Aim: The North American Mitochondrial Disease Consortium (NAMDC) comprises a network of 17 clinical centers with a mission to conduct translational research on mitochondrial diseases. NAMDC is a part of the Rare Disease Clinical Research Network (RDCRN) and is funded by the National Institutes of Health. To foster its mission, NAMDC has implemented a comprehensive Mitochondrial Disease Clinical Registry (hereafter NAMDC Registry), collected biosamples deposited into the NAMDC Biorepository, defined phenotypes and genotypes of specific disorders, collected natural history data, identified outcome measures, characterized safety and long-term toxicity and efficacy of promising therapies, and trained young investigators interested in patient-oriented research in mitochondrial disease.

Methods: Research conducted by NAMDC is built on the foundation of the Clinical Registry. Data within the registry are encrypted and maintained in a centralized database at Columbia University Medical Center. In addition to clinical data, NAMDC has established a mitochondrial disease biorepository, collecting DNA, plasma, cell, and tissue samples. Specimens are assigned coded identifiers in compliance with all relevant regulatory entities and with emerging NIH guidelines for biorepositories. NAMDC funds two pilot projects each year. Pilot grants are small grants typically supporting an early stage concept to obtain preliminary data. Pilot grants must enhance and address major issues in mitochondrial medicine and specific areas of need for the field and for the successful outcome of NAMDC. The grant selection process is facilitated by input from multiple stakeholders including patient organizations and the strategic leadership of NAMDC. To train new mitochondrial disease investigators, NAMDC has established a Fellowship Program which offers a unique training opportunity to senior postdoctoral clinical fellows. The fellowship includes a 6-month period of intensive training in clinical trial methodology through the Clinical Research Enhancement through Supplemental Training program and equivalent programs at the other sites, along with rotations up to 3 months each to two additional consortium sites where a rich and varied training experience is provided. Nine core educational sites participate in this training program, each offering a summer grant program in mitochondrial medicine funded by our NAMDC partner the United Mitochondrial Disease Foundation (www.umdf.org). All clinical research in NAMDC depends on the participation of mitochondrial disease patients. Since individual mitochondrial disorders are often extremely rare, major communication and recruitment efforts are required. Therefore, NAMDC has forged a very close partnership with the premier patient advocacy group for mitochondrial diseases in North America, the United Mitochondrial Disease Foundation (UMDF).

Results: The NAMDC Registry has confirmed the clinical and genetical heterogeneity of mitochondrial diseases due to primary mutations in mitochondrial DNA or nuclear DNA. During the 8 years of this NIH-U54 grant, this consortium, acting in close collaboration with a patient advocacy group, the UMDF, has effectively addressed these complex diseases. NAMDC has expanded a powerful patient registry with more than 1600 patients enrolled to date, a website for education and recruitment of patients (www.namdc.org), a NAMDC biorepository housed at the Mayo Clinic in Rochester, MN, and essential diagnostic guidelines for consensus research. In addition, eight clinical studies have been initiated and the NAMDC fellowship program has been actively training the next generation of mitochondrial disease clinical investigators, of which six have completed the program and remain actively involved in mitochondrial disease research.

Conclusion: The NAMDC Patient Registry and Biorepository is actively facilitating mitochondrial disease research, and accelerating progress in the understanding and treatment of mitochondrial diseases.

Primary coenzyme Q₁₀ (CoQ₁₀) deficiency encompasses a subset of mitochondrial diseases caused by mutations affecting proteins involved in the CoQ₁₀ biosynthetic pathway. One of the most frequent clinical syndromes associated with primary CoQ₁₀ deficiency is the severe infantile multisystemic form, which, until recently, was underdiagnosed. In the last few years, the availability of genetic screening through whole exome sequencing and whole genome sequencing has enabled molecular diagnosis in a growing number of patients with this syndrome and has revealed new disease phenotypes and molecular defects in CoQ₁₀ biosynthetic pathway genes. Early genetic screening can rapidly and non-invasively diagnose primary CoQ₁₀ deficiencies. Early diagnosis is particularly important in cases of CoQ₁₀ deficient steroid-resistant nephrotic syndrome, which frequently improves with treatment. In contrast, the infantile multisystemic forms of CoQ₁₀ deficiency, particularly when manifesting with encephalopathy, present therapeutic challenges, due to poor responses to CoQ₁₀ supplementation. Administration of CoQ₁₀ biosynthetic intermediate compounds is a promising alternative to CoQ₁₀; however, further pre-clinical studies are needed to establish their safety and efficacy, as well as to elucidate the mechanism of actions of the intermediates. Here, we review the molecular defects causes of the multisystemic infantile phenotype of primary CoQ₁₀ deficiency, genotype-phenotype correlations, and recent therapeutic advances.

Electron paramagnetic resonance spectroscopy (EPR) is an analytical technique that, uniquely, can be used to directly interrogate flash-frozen tissue. Quantitative information on the thermodynamic potential of the mitochondrion to synthesize ATP, and the extent of reactive oxygen species-mediated oxidative stress on the mitochondrion and the cell at large, can be obtained. A compromised ability to synthesize ATP and oxidative stress are two of the characteristic sequelae of mitochondrial disease and therapeutic approaches may differ widely depending on which of these is dominant. EPR, therefore, has a role to play in the characterization, diagnosis, and ongoing evaluation of therapies for mitochondrial disease in human patients and model systems. An introduction to mitochondrial disease is followed by a description of EPR, a summary of the EPR signals that can be expected from tissue samples, sample preparation and analytical methods, and a case study in which EPR and complementary techniques were employed on a rat model to study human mitochondrial disease.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease caused by mutations in TYMP, the gene encoding for the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of thymidine and 2’-deoxyuridine and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. MNGIE is characterised by gastrointestinal dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, ptosis and leukoencephalopathy. The disease is progressively degenerative and leads to death at an average age of 37.6 years. Patients invariably encounter misdiagnoses, diagnostic delays, and non-specific clinical management. Despite its rarity, MNGIE has invoked much interest in the development of therapeutic strategies, mainly because it is one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation. This review provides a résumé of the current diagnosis and treatment approaches and aims to increase the clinical awareness of MNGIE and thereby facilitate early diagnosis and timely access to treatments, before the development of untreatable and irreversible organ damage.