Expanding the clinical phenotype of the mitochondrial m.13513G>A mutation with the first report of a fatal neonatal presentation: importance of DNA collection for post‐mortem diagnosis

The evolving symbiotic union of infectious prokaryotes and eukaryotic hosts has led to the presence of mitochondria within cells. The mitochondria are now recognized to be of central importance in the milieu of cellular metabolism and transport where they carry out a variety of functions, ranging from disposal of toxic substances to the storage of excess energy as fat. The ubiquity of mitochondria results in the potential for any tissue to dysfunction in the context of an inborn metabolic defect of the respiratory chain. The universal role of the mitochondria is in the process of oxidative phosphorylation (OXPHOS), which is the transformation of energy from the breakdown of nutrients in the presence of oxygen to the synthesis of adenosine triphotphate (ATP). After the discovery of the first human mitochondrial disorders and realization that mutations in mitochondrial and nuclear DNA are associated with these conditions, a new field was born. Mitochondrial diseases are difficult to identify because of the variable presentations involving multiple combinations of organ systems, age at onset, and range of severity from mild to severe. Mitochondrial disorders may begin at birth or not occur until adult life, often precipitated by illness or other significant metabolic stressors. Debilitating or fatal forms are more frequent in children than in adults, but adults often have chronic multi-systemic manifestations requiring symptomatic treatment and long-term surveillance to minimize life-threatening episodes of acute illness. The central and peripheral nervous systems engender some of the body’s most metabolically demanding cells, highly dependent upon ATP produced by OXPHOS. Thus, the nervous system is more often frequently involved in patients with mitochondrial disease. Symptoms differ depending on the part of the nervous system affected, although almost any neurological symptom can be due to mitochondrial disease. For clinicians to predict and ultimately prevent transmission of mitochondrial disorders knowledge about mitochondrial genetics and cell biology of mitochondrial DNA (mtDNA) inheritance is critical, in particular the genetic bottleneck which accounts for the segregation of mtDNA in the female germline. A key aspect of mitochondrial transmission genetics, whose importance has only begun to be recognized rather recently, concerns the highly dynamic nature of the mitochondria, which undergo fission, fusion, and intracellular movement in the majority of cell types. van Karnebeek et al. present a fatal presentation of the mitochondrial m.13513G>A mutation with the first report of a fatal neonatal presentation. This mutation was initially reported as causal of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, but subsequently has been described in patients with other phenotypes with hypotonia, ptosis, and ataxia being the recognizable symptoms. In the newborn, the repertoire of responses to illness are typically limited and include poor feeding, poor temperature regulation, tone, and central nervous system effects such as seizures and encephalopathy. If the infant dies prior to diagnosis, valuable information may be preserved if blood and tissues are obtained for post-mortem diagnosis. This information will be helpful to bring closure as well as to provide genetic counseling for other family members, either those currently suspected to have a mitochondrial disorder or those at risk. Given the advances in mitochondrial genetics, mutations are being recognized with increasing pace. What was once unknown a year ago, may be understood to be due to a defined sequence alteration in DNA. Therefore, in acutely ill patient cases where the diagnosis is suspected, but not proven, it is valuable to collect blood for future studies. This blood can be used for DNA banking, as a resource for future mtDNA and nuclear gene testing. DNA from non-invasive sample types such as hair follicles, buccal cells, and urine epithelial cells can also be useful, as the sensitivity of testing for some mtDNA mutations is higher in these sample types than in blood and is also due to heteroplasmy. Since most pathogenic mtDNA mutations are heteroplasmic, quantification of mutation heteroplasmy is important to correlate with disease expression. Availability of lower-cost, higher-throughput technologies for DNA analysis will facilitate mitochondrial diagnostic investigations.