<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01676077</url>
  </required_header>
  <id_info>
    <org_study_id>85750</org_study_id>
    <nct_id>NCT01676077</nct_id>
  </id_info>
  <brief_title>Clinical Outcome Study for Dysferlinopathy</brief_title>
  <acronym>Jain COS</acronym>
  <official_title>International Clinical Outcome Study for Dysferlinopathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Newcastle-upon-Tyne Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Jain Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Newcastle-upon-Tyne Hospitals NHS Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The &quot;Clinical Outcome Study for Dysferlinopathy&quot; is being performed in centres in Europe (UK-&#xD;
      Newcastle; Spain- Barcelona, Sevilla; San Sebastian;Denmark, Copenhagen, Italy- Padova;&#xD;
      France- Paris,), USA (Charlotte, NC; Columbus, OH; St.Louis, MO, Stanford CA, Irvine CA and&#xD;
      Columbia NY), Chile (Santiago) Japan (Tokyo) and South Korea (Pusan). Oversight is provided&#xD;
      by Newcastle upon Tyne Hospitals Trust. Funding for this study is being provided by the Jain&#xD;
      Foundation, a non-profit foundation dedicated to finding therapies for&#xD;
      dysferlinopathies(LGMD2b/Miyoshi). The aim of this &quot;Clinical Outcome Study&quot; is to determine&#xD;
      the clinical outcome measures required for future clinical trials, characterize the disease&#xD;
      progression of dysferlinopathy and collect biological samples for the identification of&#xD;
      disease markers that are needed to non-invasively monitor the disease during clinical trials.&#xD;
      Without this information, effective clinical trials cannot be performed.&#xD;
&#xD;
      This study is recruiting a large number of genetically confirmed dysferlinopathy patients&#xD;
      aged 10 years or older, who are ambulant or non-ambulant. The study has reopened for a&#xD;
      further two years (COS2). Participants will be assessed at 4 further visits over 2 years via&#xD;
      medical, physiotherapy, and MRI/MRS assessments, as well as standard blood tests. Optionally,&#xD;
      the participants can donate blood samples and a skin sample for use in the identification of&#xD;
      disease markers and other approved research. There is a sub-study running in MRI at selected&#xD;
      sites.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Dysferlinopathy represents a rare group of muscular dystrophies, presenting a particular&#xD;
      challenge for the definition of natural history and &quot;trial readiness&quot;. In the early days&#xD;
      after the cloning of the dysferlin gene, several papers described the clinical phenotype over&#xD;
      time of collections of patients leading to the recognition of the &quot;core&quot; phenotypes of&#xD;
      Miyoshi Myopathy (MM), LGMD2B and the rarer distal myopathy with anterior tibial involvement.&#xD;
      Most of these papers dealt with inbred populations with a limited number of mutations&#xD;
      represented. Subsequent studies have reported larger numbers of patients with outbred&#xD;
      mutations and extended the clinical spectrum to include onset as young as early childhood and&#xD;
      as late as old age, with a large group of patients in whom a clear distinction in their&#xD;
      pattern of muscle involvement into Miyoshi or LGMD was not possible, with involvement of both&#xD;
      the proximal and distal musculature in most patients, especially as the disease progresses. A&#xD;
      limitation of all of these studies however is that with few exceptions, again mainly in&#xD;
      inbred groups, long-term follow-up data are not presented and data on clinical progression&#xD;
      are collected in different ways making precise comparisons between their conclusions&#xD;
      difficult. Nonetheless, the studies overall are in agreement that dysferlinopathy is a&#xD;
      chronically progressive condition sometimes with periods where there is a plateauing of&#xD;
      muscle function, with variable age at wheelchair dependency and probably a low risk of&#xD;
      cardiac and respiratory complications compared to other types of muscular dystrophy.&#xD;
      Intriguing suggestions from these publications which require more systematic study include&#xD;
      the definition of a particularly good level of sporting prowess before the onset of symptoms&#xD;
      and the description of a subacute onset with muscle pain and swelling, both features, if&#xD;
      better understood, that potentially could help in our understanding of the pathogenesis of&#xD;
      the disease.&#xD;
&#xD;
      Recently, two as yet unpublished studies have addressed the topic of charting the natural&#xD;
      history of dysferlinopathy more systematically. In a study of 9 genetically confirmed LGMD2B&#xD;
      and MM patients studied over 18 months, Isabel Illa and colleagues found a significant&#xD;
      decline in muscle strength in a set of muscle groups measured by manual muscle testing, and&#xD;
      in knee flexion measured by quantitative muscle testing, accompanied by a detectable&#xD;
      deterioration on MRI imaging in biceps femori and tibialis posterior. Maggie Walter and&#xD;
      colleagues assessed the natural course of disease and efficacy of deflazacort treatment in 25&#xD;
      patients (between 25 and 63 years of age) with genetically confirmed dysferlinopathy in a&#xD;
      double-blind, cross-over trial. During the first year of the study, they assessed the natural&#xD;
      course of disease in 6-month intervals, evaluating MRC scores, quantitative strength&#xD;
      measurement by hand-held dynamometry (Citec, Groningen, Netherlands), and torque measurement&#xD;
      (M3 diagnose system, Fa. Schnell, Germany), Neuromuscular Symptoms Score (NSS), Timed&#xD;
      Function Tests (getting up from lying and sitting position, climbing 4 stairs, running 10m),&#xD;
      Vignos Scale, Hammersmith Motor Ability Score, and Global Assessment CGI Scale, quality of&#xD;
      life SF-36 scale and laboratory parameters (sodium, potassium, creatinine, urea, GOT, GPT,&#xD;
      gamma-GT, CK, blood count, ESR, CRP). Medication (placebo or deflazacort in a cross-over&#xD;
      design) was only started in the 2nd year of the study. All patients showed a decline in&#xD;
      muscle strength over one year, which was reflected in the tests performed.&#xD;
&#xD;
      It is reassuring that from these data we can conclude that it is likely that there will be&#xD;
      changes detectable with time in dysferlinopathy that could inform the design of future&#xD;
      clinical trials, but the optimal measurements have yet to be defined and mapped in a much&#xD;
      larger group of dysferlinopathy patients representing the entire clinical spectrum of this&#xD;
      diverse disease group. Extrapolating from the requirements for studies in other types of&#xD;
      muscular dystrophies, including the regulatory advice for establishing pivotal trials of&#xD;
      therapies in these disorders, these measures would need to include not only measures of&#xD;
      muscle strength, but also of function and some degree of patient reported outcomes. The&#xD;
      unpublished results of Isabel Illa and colleagues, as well as another small study of MRI in&#xD;
      dysferlinopathy, also show some hope for the use of MRI as a measure of change in muscle over&#xD;
      time which might be applicable as an outcome measure. Up until now, muscle MRI has been seen&#xD;
      more as a tool for delineating the pattern of muscles involved than for monitoring change -&#xD;
      the use of MRI for monitoring disease progression in a non-invasive manner is however&#xD;
      attracting a lot of current interest, though more study is needed especially in respect of&#xD;
      functional correlates and patient relevance.&#xD;
&#xD;
      The frequency of dysferlinopathy provides a further challenge to the collection of natural&#xD;
      history data. The relative frequency of different forms of muscular dystrophy depends to a&#xD;
      certain extent on the population studied. Dysferlinopathy appears to be a more common cause&#xD;
      of LGMD in Southern European populations than in Northern European ones. Founder mutations&#xD;
      exist in only a few small communities. There is little doubt that dysferlinopathy is&#xD;
      under-diagnosed and, in fact, the clinical diagnostic process by which dysferlinopathy is&#xD;
      diagnosed is also variable. Most laboratories still rely on the suggestion of the diagnosis&#xD;
      by muscle immunocytochemistry or (more reliably) immunoblotting. Some laboratories carry out&#xD;
      protein testing on monocytes as an alternative screening methodology. The gold standard for&#xD;
      dysferlinopathy diagnosis has however become DNA testing, with sequencing carried out in a&#xD;
      small number of commercial laboratories as well as a series of diagnostic laboratories in&#xD;
      Europe and the USA. The Jain Foundation (www.jain-foundation.org) can help guide those who&#xD;
      are unsure about their diagnosis through the process of getting a genetic analysis. Please&#xD;
      contact Sarah Shira at the Jain Foundation for help with diagnosis at +1 425 882 1492&#xD;
&#xD;
      With the perspective of different approaches to therapy in dysferlinopathy, a clearer&#xD;
      definition of the natural history of the disease and the delineation of suitable outcome&#xD;
      measures for clinical trials needs to be prioritised. The current protocol builds on existing&#xD;
      national and international networks to bring together a critical mass to address the&#xD;
      following specific aims:&#xD;
&#xD;
        1. To define the natural history of Dysferlinopathies with respect to age and nature of&#xD;
           onset, progression and presence of complications.&#xD;
&#xD;
        2. To determine the most suitable and robust outcomes measures for evaluation of disease&#xD;
           progression in patients with Dysferlinopathy at different stages of the disease.&#xD;
&#xD;
        3. To evaluate whether cardiac manifestations are clinically significant in patients with&#xD;
           Dysferlinopathy.&#xD;
&#xD;
        4. To explore if sodium MRI could be useful to identify muscle damage on skeletal muscle of&#xD;
           patients with Dysferlinopathy&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 2012</start_date>
  <completion_date type="Anticipated">March 2024</completion_date>
  <primary_completion_date type="Anticipated">March 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>North Star assessment for limb girdle-type muscular dystrophies (NSAD)</measure>
    <time_frame>24 months</time_frame>
    <description>A functional scale that will be used to measure motor performance in individuals with LGMD</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Dysferlinopathy</condition>
  <condition>LGMD2B Now Classified as LGMDR2</condition>
  <condition>Miyoshi Myopathy</condition>
  <arm_group>
    <arm_group_label>Patients with a genetically confirmed dysferlinopathy</arm_group_label>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Serum, Plasma, DNA, RNA, Skin fibroblasts, Urine&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        A diagnosis of Limb Girdle Muscular Dystrophy type 2B (LGMD2B/ LGMDR2), Miyoshi myopathy,&#xD;
        or any other clinical diagnosis associated with dysferlinopathies&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        - Confirmed diagnosis of dysferlinopathy proven by a) two (predicted) pathogenic dysferlin&#xD;
        mutations, b) one (predicted) pathogenic dysferlin mutation and absent dysferlin protein on&#xD;
        muscle immunoblot, or c) one (predicted) pathogenic dysferlin mutation and dysferlin&#xD;
        protein level ≤20% of normal level determined by blood monocyte testing. Mutations will be&#xD;
        checked for pathogenicity via the UMD bioinformatics tools and and by checking the&#xD;
        literature and mutation /variant databases.&#xD;
&#xD;
        NOTE: Contact Sarah Shira at the Jain Foundation for help with diagnosis at +1 425 882 1492&#xD;
&#xD;
          -  Ambulant with or without aids; or full-time wheelchair user, i.e. non-ambulant; with&#xD;
             the ratio 2:1 between recruited ambulant and recruited non-ambulant patients.&#xD;
&#xD;
          -  All ages ≥ 10 years of age.&#xD;
&#xD;
          -  Ability to perform assessments (there will be different assessments for ambulant and&#xD;
             non-ambulant patients).&#xD;
&#xD;
          -  Ability to attend scheduled investigations.&#xD;
&#xD;
          -  Informed consent to participate in the clinical outcome study.&#xD;
&#xD;
        NOTE: Funds are available to cover necessary hotel stays and travel costs to the study&#xD;
        centres for the participant and a helper (if needed).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known current or planned medical or other interventions that might interfere with the&#xD;
             possibility to undertake the planned tests.&#xD;
&#xD;
          -  Other concomitant pathology that in the view of the investigator would jeopardise the&#xD;
             ability to take part in the protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Volker Straub</last_name>
    <role>Principal Investigator</role>
    <affiliation>Newcastle University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Meredith K James</last_name>
    <role>Principal Investigator</role>
    <affiliation>Newcastle University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UC Irvine</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University Medical Center</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>944305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neurology &amp; Pathology, Washington University, School of Medicine in St Louis</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Centre</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Carolinas Medical Center, Neuroscience &amp; Spine Institute, Dept of Neurology</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28207</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Neuromuscular Center at the Research Institute of Nationwide Children's Hospital</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43230</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinica Davila</name>
      <address>
        <city>Santiago</city>
        <country>Chile</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rigshospitalet Neuromusculaer Klinik</name>
      <address>
        <city>Copenhagen</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut de Myologie</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Neurosciences, University of Padova</name>
      <address>
        <city>Padova</city>
        <zip>35128</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Center of Neurology and Psychiatry</name>
      <address>
        <city>Kodaira</city>
        <state>Tokyo</state>
        <zip>187-8551</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pusan National University Hospital</name>
      <address>
        <city>Busan</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Sant Pau, Neurology Department</name>
      <address>
        <city>Barcelona</city>
        <zip>08041</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Donostia</name>
      <address>
        <city>San Sebastián</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen del Rocio, IBiS, Neurology Department</name>
      <address>
        <city>Sevilla</city>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Translational and Clinical Research, Newcastle University, International Centre for Life</name>
      <address>
        <city>Newcastle upon Tyne</city>
        <zip>NE1 3BZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Chile</country>
    <country>Denmark</country>
    <country>France</country>
    <country>Italy</country>
    <country>Japan</country>
    <country>Korea, Republic of</country>
    <country>Spain</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Australia</country>
    <country>Germany</country>
  </removed_countries>
  <link>
    <url>http://www.Jain-foundation.org</url>
    <description>This study is fully funded by the Jain Foundation, a non-profit foundation whose mission is to cure muscular dystrophies caused by dysferlin protein deficiency.</description>
  </link>
  <link>
    <url>http://www.dysferlinoutcomestudy.org</url>
    <description>All information for this study can be found on the study website (www.dysferlinoutcomestudy.org), including contact details and participating sites</description>
  </link>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>August 28, 2012</study_first_submitted>
  <study_first_submitted_qc>August 28, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 30, 2012</study_first_posted>
  <last_update_submitted>July 21, 2022</last_update_submitted>
  <last_update_submitted_qc>July 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 26, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>LGMD2B/ LGMDR9</keyword>
  <keyword>Miyoshi Myopathy</keyword>
  <keyword>Dysferlin</keyword>
  <keyword>Dysferlinopathy</keyword>
  <keyword>Limb Girdle muscular dystrophy type 2b</keyword>
  <keyword>Muscular Dystrophy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Muscular Diseases</mesh_term>
    <mesh_term>Muscular Dystrophies, Limb-Girdle</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01676077
org study id: 85750
nct id: NCT01676077
lead sponsor: 
collaborator: 
has dmc: Yes
The "Clinical Outcome Study for Dysferlinopathy" is being performed in centres in Europe (UK-
      Newcastle; Spain- Barcelona, Sevilla; San Sebastian;Denmark, Copenhagen, Italy- Padova;
      France- Paris,), USA (Charlotte, NC; Columbus, OH; St.Louis, MO, Stanford CA, Irvine CA and
      Columbia NY), Chile (Santiago) Japan (Tokyo) and South Korea (Pusan). Oversight is provided
      by Newcastle upon Tyne Hospitals Trust. Funding for this study is being provided by the Jain
      Foundation, a non-profit foundation dedicated to finding therapies for
      dysferlinopathies(LGMD2b/Miyoshi). The aim of this "Clinical Outcome Study" is to determine
      the clinical outcome measures required for future clinical trials, characterize the disease
      progression of dysferlinopathy and collect biological samples for the identification of
      disease markers that are needed to non-invasively monitor the disease during clinical trials.
      Without this information, effective clinical trials cannot be performed.

      This study is recruiting a large number of genetically confirmed dysferlinopathy patients
      aged 10 years or older, who are ambulant or non-ambulant. The study has reopened for a
      further two years (COS2). Participants will be assessed at 4 further visits over 2 years via
      medical, physiotherapy, and MRI/MRS assessments, as well as standard blood tests. Optionally,
      the participants can donate blood samples and a skin sample for use in the identification of
      disease markers and other approved research. There is a sub-study running in MRI at selected
      sites.
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. To define the natural history of Dysferlinopathies with respect to age and nature of
           onset, progression and presence of complications.

        2. To determine the most suitable and robust outcomes measures for evaluation of disease
           progression in patients with Dysferlinopathy at different stages of the disease.

        3. To evaluate whether cardiac manifestations are clinically significant in patients with
           Dysferlinopathy.

        4. To explore if sodium MRI could be useful to identify muscle damage on skeletal muscle of
           patients with Dysferlinopathy
observational model: Cohort
time perspective: Prospective
measure: North Star assessment for limb girdle-type muscular dystrophies (NSAD)
time frame: 24 months
description: A functional scale that will be used to measure motor performance in individuals with LGMD
arm group label: Patients with a genetically confirmed dysferlinopathy
Serum, Plasma, DNA, RNA, Skin fibroblasts, Urine
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 10 Years
maximum age: N/A
healthy volunteers: No
last name: Volker Straub
role: Principal Investigator
affiliation: Newcastle University
last name: Meredith K James
role: Principal Investigator
affiliation: Newcastle University
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country: Chile
country: Denmark
country: France
country: Italy
country: Japan
country: Korea, Republic of
country: Spain
country: United Kingdom
country: United States
country: Australia
country: Germany
url: http://www.Jain-foundation.org
description: This study is fully funded by the Jain Foundation, a non-profit foundation whose mission is to cure muscular dystrophies caused by dysferlin protein deficiency.
url: http://www.dysferlinoutcomestudy.org
description: All information for this study can be found on the study website (www.dysferlinoutcomestudy.org), including contact details and participating sites
responsible party type: Sponsor
mesh term: Muscular Diseases
mesh term: Muscular Dystrophies, Limb-Girdle