Natural History in Primary Mitochondrial Myopathies (NHPMM)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Primary Mitochondrial Myopathies

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Cristina Domínguez González, MD, PhD; Phone Number: +34917792582; Email: Neuromuscular.hdoc@salud.madrid.org

Study Locations

• Spain
  • Madrid
    • Madrid, Madrid, Spain, 28041
      • Recruiting
      • Hospital Universitario 12 Octubre
      • Contact: Cristina Domínguez González, PhD; Phone Number: 4582 913 90 80 00; Email: cdgonzalez@salud.madrid.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with Primary Mitochondrial Myopathy with a genetic diagnosis

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Mitochondrial myopathy; Mitochondrial myopathy, confirmed genetically

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor Function (endurance)	6 minute walking test (6MWT)	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers	Analysis of levels of GDF15 y FGF21 annually	36 months
Levels of heteroplasmy	Analysis of levels of heteroplasmy annually	36 months
Motor Function (functional scale)	North Star Ambulatory Assessment (NSAA)	36 months
Muscle magenitc resonance image (MRI)	Quantification of the fat fraction in muscle MRI, annually	36 months

Collaborators and Investigators

• Sponsor: Cristina Domínguez González

Publications and helpful links

General Publications

• 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 Jul 16.
• 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/s00415-021-10957-0. Epub 2022 Mar 14.
• 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 Mutations. J Clin Med. 2021 Dec 22;11(1):22. doi: 10.3390/jcm11010022.
• 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. Epub 2020 Mar 11.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 29, 2022
• First Submitted That Met QC Criteria: December 7, 2022
• First Posted (Actual): December 16, 2022

Study Record Updates

• Last Update Posted (Estimated): September 16, 2025
• Last Update Submitted That Met QC Criteria: September 10, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: mtDNA; TK2; POLG; large scale single deletion; multiple deletions; TWNK
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Mitochondrial Diseases; Muscular Diseases; Mitochondrial Myopathies
• Other Study ID Numbers: 22/493

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No