The Effect of Neurological Genomics and Personalized Mitochondrial Medicine

Abstract

Genetic diagnostics have undergone a revolution in the last decade, fueled by technological advances heralded by the development of massively parallel DNA sequencing. Within a remarkably short time, the new chemistry moved from the research laboratory into clinical practice, accelerating the pace of gene discovery and allowing the rapid diagnosis of genetic disorders on an unprecedented scale. There is a strong argument that so-called next or third generation sequencing will have the greatest effect in neurology, which is characterized by a seemingly endless list of discrete clinical syndromes, many thought to have a unique genetic basis. Until 2011, clinical neurogenetic practice has been frustrating. It has been difficult to screen more than a handful of the known genetic causes of a particular disorder, but we now face the real prospect of a reaching genetic diagnosis for every patient walking to the clinical door. Mitochondrial disorders provide a good illustration of the effect of this new technology in neurogenetic practice.Mitochondrial disorders are the bane of the generalist. The myriad of clinical features overlap with common neurological and nonneurological diseases. Despite entering the differential diagnosis of the most common neurological diseases, mitochondrial disorders themselves are rare, and the diagnostic approach is complex, time consuming, and expensive. Following a detailed history, examination, and clinical investigations, many patients require an invasive biopsy of clinically affected tissue before samples are dispatched on ice to a limited number of laboratories worldwide. Although a positive biochemical result can substantiate a clinical diagnosis (muscle histochemistry or respiratory chain complex analysis), the results are often inconclusive. Subtle histochemical defects can occur as part of healthy aging, and individuals deconditioned from any cause can have low respiratory chain enzyme activities in skeletal muscle. However, pursuing a genetic diagnosis is important because similar clinical and biochemical phenotypes can be sporadic, maternally inherited (through mitochondrial DNA [mtDNA]), autosomal dominant, autosomal recessive, and occasionally X-linked. Thus, defining the underlying gene defect can sway the recurrence risks from zero to very high and everything in between. Targeted genetic analysis typically proceeds on a stepby-step basis, guided by the clinical picture and the biochemical profile. A thorough laboratory workup takes months or years and is still inconclusive in approximately one-third of cases. If ever there was a need for a genetic revolution, mitochondrial disorders have a strong case.