Clinical diagnosis in the era of DNA testing

Abstract

An exchange of letters in this issue of Documenta Ophthalmologica highlights the tension which arises as we incorporate the results of genetic testing into the diagnosis of patients on clinical grounds (Finsterer and Zarrouk-Mahjoub, Letter to the Editor, ‘‘Diagnosing MELAS requires not only an mtDNA variant but also an appropriate phenotype’’, and the Reply by Ozawa et al., authors of the original case report, ‘‘Retinal dystrophy associated with a single-base deletion mutation in mitochondrial DNA 3271 in patient with MELAS syndrome.’’ Ozawa K, Mochizuki K, Manabe Y, Yoshikura N, Shimohata T, Nishino I, Goto YI. Doc Ophthalmol. 2019 Jan 30. https://doi.org/10. 1007/s10633-019-09673-y. [Epub ahead of print]). ‘‘MELAS’’ (i.e. Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and recurrent cerebral episodes resembling Strokes) was proposed as a new syndromic entity by Pavlakis et al. [1]. They reported on two patients, and identified nine others in the existing literature, characterized by ‘‘ragged red fibers evident on muscle biopsy, normal early development, short stature, seizures, and hemiparesis, hemianopia, or cortical blindness, with lactic acidemia as a common finding.’’ The most common causative mitochondrial mutation—3243A-G transition in MTTL1—was first identified by Goto et al. [2], though several other mitochondrial mutations have also been reported. Of course, the clinical presentations of these various patients, even those of the original cohort, have differed in detail. It is thus not surprising that different investigators may choose to emphasize different sets of features as the ‘‘key’’ findings in applying the label ‘‘MELAS’’ to these patients. Finsterer and Bastovansky [3] have suggested the term ‘‘MIMODS’’ (MItochondrial Multiorgan Disorder Syndrome) for those patients with mitochondrial disorders which do not fit any of the more than 50 acronyms which stand for specific mitochondrial syndromes, but it is not clear that this suggestion has been widely adopted. On the other hand, Ozawa and colleagues originally chose to label their patient as having ‘‘MELAS’’ based on a subset of the list of findings typical of MELAS patients, together with identification of a mitochondrial deletion mutation (m.3271delT) reported in a minority of MELAS patients [4]. The discrepancy is a manifestation of the everevolving state of our ability to name and classify diseases (‘‘nosology’’). The historical approach has necessarily been based on clinical findings but has always evolved with the availability of new diagnostic tools—indeed, this journal has been dedicated to the elucidation of one such family of diagnostic tools, clinical electrophysiology of vision. With the S. E. Brodie (&) NYU Langone Health, New York, NY, USA e-mail: [email protected]