MERRF Classification: Implications for Diagnosis, and Clinical Trials

Publication date: Available online 13 December 2017
Source:Pediatric Neurology
Author(s): Josef Finsterer, Sinda Zarrouk-Mahjoub, John M. Shoffner
ObjectivesGiven the etiologic heterogeneity of disease classification using clinical phenomenology, we employed contemporary criteria to classify variants associated with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome and to assess the strength of evidence of gene-disease associations. Standardized approaches are used to clarify the definition of MERRF which is essential for patient diagnosis, patient classification, and clinical trial design.MethodsSystematic literature and database search with application of standardized assessment of gene-disease relationships using modified Smith criteria and of variants reported to be associated with MERRF using modified Yarham criteria.ResultsReview of available evidence supports a gene-disease association for two MT-tRNAs and for POLG. Using modified Smith criteria, definitive evidence of a MERRF gene-disease association is identified for MT-TK. Strong evidence gene-disease evidence is present for MT-TL1 and POLG. Functional assays that directly associate variants with oxidative phosphorylation impairment were critical to mtDNA variant classification. In silico analysis was of limited utility to the assessment of individual MT-tRNA variants. Using contemporary classification criteria, several mtDNA variants previously reported as pathogenic/possibly pathogenic are reclassified as neutral variants.ConclusionsMERRF is primarily a MT-TK disease with pathogenic variants in this gene accounting for ~90% of MERRF cases. Although MERRF is phenotypically and genotypically heterogeneous, myoclonic epilepsy is the clinical feature that distinguishes MERRF from other categories of mitochondrial disorders. Given its low frequency in mitochondrial disorders, myoclonic epilepsy is not explained simply by an impairment of cellular energetics. Although MERRF phenocopies can occur in other genes, additional data is needed to establish a MERRF disease-gene association. This approach to MERRF emphasizes standardized classification rather than clinical phenomenology, thus improving patient diagnosis and clinical trials design.



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