Krankenanstalt Rudolfstiftung, Vienna, Austria.
University of Tunis El Manar and Genomics Platform, Pasteur Institute of Tunis, Tunisia.
Pediatr Neurol. 2018 Mar;80:8-23. doi: 10.1016/j.pediatrneurol.2017.12.005. Epub 2017 Dec 13.
Given 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.
Systematic 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.
Review 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 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. With the use of contemporary classification criteria, several mtDNA variants previously reported as pathogenic or possibly pathogenic are reclassified as neutral variants.
MERRF is primarily an MT-TK disease, with pathogenic variants in this gene accounting for ~90% of MERRF patients. 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 are 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 trial design.
鉴于采用临床表型学对疾病分类的病因异质性，我们采用了当代标准来对与肌阵挛性癫痫伴破碎红纤维（MERRF）综合征相关的变异进行分类，并评估基因-疾病关联的证据强度。标准化方法用于澄清 MERRF 的定义，这对于患者诊断、患者分类和临床试验设计至关重要。
系统文献和数据库搜索，并应用改良的 Smith 标准评估基因-疾病关系，以及应用改良 Yarham 标准评估与 MERRF 相关的变异。
对现有证据的审查支持两种 MT-tRNAs 和 POLG 与疾病的关联。使用改良的 Smith 标准，确定 MT-TK 与 MERRF 之间存在基因-疾病关联。MT-TL1 和 POLG 存在强烈的基因-疾病证据。直接将变异与氧化磷酸化损伤相关联的功能测定对于 mtDNA 变异分类至关重要。基于计算机的分析对于评估个别 MT-tRNA 变异的作用有限。使用当代分类标准，以前报告为致病性或可能致病性的几种 mtDNA 变异被重新分类为中性变异。
MERRF 主要是一种 MT-TK 疾病，该基因的致病性变异占 MERRF 患者的~90%。尽管 MERRF 在表型和基因型上存在异质性，但肌阵挛性癫痫是将 MERRF 与其他线粒体疾病分类区分开来的临床特征。鉴于其在线粒体疾病中的低频率，肌阵挛性癫痫不能简单地用细胞能量代谢受损来解释。尽管 MERRF 表型可以发生在其他基因中，但需要更多的数据来建立 MERRF 疾病-基因关联。这种 MERRF 方法强调标准化分类而不是临床表型学，从而改善了患者的诊断和临床试验设计。
