current ventilation method, cardiac
comorbidities) of the Registry patients for the three cohorts of
CNM patients, XLMTM female carriers (including both symptomatic
and asymptomatic individuals), and deceased patient entries (this
is different to patients who have died after registration). These
data are summarised in Table 1 for all 444 patients.
In addition, we examine the relationship between some
patient attributes that were deemed clinically important – last
known age (including age at death), diagnosis (XLMTM or CNM),
genotype, best motor function and current ventilation method. We
investigated the following relationships:
1 Last known age versus diagnosis (living patients).
2 Age at death versus diagnosis (deceased patients, including
deaths after registration).
3 Past (best) motor function versus genotype.
4 Current ventilation method versus genotype.
5 Current age versus current ventilation method (here age is at
the time of recorded ventilation)
6 Current age versus current ventilation method and genotype
(here age is at the time of recorded ventilation)
7 Correlation of current ventilation method, best motor function
and genotype.
For the comparison of a quantitative variable (age) with one
or more categorical variables we present a box and whisker
plot visualisation (list items 1, 2, 5 and 6). For comparing two
categorical variables we present a stacked bar plot visualisation
(list items 3 and 4). For comparing three categorical variables,
we use a 3D heatmap (list item 7). Accompanying tables
with summary statistics are also provided wherever quantitative
variables are involved.
The analyses of the list items 1 through 7 consider the 204
participants whose registration has been validated by the registry
team, following review of the genetic report. For the analysis of the
relationships between genotype, motor function and ventilation
(list items 3, 4, 6, 7), all genetically confirmed female carriers
were included in the MTM1 category. Equivalent analyses with 444
participants are provided in the Appendices A to G (except list
item 2 above, where both versions are presented in the appendix).
Numbers of participants who have not answered a particular
question have not been included in the corresponding analyses.
Before reading these data, it is also important to note that any
values labelled with the term ‘current’ or ‘last known’, such as
current age or current ventilation method, refer to the age at the
time of the last user login unless otherwise specified, as this is the
last time the patient was known to be living and the value was
known to be correct.
46
Neuromuscular Disorders 35 (2024) 42–52
3. Results
On 23/02/23 the Registry contained data on 444 participants,
of which 204 had provided genetic confirmation of their diagnosis.
Table 1 gives aggregate participant numbers against the eleven
major attributes presented.
The mean age of living patients varies substantially when
patients are stratified into XLMTM, CNM, or XLMTM female
carriers. Table 2 and Fig. 5 summarise the age of living patients
stratified by diagnosis (patients and female carriers shown
separately). Patients with XLMTM had a mean age of 10.84 years
which is substantially lower than the 35.48 years for CNM. Female
carriers had the highest mean age of 46.18 years. Corresponding
data for all patients is presented in Table A3 and Fig. A3.
The age at death of patients with XLMTM compared to
those with CNM varies largely when considered for all patients
(Fig. A2). However, no meaningful comparisons can be made for
the genetically confirmed cases as the only deceased patients with
genetic reports provided were those with a diagnosis of XLMTM
(Fig. A1). The results for both genetically confirmed (Fig. A1 and
Table A1) and all (Fig. A2 and Table A2) patients is provided in the
appendix.
Looking at best motor function by genotype (Fig. 6), for DNM2
83% of patients had been able to walk without support and 0%
reported never being able to sit independently. For XLMTM, the
most common response (46%) was that they had never been able
to sit independently, whilst 14% had been able to sit independently,
8% had been able to walk with support, and 32% had been able
to walk without support. For other genotypes, the number of
patients was too small to make any meaningful generalisation or
comparison. Age at which best motor function was achieved is
recorded in the Registry, however due to a low response rate, no
meaningful comparisons could be made. Corresponding data for all
patients is presented in Fig. A4.
When we analysed the current ventilation method by genotype
(Fig. 7), as with the best motor function, DNM2-related CNM
appeared to be associated with better outcomes than XLMTM,
with 75% of DNM2 patients requiring no ventilation versus 18% for
XLMTM. 34% of XLMTM patients used non-invasive ventilation and
the remaining 49% used invasive ventilation. Corresponding data
for all patients is presented in Fig. A5.
Analysing age by current ventilation method (Table 3 and
Fig. 8), higher levels of ventilatory requirements are typically seen
in younger patients, likely due to the lower mean age of XLMTM
patients in the registry. The mean age of patients requiring no
ventilation (30.79 years) was substantially higher than that of
patients requiring invasive ventilation (8.7 years) and non-invasive
ventilation (18.83 years). The age ranges for all ventilation methods
were broad, with invasive ventilation being reported from 0.16 to
48.54 years, and non-invasive ventilation being reported from 0.09
to 85.78 years. Age here refers to the age at which the ventilation
was recorded. Corresponding data for all patients is presented in
Table A4 and Fig. A6.
For each ventilation method, the central line denotes the
median. The box is the interquartile range (IQR). The whisker
length is defined as 1.5 times the IQR beyond its extremities.
The actual whisker is drawn up to the furthest data point
that is still within the whisker length. Data points that are
beyond the whisker length are considered outliers and marked
individually.
When we analysed current age by current ventilation and
genotype (Fig. 9), the observations are consistent with what
was observed in Figs 7 and 8, with the median age of MTM1
patients with invasive ventilation being the lowest and that of
DNM2 patients with no ventilation being the highest. The table
corresponding to this figure is presented in Appendix F (Table A5).
J. Bullivant, A. Sen, J. Page et al. Neuromuscular Disorders 35 (2024) 42–52

Table 1
Attributes of Registry participants.
PATIENTS FEMALE CARRIERS1 DECEASED
ATTRIBUTE
All Conf All Conf All Conf
COHORT SIZE 308 156 89 38 47 10
SEX
MALE 235 126 0 0 44 10
FEMALE 73 30 89 38 3
DIAGNOSIS
XLMTM 153 104 33 10
CNM 70 48 4
OTHER2 8 4 3
UNSPECIFIED 77 7
GENOTYPE
MTM1 145 104 89 8 36 10
DNM2 41 37 1
BIN1 4 2 10
TTN 4 4
RYR1 12 8
OTHER 4 1
UNKNOWN3 98
GENETIC REPORT RECEIVED
NO 152 0 51 0 37 0
YES 156 156 38 38 10 10
LAST KNOWN AGE4
0 – <1 29 14 0 0 18 4
1 – <2 13 10 1 0 3 0
2 – <3 19 10 0 0 3 2
3 – <4 12 9 0 0 4 2
4 – <5 7 4 0 0 0 0
5 – <10 47 23 1 1 5 1
10 – <15 35 15 1 0 0 0
15 – <20 26 15 0 0 1 1
20 – <25 19 11 0 0 2 0
25 – <30 17 6 7 2 0 0
30 – <35 17 9 13 5 0 0
35 – <40 14 4 14 7 0 0
40 – <45 12 7 14 6 0 0
45 – <50 8 3 7 3 1 0
50 – <55 13 8 9 4 0 0
55 – <60 7 3 9 4 1 0
60 – <65 2 0 6 2 0 0
65 – <70 4 2 3 1 0 0
70 – <75 4 2 2 2 1 0
75 – <80 3 1 1 0 0 0
≥80 0 0 1 1 1 0
DECEASED5 9 6 47 10
COUNTRY OF RESIDENCE
GREAT BRITAIN & NORTHERN IRELAND 61 31 22 11 14 <5
UNITED STATES 80 29 25 8 16 <5
GERMANY 29 24 5 <5 <5 <5
SPAIN 15 8 <5 <5 <5 <5
POLAND 14 6 <5 <5 <5 <5
AUSTRALIA 10 <5 <5 <5 <5 <5
IRELAND 6 <5 <5 <5 5 <5
NETHERLANDS 8 <5 <5 <5 <5 <5
PORTUGAL 5 <5 <5 <5 <5 <5
ARGENTINA 9 6 <5 <5 <5 <5
CANADA 7 <5 <5 <5 <5 <5
43 OTHER COUNTRIES (<5 IN EACH) <5 <5 <5 <5 <5 <5
BEST EVER MOTOR FUNCTION
UNABLE TO SIT INDEPENDENTLY 64 44 29 7
ABLE TO SIT INDEPENDENTLY 31 16 3 2
WALK WITH SUPPORT 17 14 1 1
WALK WITHOUT SUPPORT 93 59 3
UNKNOWN 17 11 3
UNSPECIFIED 1
CURRENT VENTILATION METHOD
INVASIVE 86 54 7 5
NON-INVASIVE 58 43 15 5
NONE 78 49
UNKNOWN 3 1
CARDIAC COMORBIDITIES
ABNORMAL ECG 26 15 7 3 7 1
ABNORMAL ECHO 26 15 10 5 5
1
The female carrier number includes both symptomatic and non-symptomatic female carriers.
2
The four genetically confirmed patients with a diagnosis of ‘Other’ had a mutation genetically confirmed in a gene known to be associated with CNM and reported a
tentative (not yet confirmed) clinical diagnosis of CNM.
3
The genetically confirmed patient with unknown genotype has provided a clinical letter confirming genetically confirmed CNM, but we have not yet seen a genetic
report.
4
Last known age for a deceased patient is the age of death.
5
The 47 patients in the deceased column were registered by family members as already deceased. The 9 deceased patients in the main patient cohort were registered
as living patients and we were subsequently notified of their death.

47
J. Bullivant, A. Sen, J. Page et al. Neuromuscular Disorders 35 (2024) 42–52

Table 2
Summary statistics for the age (years) of living patients stratified
by diagnosis and carrier status (see also Fig. 5 below).

Mean Median Range

XLMTM (n=104) 10.84 7.38 0.16 – 58.93

CNM (n=47) 35.48 36.06 2.10- 77.56
Others (n=4) 35.98 42.18 1.32 – 58.24
XLMTM Carriers (n=38) 46.18 42.89 9.89 - 85.79

Fig. 7. Stacked bar plot for the current ventilation method stratified by genotype

Fig. 5. Box and whisker plot for the age of living patients stratified by diagnosis
and carrier status (also summarised in Table 2 above). For each pair of diagnosis
and female carrier status, the central line denotes the median of the current age.
The box is the interquartile range (IQR). The whisker length is defined as 1.5 times
the IQR beyond its extremities. The actual whisker is drawn up to the furthest
data point that is still within the whisker length. Data points that are beyond the
whisker length are considered outliers and marked individually.

Fig. 8. Box and whisker plot for age of current ventilation by ventilation method
(see also Table 3 above)

Corresponding data for all patients is presented in Table A6 and

Fig. A7.
We assessed the association between the best motor function
ever achieved, genotype and current ventilation method which
is presented in Fig. 10 as a 3D heatmap. The highest density
of patients are observed for DNM2 patients who reported
walking without support as their best motor function and
required no ventilation (least severe outcome) and MTM1 patients
who had never been able to sit independently and required
invasive ventilation (most severe outcome). This indicates a strong
association between genotype and patient outcomes.

4. Discussion
Fig. 6. Stacked bar plot for the best motor function stratified by genotype
The Registry data presented in this paper are consistent with
the current literature and the common understanding of a strong
Table 3
association between genotypes and patient outcomes in CNM,
Summary statistics for age stratified by current ventilation method (see also Fig. 8
below). particularly the observed milder phenotype of autosomal-dominant
(DNM2) and autosomal-recessive (TTN, RYR1, BIN1) forms of CNM
Mean age Median age Age range
versus XLMTM [4,5,18]. In addition to this, the data supports the
Invasive Ventilation (n=54) 8.70 4.79 0.16 – 48.54 understanding that successful management of XLMTM requires a
Non-Invasive Ventilation (n=48) 18.83 10.41 0.09 – 85.78 high degree of technology dependence with a strong emphasis
None (n=54) 30.79 32.94 0.76 – 77.18
on ventilatory support however premature death is still expected

48
J. Bullivant, A. Sen, J. Page et al.
Fig. 9. Box and whisker plot for age of current ventilation by ventilation method
and genotype. For each stratification (a pair consisting of a genotype and a
ventilation method), the central dotted circle denotes the median. The solid box
is the interquartile range (IQR). The whisker length is defined as 1.5 times the IQR
beyond its extremities. The actual whisker is drawn up to the furthest data point
(line beyond the box) that is still within the whisker length. Data points that are
beyond the whisker length are considered outliers and marked individually.
[19–21]. XLMTM patients had a significantly lower mean age of
10.84 years compared to 35.48 years for the other autosomal
forms of CNM, and younger patients required higher levels of
ventilatory support, further supporting the view that XLMTM is
typically more severe and potentially life-limiting than the other
subtypes. In addition, 75% of DNM2-related CNM patients required
no ventilation, compared to only 18% of XLMTM patients. When
examining the best motor function ever achieved, 83% of DNM2-
related CNM patients were able to walk independently, compared
to 32% of XLMTM patients, and no DNM2-related CNM patients
reported an inability to sit independently, whereas 46% of XLMTM
patients had not achieved this milestone. Continued investment in
the registry will allow recruitment efforts to persist and enable
better characterization of the genotype-phenotype correlations
between all subtypes, particularly the autosomal-recessive (TTN,
RYR1, BIN1) forms of CNM.
Since 2019, the Registry has participated in 10 enquiries which
have informed a diverse range of research including, but not
limited to; incidence and prevalence of CNM, experiences of
conception, pregnancy and postpartum in neuromuscular diseases,
genotypes in CNM, validity of wearable devices in neuromuscular
diseases, drug repurposing, experiences of powered wheelchair
users in the built environment, clinical features of XLMTM boys
and muscular symptoms in XLMTM carriers [22–25].
4.1. Case studies
In addition to providing reports on existing data, the Registry
can serve as a valuable data collection tool to support external
groups or studies. As demonstrated by the case studies below,
using the Registry in this way reduces duplication of data
and effort, ensures appropriately controlled data access for the
whole disease community, and minimises the burden of research
participation on patients and families.
• Registry Case Study 1 – Brain MRI study for The Hospital for
Sick Children, Toronto, Canada
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Neuromuscular Disorders 35 (2024) 42–52
The Registry can serve as a vital tool for standalone research
studies, managing the consent and data collection processes, and
communications with participants, and transferring the relevant
deidentified data to the study sponsors. We have partnered with
Canadian researchers from The Hospital for Sick Children (SickKids)
in Toronto and Montreal Children’s Hospital to provide recruitment
support and data collection services for an XLMTM Brain MRI
Study. This study aims to determine the prevalence and type of
neuroimaging abnormalities detectable by brain MRI in individuals
with XLMTM. The study will run for approximately 12 months and
involves quarterly deidentified data transfers to the study team.
• Registry Case Study 2 – Liver questionnaire for the MTM-CNM
Liver Collaborative Working Group
With an established infrastructure for communicating with
patients and collecting data internationally, and a cohort of
research-ready participants, the Registry can respond quickly to
the changing needs of the community by integrating new areas
of research interest. The MTM-CNM Liver Collaborative Working
Group (“the Liver Collaborative”) was initiated in August of 2021
by two patient organizations, MTM-CNM Family Connection (US),
and The Myotubular Trust (UK). It gathers academic researchers
and medical experts who seek a better understanding of liver
challenges experienced in the community, from both a natural
history perspective and in the context of emerging clinical
trials. We have supported the Liver Collaborative with their data
requirements by adding a new section on liver involvement into
our existing longitudinal questionnaires. By using the Registry as
their platform for this research, the group has ensured that the
data will be available in a timely manner for all stakeholders to
access in a safe and appropriate way, and that the burden on
patients and families is kept to a minimum.
4.2. Registry impact and potential
A disease-specific international registry is often considered the
ideal model to support research and standardise data collection
on rare diseases. We have demonstrated that not only is the
Registry an effective tool to centralise data collection and avoid
data silos, but that it can act as ready-made infrastructure
to support standalone research studies. The Bogard model of
registry development illustrates the importance of a registry
acting in this kind of dynamic and responsive fashion [26].
Since its establishment in 2013 by the Myotubular Trust, the
role of the Registry has evolved, from connecting patients with
researchers and advancing knowledge on the disease, to supporting
clinical trial and other research recruitment, and from informing
epidemiology studies, to providing data collection services for
other research studies.
It is envisioned that with sufficient development the Registry
will also be ideally placed to underpin registry-based studies in
support of post marketing surveillance when treatments enter the
commercial market and be a powerful tool to collect and magnify
the patient and carer voice. The European Medicines Agency
(EMA) advocate that patient registries can play an important role
in monitoring the safety of medicines, and in 2015 set up the
initiative for patient registries to make better use of existing
registries to provide an adequate source of post-authorisation
data for regulatory decision-making [27]. In 2021 EMA’s Cross-
Committee Task Force on Registries and the Committee for
Medicinal Products for Human Use (CHMP) published a final
‘Guideline on registry-based studies’ to provide recommendations
on key methodological aspects specific to the use of patient
registries by marketing authorisation applicants and holders
planning to conduct registry-based studies [28]. To date, EMA
has provided qualification opinion on the suitability of three
J. Bullivant, A. Sen, J. Page et al. Neuromuscular Disorders 35 (2024) 42–52

Fig. 10. A 3D heatmap demonstrating the correlation between past motor function, current ventilation method and genotype. Each 2D subplot corresponds to a ventilation
method where the axes represent past (best) motor function and genetic mutation. Each cell within the 2D subplot represents the density (count) of patients for a triple
consisting of genetic mutation, ventilation method and best motor function. Darker shades correspond to higher densities. Corresponding data for all patients is presented
in Fig. A8.

patient registries to be used in this manner; the use of Enroll-
HD (a Huntington’s disease patient registry) as a data source
and infrastructure support for post-authorisation monitoring of
medical products, the cellular therapy module of the European
Society for Blood & Marrow Transplantation (EBMT) Registry, and
the European Cystic Fibrosis Society Patient Registry (ECFSPR)
and CF Pharmaco-epidemiology Studies [29]. The documents
associated with these qualifications provide an invaluable source
of information and guidance for the future development of the
Registry.
4.3. Challenges
Out of the 444 participants currently enrolled in the Registry,
we have received genetic confirmation – either from the
participant or from their doctor - for 46%, and 5% reported never
having had a genetic test. We have focused significant effort on
improving this metric, as genetic confirmation of registrations is
central to the credibility of the data and to the potential for
participants to access research studies or treatment. However, if
the patients or families do not have a copy of their genetic report
which they can upload themselves, it is often time-consuming and
circuitous to obtain the necessary documents from their healthcare
providers or genetic testing centre.
Almost half of the living patients in the Registry (47%) have
reported a diagnosis of XLMTM which is typically the most severe
form of CNM and therefore results in complex care needs and
significant burden of disease [20,30]. This may account for the
difficulties experienced in prompting Registry users to log in
regularly (every 6 months is requested) to update their data. It
is similarly important to recognise the self-selecting nature of
a patient-initiated registry and the notion that even with broad
awareness, participation is largely limited to those who are able
and willing. This is the case for any patient-initiated registry, but
especially so within these conditions considering the severity and
variability in the clinical presentation.
In March 2022, we launched a clinician portal whereby the
patients’ treating doctor is invited to contribute data to their
patient’s Registry record. This aims to enhance the credibility
and validity of the data and increase the likelihood of obtaining
genetic reports if patients do not have them available. To date,
27 doctors have been invited by their patients (via the Registry
team) to participate in this way. Of these 27, 16 have agreed
and therefore their names appear on the Registry as participating
doctors, available to be linked to patients’ profiles. 13 patients

50
J. Bullivant, A. Sen, J. Page et al.
have subsequently selected a doctor from this list, and of these
13 patients, 6 have had the requested data added to their record
by their doctor. Although this feature is still in its infancy, the low
level of take-up from both patients and doctors is disappointing
and will be addressed as a priority area in the next registry grant.
Strategies to address this include disseminating registry leaflets
to relevant clinical centres, working with testing centres to add
registry information to relevant genetic reports, and promoting the
registry at relevant clinical meetings and conferences. Momentum
and engagement in the clinical community will also build as the
registry is utilised for more clinical studies. At its full potential,
this combined reporting method will leverage the benefits of two
different data collection methods and promote a balance between
data quantity and data quality, further increasing the credibility of
the Registry.
Recruitment remains an ongoing priority and every opportunity
is taken to raise awareness in the patient community of the
existence of the Registry as well as the benefits of participation.
Participants receive semi-annual data summaries and a new
section of the website titled ‘impact & activity’ allows for
individuals to be updated on the use of registry data in posters
for scientific conferences, publications, and registry enquiries.
Similarly, it is imperative to alert the medical, scientific, research
and pharmaceutical communities to the existence and availability
of the Registry’s data, or data collection services.
The challenges described above are common across many
patient registries and can be significantly diminished by increasing
the level of resource. Registries thrive and grow from engagement,
interaction, and use, but with insufficient or intermittent funding,
engagement with stakeholders and attention to data quality is
inconsistent, putting Registry sustainability at risk.
Conclusions
The Registry contains important data on a diverse and
growing international cohort of individuals diagnosed with these
conditions. The data within the Registry are consistent with
existing literature on the correlation of patient outcomes with
genotypes and represent a powerful resource to inform all areas
of translational research including epidemiology, clinical trial
planning and recruitment, outcome measure development, natural
history, standards of care, and real-world data for regulatory
decision-making. Registry data are a helpful clinical resource to
advise on prognosis when counselling families and identifying gaps
in care provision. In addition, as an established data collection
infrastructure with a global patient cohort the Registry can
respond to the changing needs of the community by adding new
modules focussed on emerging research questions, or by providing
data collection services for new studies. The review of the data
currently held in the Registry has allowed us to identify areas
of improvement that will benefit the quality of the data and
ultimately provide a better understanding of this group of diseases.
As an example, data on cardiac function is currently limited and a
more detailed data collection on this aspect may provide a better
understanding of cardiac comorbidity and management in this
cohort of patients. Continued investment will lead to continued
improvement in data quality and patient ascertainment as well
as unlocking new areas of development to fulfil the Registry’s
potential as a prominent and fully utilised translational research
tool for the entire disease community.
Summary points
• This international open-ended registry collects genetic and
longitudinal clinical data on individuals diagnosed with XLMTM
or CNM, and female carriers of XLMTM.
51
Neuromuscular Disorders 35 (2024) 42–52
• Registrations are initiated by participants and validated by
review of genetic report where it can be obtained. Data are
reported by participants or clinicians depending on context or
study requirements.
• Registry data are available to third parties through registry
enquiries and support all aspects translational research in a
multitude of ways.
• The Registry also serves as a data collection tool for standalone
research studies and can be developed in response to new
research questions.
• With development the Registry is ideally placed to provide
post-authorisation data for regulatory decision-making and can
leverage the experience of other registries already doing so.
• Current key challenges, including obtaining copies of
genetic reports, data completeness and patient and clinician
engagement, are common across most patient registries
and can be significantly diminished through consistent and
sustainable investment.
Author contributions
Joanne Bullivant (Registry Project Manager, article preparation)
Anando Sen (statistical analysis, article preparation)
Jess Page (Registry Project Coordinator, article preparation)
Robert J. Graham (Steering Committee member, article editing)
Heinz Jungbluth (Steering Committee member, article editing)
Ulrike Schara-Schmidt (Steering Committee member, article
editing)
Orla Lynch (Steering Committee member, article editing)
Carsten Bönnemann (Steering Committee member)
Aart den Hollander (Steering Committee member)
Anne Lennox (Steering Committee member)
Dionne Moat (Steering Committee member)
Claudia Saegert (Steering Committee member)
Kimberly Amburgey (Steering Committee member)
Ana Buj-Bello (Steering Committee Co-Chair, article editing)
James J. Dowling (Steering Committee Co-Chair, article editing)
Chiara Marini-Bettolo (Senior Author, Principal Investigator,
Steering Committee Chair, article preparation and editing)
Funding
The Registry is jointly funded by the Myotubular Trust,
Muscular Dystrophy UK and Astellas Gene Therapies (formerly
Audentes Therapeutics) of Astellas Pharma Inc. Funders are
involved in agreeing the aims and objectives of the registry during
the term of their grant and have had the opportunity to review
this paper. Funders do not have any access to registry data.
Declaration of Competing Interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgements
The Registry software platform is provided by Marcel
Heidemann, freelance IT consultant and developer.
Supplementary material
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.nmd.2023.10.014.
J. Bullivant, A. Sen, J. Page et al.
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