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.
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.