Mitochondrial Disease Diagnosis

Overview of Mitochondrial Disease

Mitochondrial diseases are multisystemic energy failure states with extensive clinical and genetic heterogeneity. Their common basis is best understood through recognition that mitochondria function as biologic “fuel cells” or “batteries,” producing chemical energy in the form of adenosine triphosphate (ATP) by aerobic metabolism of nutrient-derived reducing equivalents, through the integrated function of the 5-complex mitochondrial respiratory chain (RC) ( Fig. 106.1 ). Mitochondria also play other essential roles that can be variably disrupted in disease states, such as regulating calcium homeostasis, diverse aspects of intermediary nutrient metabolism, nucleotide metabolism, and oxidative stress. Primary mitochondrial disease results from deficient RC function, which can be caused by mutations in genes that encode RC subunits, assembly factors or cofactors, components of mitochondrial DNA (mtDNA) metabolism and maintenance, or a host of other basic metabolic processes ongoing within mitochondria. Approximately 1,500 proteins exist within the mitochondrial proteome of different tissues, with variants in more than 350 unique genes across both the nuclear and the mitochondrial genomes already implicated as causal in human mitochondrial disease.

Collectively recognized as the most common group of inherited metabolic diseases, primary (genetic-based) mitochondrial disease has a combined minimal prevalence of 1 in 4,300 individuals across all ages. In addition, secondary mitochondrial dysfunction is broadly implicated in the pathogenesis of a host of complex diseases, ranging from metabolic syndrome to ischemia-reperfusion injury after stroke, to neurodegenerative diseases. Failure of high-energy demand organs in mitochondrial diseases may clinically present as severe neurodevelopmental, cardiac, myopathic, renal, hepatic, endocrine, immune, gastrointestinal, hearing, and vision disabilities, as well as global metabolic instability with lactic acidosis ( Fig. 106.2 ) (see Tables 105.2 and 105.3 ). In most mitochondrial disorders, the phenotype may vary depending on the patient's age or the specific gene or genetic variant. Particularly common mitochondrial disease clinical syndromes that present in children include Leigh syndrome (for which there are more than 90 causal genes), mtDNA depletion syndrome (MDS, for which there are dozens of causal genes), mtDNA deletion syndromes (Pearson, Kearns Sayre), primary lactic acidosis, and pyruvate dehydrogenase deficiency. Common clinical features in children present in at least 90 percent of patients include fatigue, exercise intolerance, weakness, gastrointestinal problems, ataxia, and developmental delay. Thus, mitochondrial diseases present to and must be considered by clinicians across every medical specialty.

Patients with suspected mitochondrial disease may frequently experience a diagnostic odyssey , both clinically and genetically. Their extensive phenotypic heterogeneity without a common biomarker (GDF-15 may be one screening test that may be elevated in some mitochondrial myopathies particularly involving mtDNA deletions or depletion, along with lactic acidosis) presents a challenge to the readily available and accurate clinical diagnosis of mitochondrial disorders in many medical settings. Similarly, their extensive genetic heterogeneity involving known etiologies in >300 nuclear genes and all 37 mitochondrial DNA (mtDNA) genes, with likely dozens to hundreds more causative nuclear disease genes awaiting discovery, can make the accurate genetic diagnosis of an individual patient challenging. The diagnostic uncertainty can be further compounded by poor genotype-phenotype correlations and variable clinical presentations of individual gene disorders, high locus heterogeneity (i.e., multiple different causal disease genes) for similar clinical phenotypes, incomplete penetrance for some gene disorders, variable life stressors or environmental exposures that may exacerbate a given child's disease, and the unique biologic aspects of maternal inheritance for the subset of mitochondrial diseases caused by mtDNA gene mutations.