The Spectrum of Maculopathy in Mitochondrial DNA A3243G Mutation: A Case Series of Six Patients

Abstract

Background The mitochondrial DNA (mtDNA) A3243G point mutation encompasses a heterogenous group of disorders including mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD), and, rarely, chronic progressive external ophthalmoplegia (CPEO). Regardless of the clinical phenotype, a specific retinopathy has been associated with the presence of this mitochondrial DNA mutation. We present six female patients exhibiting retinopathy of the A3243G point mutation at various stages. History and Signs Six female patients (37 – 70 years old) with the A3243G point mutation (four MELAS, one MIDD, and one CPEO) exhibited a maculopathy. Visual acuity ranged from 1/60 to 10/10. Visual field abnormalities varied from minimal decreased sensitivity to absolute central scotomas. They all exhibited, at various degrees, a characteristic pattern of perimacular and peripapillary retinal pigment epithelium (RPE) alterations, with mottled dys-autofluorescence and RPE atrophy and deposits on OCT. Therapy and Outcome The level of visual impairment depended on the foveal involvement and the extension of RPE atrophy. The severity of the maculopathy was not related to age. In the only long-term follow-up (15 years), evolution was slowly progressive. Conclusions A single mtDNA point mutation at locus 3243 can result in a variety of clinical presentations (MELAS, MIDD, or CPEO). Ocular involvement may manifest as a perimacular/peripapillary RPE atrophy/deposit, which can variably impact central visual function (from asymptomatic to legal blindness). The discovery of such a maculopathy should prompt the ophthalmologist to complete the personal and family history, namely, asking for the presence of diabetes mellitus and/or deafness.

m.3243A>G Maculopathy

“…We do not agree with the statement that "all mitochondrial disorders (MIDs) are strictly maternally inherited" [1]. In addition to the maternal trait, MIDs can follow an autosomal dominant, autosomal recessive, or X-linked trait of inheritance.…”

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With interest we read the article by Kaisari and Borruat about six female patients with maculopathy due to the mtDNA variant m.3243A>G [1]. Visual acuity ranged from 1/60 to 10/10, visual field abnormalities ranged from minimal decreased sensitivity to absolute central scotoma, and three patients exhibited variable degrees of characteristic perimacular and peripapillary retinal pigment epithelium abnormalities, with mottled dye autofluorescence and retinal pigment epithelium atrophy, and deposits on optic coherence tomography [1]. The study is appealing but raises a number of concerns.

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“…A third limitation is that no family history or genetic data of the six included patients was provided [1]. Since mtDNA mutations are transmitted via a maternal trait iñ 75 % of the cases [2], we should know in how many of the patients the genetic defect was inherited from the motherʼs side or occurred spontaneously.…”

Diagnosis of Kearns–Sayre syndrome requires genetic confirmation

“…A limitation of the study is that the diagnosis of KSS was not genetically confirmed. [ 1 ] KSS is commonly due to single mitochondrial DNA (mtDNA) deletions and rarely due to the variants m. 3243A >G[ 2 ] or m. 3249G >A. [ 3 ] Because ophthalmoparesis together with retinopathy may occur in several other syndromic and non-syndromic mitochondrial disorders,[ 4 ] it is crucial that the diagnosis KSS is substantiated by documentation of an appropriate pathogenic genetic defect.…”