Mitochondrial Myopathy Rating Scale

Children's Hospital of Philadelphia (Other)
Overall Status
Recruiting ID
University of Pennsylvania (Other), United Mitochondrial Disease Foundation (UMDF) (Other)

Study Details

Study Description

Brief Summary

Investigators have assembled an existing infrastructure of physical therapists, clinical coordinators and Bioinformatics; as well as expertise in developing and validating tools to measure disease course in a longitudinal study, to support completion of the proposed studies. Aim 1 serves to validate the Mitochondrial Myopathy Objective Assessment Tool (MM-COAST) and Mitochondrial Myopathy Functional Scale (MMFS) in nucleotide-binding protein-like (NUBPL)-subjects. Aim 2 aims to devise a Primary Mitochondrial Diseases (PMD)-specific cerebellar ataxia outcome measure for future clinical trials.

Nucleotide-binding protein-like (NUBPL)-Natural history data will be used to inform future interventional clinical trial design, while the validated MM-COAST, Mitochondrial Myopathy Rating Scale (MMRS) and newly devised PMD-ataxia scale would be utilized as meaningful quantitative outcome measures in future NUBPL-multicenter natural history and clinical trials.

Condition or Disease Intervention/Treatment Phase

    Detailed Description

    Currently, natural history knowledge is limited for all PMD. The clinical phenotype and disease course may be distinct depending on the PMD genetic etiology, however variability between family members harboring the same genetic mutation is also well described.

    No prospective cohort studies exist for nucleotide-binding protein-like (NUBPL)- disease. NUBPL is an assembly factor for human mitochondrial complex I, which is the initial step and largest of the mitochondrial respiratory chain complexes. Patients with NUBPL pathogenic variants have decreased complex I activity. Reported clinical features in NUBPL-disease includes developmental delay, ataxia, dysarthria, nystagmus, and gross motor regression. Accurate understanding of NUBPL- natural history is needed, not only to track disease course and to inform prognosis, but also to guide clinical trial design.

    A major barrier to precise documentation of clinical progression has been the absence of meaningful and validated PMD-specific outcome measures. The Principal Investigator (PI) of this proposal was awarded a United Mitochondrial Disease Foundation (UMDF) 2016 Clinical Grant Award to support development of a Mitochondrial Myopathy Rating Scale currently being validated (Preliminary Data), established a Mitochondrial Myopathy Objective Assessment Tool, MM-COAST, developed a PMD-specific Activity Factors Scale to standardize estimation of energy expenditure and was awarded a UMDF Early Stage Investigator Award (2019) to conduct a Mitochondrial Myopathy Natural History Study. The long-term goal of these cumulative studies is to promote robust PMD clinical trial design and drug approval, as facilitated by natural history data and validation of PMD-specific objective outcome measures that enable accurate quantitation of symptoms. The overarching hypothesis of this present proposal is that deeper understanding of NUBPL-natural history will promote meaningful clinical trial design. This proposal will utilize an existing Children's Hospital of Philadelphia (CHOP), Institutional Review Board (IRB) protocol (#16-013364, PI Zolkipli) and research infrastructure including physical therapists, biostatistician and bioinformatician for automated clinical data extraction from the medical record.

    Study Design

    Study Type:
    Observational [Patient Registry]
    Anticipated Enrollment :
    20 participants
    Observational Model:
    Time Perspective:
    Official Title:
    Development and Validation of a Myopathy Rating Scale in Mitochondrial Disease
    Actual Study Start Date :
    Mar 24, 2017
    Anticipated Primary Completion Date :
    Mar 24, 2023
    Anticipated Study Completion Date :
    Mar 24, 2023

    Arms and Interventions

    Arm Intervention/Treatment
    Nucleotide-binding protein-like (NUBPL)-Primary Mitochondrial Disease adult and child subjects

    Any patient with NUBPL-Primary Mitochondrial Disease is eligible to be enrolled

    Outcome Measures

    Primary Outcome Measures

    1. Muscle Strength of MM-COAST [Up to one year]

      Muscle strength will be measured longitudinally by handheld dynamometry strength assessments to confirm muscle weakness in proximal and distal muscle groups.

    2. Balance of the MM-COAST [Up to one year]

      Balance will be measured by: (1) Standing tandem with eyes closed, (2) Standing tandem with eyes open, and (3) Single leg stand with eyes closed tests.

    3. Dexterity of the MM-COAST [Up to one year]

      Dexterity will be measured by 9 Hole Peg Test (9HPT) and Functional Dexterity Test (FDT).

    4. Mitochondrial Disease Burden for Adults [Up to one year]

      All subjects will complete the 'gold standard' Newcastle Scale of disease burden. Newcastle Adult Scale (NMDAS): Each question in the NMDAS has a possible score from 0-5. Each of the first 3 section scores are calculated by simply summing the scores obtained for each question in that section. The higher the score the more severe the disease. The quality of life section has separate scoring.

    5. Mitochondrial Disease Burden for Children [Up to one year]

      All subjects and their parents will complete the 'gold standard' Newcastle Scale of disease burden. Newcastle Pediatric Scale (NPMDS): NPMDS is scored by section and the final (total) score is the sum of all section scores. The section scores vary by age group (0-24 months, 2-11 years, and 12-18 years). Maximum possible total NPMDS scores are 95 for subjects under 24 months of age and 107 for those between two and 18 years of age. Higher scores indicate worse conditions.

    6. Challenges in Activities of Daily Life (ADLs) [Up to one year]

      All subjects and their parents will complete the Karnofsky-Lansky score to assess functional abilities at each visit. Karnofsky Lansky Scale: 0-100. 0-40: Unable to care for self, requires equivalent of institutional or hospital care; disease may be progressing rapidly. 50-70: Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed. 80-100: Able to carry on normal activity and to work; no special care needed.

    7. Functional Tasks of the Mitochondrial Myopathy Functional Scale (MMFS) [Up to one year]

      The MMFS (In Person and Telemedicine Versions) will be used to quantify motor performance in NUBPL-disease in abilities to complete functional tasks such as standing, walking and gait. MMFS data will be correlated using Pearson correlation coefficient to Newcastle and Karnofsky scores, and objective measures to assess for clinical meaning. MMFS Scale: 3: Able (fully meets criteria); 2: Moderately Able (partially meets, some compensation needed); 1: Minimally Able (significant compensation needed); 0: Unable MMFS Totals: In-person Version: Total score: */ 66 (max score), Telemedicine Version: Total score: */54 (max score)

    8. Clinical Progression: Survival [Up to one year]

      Patients will be marked as either "alive" or "deceased" at the time of a given visit date.

    9. Clinical Progression: Growth [Up to one year]

      Patients will have their vitals recorded at the date of visit to obtain BMI (Kg/m^2)) measurement, Height (m) and weight (kg) are required to calculate BMI.

    10. Clinical Progression: Other Illnesses [Up to one year]

      Patients will have other illnesses not related to their mitochondrial disease recorded along with date of diagnosis and stability.

    11. Clinical Progression: Hospitalizations [Up to one year]

      Patients will have prior hospitalizations counted and recorded. Any hospitalizations occurring within a year from the visit date will have specific information recorded including the dates of admission and discharge, and the reasons for admission and discharge.

    12. Clinical Progression: Ambulatory Status [Up to one year]

      Patients will have their ambulatory status assessed by recording whether or not they can take 5 steps on their own. Patients' use of different kinds of wheelchairs will be recorded (manual, power assist, or power wheelchair or scooter) along with whether they are able to ambulate in the community or only in the household.

    13. Clinical Progression: Pacemaker Requirement [Up to one year]

      As part of a patient's cardiopulmonary exercise test (CPET), pacemaker status will be assessed, and if a patient utilizes a pacemaker, it's make, model, and settings will be recorded.

    14. Clinical Progression: Ventilatory Support [Up to one year]

      As part of a patient's respiratory history, ventilatory support status will be assessed by recording whether a patient uses the any of the following respiratory equipment: cough assist device, non-invasive ventilation including continuous positive airway pressure (CPAP) and Bi-pap, chest percussion, suctioning devices, other ventilation devices.

    15. Clinical Progression: Gastrostomy Status [Up to one year]

      As part of a patient's nutritional assessment, a patient's gastrostomy status will be assessed by determining whether a patient utilizes a gastrostomy tube (or g-tube), when they had their g-tube placed and why, and whether it resulted in weight gain.

    Secondary Outcome Measures

    1. Cerebellar Ataxia Outcome Measure for Primary Mitochondrial Disease (PMD) [Up to one year]

      Investigators will utilize a similar approach to development of the MM-COAST and MMFS and systematically collate and administer existing ataxia scales, focusing on quantitation of cerebellar ataxia, dysarthria and tremor, and introduce modifications to ensure PMD-specificity of this outcome measure. Once developed, investigators will administer the devised ataxia scale to the NUBPL subjects at every clinic visit, where the time to completion and modifications needed are assessed. Further iterations of the ataxia scale will be re-assessed in the NUBPL-subjects at every clinic visit and compared to the performance of the scale in PMD patients with other genetic etiologies. Participants will be instructed to refrain from strenuous exercise 24 hours prior to each visit. Feasibility and testing reproducibility of the PMD-ataxia scale will be evaluated at 2 different time points. The ataxia scale will be developed in months 0-6 and administered in months 6-12 of the 1-year project period.

    2. Clinical Meaningfulness of Ataxia Quantification. [Up to one year]

      All subjects will complete the following patient/parent-reported surveys: Newcastle Adult Scale (NMDAS) has 3 section scores that are calculated by summing the scores of each question (0-5). The Newcastle Quality of Life (Section IV) has separate scoring. Newcastle Pediatric Scale (NPMDS) is scored by section(scores vary by age group) and the final (total) score is the sum of all section scores. The maximum possible total NPMDS scores are 95 for subjects under 24 months of age and 107 for those 2-18 years of age. In both, higher scores indicate worse conditions. Karnofsky Lansky Scale is scaled 0-100. 0-40: unable to care for self, 50-70: unable to work; able to live at home, care for most personal needs, 80-100: Able to carry on normal activity and work; no special care needed. To assess if the quantified ataxia scores will be clinically meaningful: correlation to the 'gold standard' Newcastle Scale of disease severity and MM-COAST objective assessments in Aim 1 will be assessed.

    3. Evaluation of Health-Related Quality of Life by PedsQL [Up to one year]

      PedsQL is a 23-item questionnaire that evaluates health-related quality of life that is reported as a total score and 3 summary scores that include Physical Health, Psychosocial Health and School/Work with a higher score indicating better quality of life. The range for the scores are 0-100.

    4. Evaluation of daily functional activities by PEDI-CAT [Up to one year]

      The Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT) is a test that evaluates daily functional activities. A t-score of 50 represents the function of the general population (SD of 10). A t-score below 30 reflects poor performance compared to the general population. The range for the scores are 20-80.

    Eligibility Criteria


    Ages Eligible for Study:
    6 Years and Older
    Sexes Eligible for Study:
    Inclusion Criteria:
    1. All subjects confirmed to have definite nucleotide-binding protein-like (NUBPL)-disease of any age, gender, race, ethnicity or ambulatory status will be enrolled.

    2. Subjects may receive standard-of-care clinical support, including mitochondrial supplements.

    3. Subjects can be asymptomatic (e.g. carrier siblings of known NUBPL-patients) at time of study enrollment.

    4. Individual or parental informed consent and, if appropriate, assent must be provided.

    Exclusion Criteria:
    1. Subject does not have a pathogenic NUBPL variant.

    2. Unable to travel to Children's Hospital of Philadelphia (CHOP) for clinic visits.

    3. Actively enrolled in a drug trial and received study drug within 90 days of this study.

    Contacts and Locations


    Site City State Country Postal Code
    1 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104

    Sponsors and Collaborators

    • Children's Hospital of Philadelphia
    • University of Pennsylvania
    • United Mitochondrial Disease Foundation (UMDF)


    • Principal Investigator: zarazuela zolkipli-cunningham, MBChB, Children's Hospital of Philadelphia

    Study Documents (Full-Text)

    None provided.

    More Information


    Responsible Party:
    Children's Hospital of Philadelphia Identifier:
    Other Study ID Numbers:
    • 16-013364
    First Posted:
    Feb 22, 2022
    Last Update Posted:
    Apr 29, 2022
    Last Verified:
    Apr 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Studies a U.S. FDA-regulated Device Product:
    Keywords provided by Children's Hospital of Philadelphia
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Apr 29, 2022