Natural History in Primary Mitochondrial Myopathies

Официальное название

Natural History and Longitudinal Clinical Assessments in a Spanish Cohort of Primary Mitochondrial Myopathies

Обзор

This is a longitudinal study in a cohort of patients with a genetic diagnosis of Primary Mitochondrial Myopathy to describe the natural history of the disease and identify clinical, biochemical, molecular, and radiological variables that allow evaluation of the severity and progression of the disease and may be useful in future clinical trials.

Подробное описание

Mitochondrial Diseases (MD) are among the most frequent inherited metabolic diseases. Despite their high impact on patients, there are still no authorized drugs capable of modifying their clinical course. MD are clinically and genetically heterogeneous disorders, with muscular symptoms being one of their main manifestations. When muscular symptoms predominate, the disorder is classified as a Primary Mitochondrial Myopathy. In recent years, there have been significant advances in developing potential new treatments in this field. However, the absence of natural history studies makes the design and interpretation of clinical trials difficult and leads to long delays or even failures in the development of new treatments. The investigators propose to characterize in-depth a cohort of patients with Primary Mitochondrial Disorders due to mutations in the mitochondrial DNA (mtDNA) or in genes located in the nuclear genome (nDNA), from a clinical perspective but also a radiological, biochemical, and molecular point of view, and carry out a longitudinal follow-up of these parameters to identify those that are better correlated with severity and that allow measuring changes in the patient's clinical situation. With this objective, the investigators will analyze clinical variables (evaluation of motor function through manual force exploration, functional scales, and timed test, quality of life scales, serum biomarkers (growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21)), levels of heteroplasmy for cases harboring mtDNA mutations and mtDNA copy-number, and muscle magnetic resonance image of the lower extremities with quantification of fat replacement. All parameters will be evaluated at the beginning of the study and then annually during two years of follow-up.

Первичные конечные точки

• Motor Function (endurance) [Срок оценки: 36 months]

Вторичные конечные точки (4)

• Motor Function (functional scale) [Срок оценки: 36 months]
• Biomarkers [Срок оценки: 36 months]
• Levels of heteroplasmy [Срок оценки: 36 months]
• Muscle magenitc resonance image (MRI) [Срок оценки: 36 months]

Критерии участия

Критерии включения

• Muscle symptoms: exercise intolerance and fatigue, myalgia, recurrent rhabdomyolysis, chronic progressive external ophthalmoplegia and/or muscular weakness
• Primary mtDNA mutation or pathogenic mutations in nDNA, especially in genes related to mtDNA maintenance such as TK2, POLG, TWNK and RRM2B, among others.

Критерии исключения

• None

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Испания · 1 центр

• Hospital Universitario 12 Octubre — Madrid

Публикации

• Dominguez-Gonzalez C, Hernandez-Voth A, de Fuenmayor-Fernandez de la Hoz CP, Guerrero LB, Moris G, Garcia-Garcia J, Muelas N, Leon Hernandez JC, Rabasa M, Lora D, Blazquez A, Arenas J, Martin MA. Metrics of progression and prognosis in untreated adults with thymidine kinase 2 deficiency: An observational study. Neuromuscul Disord. 2022 Sep;32(9):728-735. doi: 10.1016/j.nmd.2022.07.399. Epub 2022 J PMID 35907766
• Dominguez-Gonzalez C, Fernandez-Torron R, Moore U, de Fuenmayor-Fernandez de la Hoz CP, Velez-Gomez B, Cabezas JA, Alonso-Perez J, Gonzalez-Mera L, Olive M, Garcia-Garcia J, Moris G, Leon Hernandez JC, Muelas N, Servian-Morilla E, Martin MA, Diaz-Manera J, Paradas C. Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis. J Neurol. 2022 Jul;269(7):3550-3562. doi: 10.1007/s00415- PMID 35286480
• Bermejo-Guerrero L, de Fuenmayor-Fernandez de la Hoz CP, Serrano-Lorenzo P, Blazquez-Encinar A, Gutierrez-Gutierrez G, Martinez-Vicente L, Galan-Davila L, Garcia-Garcia J, Arenas J, Muelas N, Hernandez-Lain A, Dominguez-Gonzalez C, Martin MA. Clinical, Histological, and Genetic Features of 25 Patients with Autosomal Dominant Progressive External Ophthalmoplegia (ad-PEO)/PEO-Plus Due to TWNK Mutati PMID 35011763
• Rodriguez-Lopez C, Garcia-Cardaba LM, Blazquez A, Serrano-Lorenzo P, Gutierrez-Gutierrez G, San Millan-Tejado B, Muelas N, Hernandez-Lain A, Vilchez JJ, Gutierrez-Rivas E, Arenas J, Martin MA, Dominguez-Gonzalez C. Clinical, pathological and genetic spectrum in 89 cases of mitochondrial progressive external ophthalmoplegia. J Med Genet. 2020 Sep;57(9):643-646. doi: 10.1136/jmedgenet-2019-106649. E PMID 32161153

Идентификаторы

NCT: NCT05653544 · 22/493

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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