tRNA variants causing Leber’s hereditary optic neuropathy?

Abstract

Letter to the Editor We read with interest the article by Shuai et al. about 138 patients with Leber’s hereditary optic neuropathy (LHON) who did not carry any of the three classical LHON mtDNA variants [1]. In 23 of these patients, 8 pathogenic tRNA variants were made responsible for the LHON phenotype [1]. It was concluded that certain tRNA variants cause LHON [1]. The study is appealing but raises the following comments and concerns. Pathogenicity of the eight tRNA variants suspected to have caused LHON is questionable. In table 4, pathogenicity of the variant m.15927G > A according to the Yarham score was assessed as 12 (“definitively pathogenic”) [1]. However, evidence of complex I, III, or IV deficiency counts maximally 2 points in the Yarham score [2]. Thus, the score for this variant is 9, while the variant is only “possibly pathogenic.” Unfortunately, Yarham scores were not provided for the other six tRNA variants made responsible for LHON [1]. The variant m.14693A > G was only reported as a haplogroup specific penetrance enhancer of LHON [3], respectively, as secondary LHON mutation [4]. Variant m.5587 T > C was found in 2 Chinese families with LHON and only assessed as potentially pathogenic [5]. Variant m.4435A > G has been reported only in association with arterial hypertension [6]. Variant m.3275C > T is unreported, and variant m.593 T > C was associated with hearing loss and described as secondary LHON mutation [7, 8]. LHON may not only affect the retinal ganglion cells but also other tissues or organs (LHON plus) [9]. To diagnose LHON plus prospective investigations for multisystem disease are crucial. Excluding “hearing loss, diabetes, cancer, or other mitochondrial diseases,” as has been done in the present study [1], is not sufficient. We should know if patients with LHON due to tRNA variants more frequently presented with LHON plus as compared to patients carrying one of the three classical LHON mutations. Patients carrying pathogenic tRNA variants frequently present with multisystem disease [10]. We should know how many of the included patients manifested in organs other than the eyes and which organs were affected in these patients. The standard therapy for LHON patients is idebenone (900 mg/day). We should know how many of the 23 patients carrying tRNA variants received idebenone and if idebenone was beneficial or not. We should know if idebenone had a similar effect as in patients carrying one of the three classical LHON mutations. Were there spontaneous remissions? A further limitation of the study is that no heteroplasmy rates and no mtDNA copy numbers were provided. Knowing heteroplasmy rates is crucial as it can strongly determine the phenotype. Though classical LHON mutations usually occur in the homoplasmic state, tRNA variants are usually heteroplasmic, which may explain variable disease expression in different mutation carriers. We should be told how to explain the variable phenotypic expression of the 8 pathogenic tRNA variants in previous and the present studies. Overall, the study has several limitations which challenge the results and their interpretation. Pathogenicity of the 8 variants needs to be demonstrated by application of the Yarham scores to all of them. An explanation for the phenotypic heterogeneity of the 8 variants should be provided.