McNeill and colleagues describe a patient suffering from leukoencephalopathy, brain calcifications and cysts (LCC). Whole-exome sequencing identified compound heterozygous mutations in EARS2, a gene classically associated to leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). As in vitro functional testing supported pathogenicity of these mutations, and EARS2 protein levels were reduced by 70% in the patient's fibroblasts, the authors could conclude that EARS2 mutations can also be associated to LCC. An unrelated genetic investigation, however, revealed the presence of compound heterozygous mutations also in SNORD118, a gene classically associated to LCC.
1. Thanks to next-generation sequencing (NGS), it seems that rare and ultra-rare neurogenetic diseases are all knowledgeable, and easy to diagnose simply by sending DNA samples to the right laboratory.
2. This is likely true, but this way of thinking may discourage attitude for clinical reasoning and eventually lead to diagnostic oversimplification and errors. Moreover, diagnostic indicators may be overlooked and atypical findings improperly highlighted, especially when subspecialists are not consulted.
3. NGS is a great problem solver, but neurologists dealing with rare, usually genetic diseases should be careful to not switch from a mindful practice to a mindless one.
McNeill N, Nasca A, Reyes A, Lemoine B, Cantarel B, Vanderver A, Schiffmann R, Ghezzi D. Functionally pathogenic EARS2 variants in vitro may not manifest a phenotype in vivo. Neurol Genet. 2017; 3: e162.Pandolfo M. This variant alters protein function, but is it pathogenic? Neurol Genet 2017; 3: e173.Pulst SM. What does phenotype have to do with it? Neurol Genet. 2017; 3: e175.