Mitochondrial Myopathy Rating Scale

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Development and Validation of a Myopathy Rating Scale in Mitochondrial Disease

Conditions
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Primary Mitochondrial Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects confirmed to have definite nucleotide-binding protein-like (NUBPL)-disease of any age, gender, race, ethnicity or ambulatory status will be enrolled. Subjects may receive standard-of-care clinical support, including mitochondrial supplements. Subjects can be asymptomatic (e.g. carrier siblings of known NUBPL-patients) at time of study enrollment. Individual or parental informed consent and, if appropriate, assent must be provided. Exclusion Criteria: Subject does not have a pathogenic NUBPL variant. Unable to travel to Children's Hospital of Philadelphia (CHOP) for clinic visits. Actively enrolled in a drug trial and received study drug within 90 days of this study.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Nucleotide-binding protein-like (NUBPL)-Primary Mitochondrial Disease adult and child subjects<br>Any patient with NUBPL-Primary Mitochondrial Disease is eligible to be enrolled | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle Strength of MM-COAST | Muscle strength will be measured longitudinally by handheld dynamometry strength assessments to confirm muscle weakness in proximal and distal muscle groups. | Up to one year | 
| Balance of the MM-COAST | 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. | Up to one year | 
| Dexterity of the MM-COAST | Dexterity will be measured by 9 Hole Peg Test (9HPT) and Functional Dexterity Test (FDT). | Up to one year | 
| Mitochondrial Disease Burden for Adults | 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. | Up to one year | 
| Mitochondrial Disease Burden for Children | 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. | Up to one year | 
| Challenges in Activities of Daily Life (ADLs) | 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. | Up to one year | 
| Functional Tasks of the Mitochondrial Myopathy Functional Scale (MMFS) | 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) | Up to one year | 
| Clinical Progression: Survival | Patients will be marked as either alive or deceased at the time of a given visit date. | Up to one year | 
| Clinical Progression: Growth | 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. | Up to one year | 
| Clinical Progression: Other Illnesses | Patients will have other illnesses not related to their mitochondrial disease recorded along with date of diagnosis and stability. | Up to one year | 
| Clinical Progression: Hospitalizations | 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. | Up to one year | 
| Clinical Progression: Ambulatory Status | 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. | Up to one year | 
| Clinical Progression: Pacemaker Requirement | 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. | Up to one year | 
| Clinical Progression: Ventilatory Support | 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. | Up to one year | 
| Clinical Progression: Gastrostomy Status | 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. | Up to one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cerebellar Ataxia Outcome Measure for Primary Mitochondrial Disease (PMD) | 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. | Up to one year | 
| Clinical Meaningfulness of Ataxia Quantification. | 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. | Up to one year | 
| Evaluation of Health-Related Quality of Life by PedsQL | 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. | Up to one year | 
| Evaluation of daily functional activities by PEDI-CAT | 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. | Up to one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NUBPL, Mitochondrial Myopathy