Expert Clinical Perspectives: Diagnosis of Primary Mitochondrial Diseases-Article

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The article discusses the challenges and advancements in diagnosing primary mitochondrial diseases (PMDs), which are rare, genetically heterogeneous disorders with diverse clinical symptoms, including fatigue, exercise intolerance, and multisystem involvement. The authors emphasize the importance of a "genetics first" diagnostic approach, which significantly reduces diagnostic delays and improves disease management compared to traditional methods that relied heavily on muscle biopsies and biochemical tests.<br /><br />Mitochondrial function relies on both nuclear and mitochondrial DNA, making diagnosis complex due to the over 350 genes implicated in PMDs. The genetic approach prioritizes molecular testing, such as whole exome sequencing (WES) and whole genome sequencing (WGS), which allow for a more comprehensive analysis of DNA mutations that could lead to PMDs. These methods also help in identifying variants of uncertain significance and inform reproductive planning and clinical trials.<br /><br />Clinically, PMDs can manifest in multiple systems, including neurological, muscular, endocrine, ophthalmic, gastrointestinal, and cardiovascular systems. Common syndromes associated with PMDs, such as MELAS, MERRF, and Leigh syndrome, have specific genetic mutations, and their diagnosis can greatly benefit from neuroimaging and histological muscle analyses.<br /><br />The authors assert that while new molecular techniques have revolutionized the diagnosis of mitochondrial diseases, challenges remain, including high data volumes from genetic tests and ethical concerns over incidental findings. They recommend a broad diagnostic pathway using molecular testing in conjunction with clinical phenotyping and traditional tests like muscle biopsies. This integrated approach aims to enhance diagnostic accuracy and patient management, emphasizing the need for genetic counseling and ongoing research to better understand these complex diseases.

Keywords

primary mitochondrial diseases

genetic diagnosis

whole exome sequencing

whole genome sequencing

MELAS syndrome

MERRF syndrome

Leigh syndrome

genetic counseling

molecular testing

diagnostic challenges