Clinical Outcome Study for Dysferlinopathy

Dysferlinopathy represents a rare group of muscular dystrophies, presenting a particular
challenge for the definition of natural history and "trial readiness". In the early days
after the cloning of the dysferlin gene, several papers described the clinical phenotype
over time of collections of patients leading to the recognition of the "core" phenotypes of
Miyoshi Myopathy (MM), LGMD2B and the rarer distal myopathy with anterior tibial
involvement. Most of these papers dealt with inbred populations with a limited number of
mutations represented. Subsequent studies have reported larger numbers of patients with
outbred mutations and extended the clinical spectrum to include onset as young as early
childhood and as late as old age, with a large group of patients in whom a clear distinction
in their pattern of muscle involvement into Miyoshi or LGMD was not possible, with
involvement of both the proximal and distal musculature in most patients, especially as the
disease progresses. A limitation of all of these studies however is that with few
exceptions, again mainly in inbred groups, long-term follow-up data are not presented and
data on clinical progression are collected in different ways making precise comparisons
between their conclusions difficult. Nonetheless, the studies overall are in agreement that
dysferlinopathy is a chronically progressive condition sometimes with periods where there is
a plateauing of muscle function, with variable age at wheelchair dependency and probably a
low risk of cardiac and respiratory complications compared to other types of muscular
dystrophy. Intriguing suggestions from these publications which require more systematic
study include the definition of a particularly good level of sporting prowess before the
onset of symptoms and the description of a subacute onset with muscle pain and swelling,
both features, if better understood, that potentially could help in our understanding of the
pathogenesis of the disease.

Recently, two as yet unpublished studies have addressed the topic of charting the natural
history of dysferlinopathy more systematically. In a study of 9 genetically confirmed LGMD2B
and MM patients studied over 18 months, Isabel Illa and colleagues found a significant
decline in muscle strength in a set of muscle groups measured by manual muscle testing, and
in knee flexion measured by quantitative muscle testing, accompanied by a detectable
deterioration on MRI imaging in biceps femori and tibialis posterior. Maggie Walter and
colleagues assessed the natural course of disease and efficacy of deflazacort treatment in
25 patients (between 25 and 63 years of age) with genetically confirmed dysferlinopathy in a
double-blind, cross-over trial. During the first year of the study, they assessed the
natural course of disease in 6-month intervals, evaluating MRC scores, quantitative strength
measurement by hand-held dynamometry (Citec, Groningen, Netherlands), and torque measurement
(M3 diagnose system, Fa. Schnell, Germany), Neuromuscular Symptoms Score (NSS), Timed
Function Tests (getting up from lying and sitting position, climbing 4 stairs, running 10m),
Vignos Scale, Hammersmith Motor Ability Score, and Global Assessment CGI Scale, quality of
life SF-36 scale and laboratory parameters (sodium, potassium, creatinine, urea, GOT, GPT,
gamma-GT, CK, blood count, ESR, CRP). Medication (placebo or deflazacort in a cross-over
design) was only started in the 2nd year of the study. All patients showed a decline in
muscle strength over one year, which was reflected in the tests performed.

It is reassuring that from these data we can conclude that it is likely that there will be
changes detectable with time in dysferlinopathy that could inform the design of future
clinical trials, but the optimal measurements have yet to be defined and mapped in a much
larger group of dysferlinopathy patients representing the entire clinical spectrum of this
diverse disease group. Extrapolating from the requirements for studies in other types of
muscular dystrophies, including the regulatory advice for establishing pivotal trials of
therapies in these disorders, these measures would need to include not only measures of
muscle strength, but also of function and some degree of patient reported outcomes. The
unpublished results of Isabel Illa and colleagues, as well as another small study of MRI in
dysferlinopathy, also show some hope for the use of MRI as a measure of change in muscle
over time which might be applicable as an outcome measure. Up until now, muscle MRI has been
seen more as a tool for delineating the pattern of muscles involved than for monitoring
change - the use of MRI for monitoring disease progression in a non-invasive manner is
however attracting a lot of current interest, though more study is needed especially in
respect of functional correlates and patient relevance.

The frequency of dysferlinopathy provides a further challenge to the collection of natural
history data. The relative frequency of different forms of muscular dystrophy depends to a
certain extent on the population studied. Dysferlinopathy appears to be a more common cause
of LGMD in Southern European populations than in Northern European ones. Founder mutations
exist in only a few small communities. There is little doubt that dysferlinopathy is
under-diagnosed and, in fact, the clinical diagnostic process by which dysferlinopathy is
diagnosed is also variable. Most laboratories still rely on the suggestion of the diagnosis
by muscle immunocytochemistry or (more reliably) immunoblotting. Some laboratories carry out
protein testing on monocytes as an alternative screening methodology. The gold standard for
dysferlinopathy diagnosis has however become DNA testing, with sequencing carried out in a
small number of commercial laboratories as well as a series of diagnostic laboratories in
Europe and the USA. The Jain Foundation (www.jain-foundation.org) can help guide those who
are unsure about their diagnosis through the process of getting a genetic analysis. Please
contact Sarah Shira at the Jain Foundation for help with diagnosis at +1 425 882 1492

With the perspective of different approaches to therapy in dysferlinopathy, a clearer
definition of the natural history of the disease and the delineation of suitable outcome
measures for clinical trials needs to be prioritised. The current protocol builds on
existing national and international networks to bring together a critical mass to address
the following specific aims:

1. Define the natural history of dysferlinopathy in a large unselected patient group with
respect to age and nature of onset, progression and presence of complications via
existing and expanded registries and databases

2. Study a selection of possible outcome measures for dysferlinopathy trials over a three
year period in a multicentre evaluation of 150 patients based in centres of excellence
for muscular dystrophy diagnosis and management

3. Extend the existing registry activities coordinated by the Jain Foundation to ensure a
comprehensive patient registry for dysferlinopathy, within the TREAT-NMD international
registry framework.

Inclusion Criteria:

- Confirmed diagnosis of dysferlinopathy proven by a) two (predicted) pathogenic dysferlin
mutations, b) one (predicted) pathogenic dysferlin mutation and absent dysferlin protein
on muscle immunoblot, or c) one (predicted) pathogenic dysferlin mutation and dysferlin
protein level ≤20% of normal level determined by blood monocyte testing. Mutations will be
checked for pathogenicity via the UMD bioinformatics tools.

NOTE: Contact Sarah Shira at the Jain Foundation for help with diagnosis at +1 425 882
1492

- Ambulant with or without aids; or full-time wheelchair user, i.e. non-ambulant; with
the ratio 2:1 between recruited ambulant and recruited non-ambulant patients.

- All ages ≥ 10 years of age.

- Ability to perform assessments (there will be different assessments for ambulant and
non-ambulant patients).

- Ability to attend scheduled investigations.

- Informed consent to participate in the clinical outcome study.

NOTE: Funds are available to cover necessary hotel stays and travel costs to the study
centres for the participant and a helper (if needed).

Exclusion Criteria:

- Known current or planned medical or other interventions that might interfere with the
possibility to undertake the planned tests.

- Other concomitant pathology that in the view of the investigator would jeopardise the
ability to take part in the protocol.