Near-identical segregation of mtDNA heteroplasmy in blood, muscle, urinary epithelium, and hair follicles in twins with optic atrophy, ptosis, and intractable epilepsy

Abstract

Importance: Mitochondrial DNA (mtDNA) disorders have emerged as major causes of inherited neurologic disease. Despite being well recognized for more than 2 decades, the clinical presentation continues to broaden. The phenotypic heterogeneity is partly owing to different percentage levels of mutant mtDNA heteroplasmy in different tissues, but the factors influencing this are poorly understood.

Observations: This case report describes monozygotic male twins with ptosis, optic atrophy, and recent-onset intractable myoclonic epilepsy. The assessment of respiratory chain enzyme activities in the muscle from 1 twin revealed a severe and isolated defect involving mitochondrial complex I. Mitochondrial DNA sequencing revealed a pathogenic m.14487T>C MTND6 mutation, which was present at very high levels of heteroplasmy in muscle (84%) and lower levels in blood (15%), urinary epithelium (75%), and buccal mucosa (58%). Of particular interest, his identical twin was found to harbor very similar levels of the m.14487T>C mutation in his blood, urine, buccal mucosa, and hair follicle DNA samples, while the presence of low levels in the mother's tissues confirmed maternal transmission.

Conclusions and relevance: It was shown that m14487T>C can also cause the unusual combination of optic atrophy, ptosis, and encephalomyopathy leading to intractable seizures. Near-identical heteroplasmy levels in different tissues in both siblings support a nuclear genetic mechanism controlling the tissue segregation of mtDNA mutations.

Figure 1. Serial brain MR imaging from Twin 1.

MR findings from Twin 1 demonstrating a fluctuating leucoencephalopathy on serial imaging. Initial brain imaging demonstrated a left posteromedial thalamic lesion and bilateral cortical lesions (A-D, arrows). Repeat imaging 8 months later, revealed a right posteromedial thalamic lesion and a new right superior temporal lesion (E, arrow). Repeat imaging, nearly 2 years later, revealed resolution of the cortical and thalamic lesions (F-H).

Figure 2. Bilateral optic atrophy in Twin 1.

Marked global thinning of the peripapillary retinal nerve fibre layer in Twin 1. OCT measurements were obtained with the Topcon 3D OCT-2000™ platform (Topcon Medical Systems, Oakland, NJ). The analysis software automatically selects the appropriate normative range for the patient and the peripapillary retinal nerve fiber layer measurements (dark traces) are represented within color-coded distribution centiles (bottom panel): (i) red < 1%, (ii) yellow 1-5%, and (iii) green 5-95%.