Author Response: Use of Whole-Genome Sequencing for Mitochondrial Disease Diagnosis

We strongly agree with Dr. Schon and Prof. Chinnery that alpha-methylacyl-CoA racemase (AMACR) deficiency should be considered in the differential diagnosis of patients presenting with combinations of stroke-like episodes, seizures, encephalopathy, and retinal pigmentary changes.(1) As described in our study,(1) causative AMACR variants in patients with clinical features suggestive of mitochondrial disease highlight a broader issue of mitochondrial disease phenocopies that require consideration by a comprehensive sequencing approach for suspected mitochondrial disease cases. Examples of this include 3 individuals from 2 families in our study,(1) 3 individuals in the 100,000 Genomes Project,(2) an individual in the study by Theunissen et al,(3) and a recent case of an individual with late-onset disease associated with stroke-like episodes and seizures.(4)

Automated summary

We strongly agree that alpha-methylacyl-CoA racemase (AMACR) deficiency should be considered in patients with combinations of stroke-like episodes, seizures, encephalopathy, and retinal pigmentary changes. Our study and other case reports highlight the importance of a comprehensive sequencing approach to identify mitochondrial disease phenocopies. Such phenocopies include individuals with causative AMACR variants, as well as those from other studies and projects.