Case Report/Case Series |

Near-Identical Segregation of mtDNA Heteroplasmy in Blood, Muscle, Urinary Epithelium, and Hair Follicles in Twins With Optic Atrophy, Ptosis, and Intractable Epilepsy

Achilles Spyropoulos, MRCP1; Mark Manford, FRCP2; Rita Horvath, MD1; Charlotte L. Alston, PhD3; Patrick Yu-Wai-Man, FRCOpth1; Langping He, PhD3; Robert W. Taylor, PhD3; Patrick F. Chinnery, FRCP, FMedSci1
[+] Author Affiliations
1Wellcome Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, England
2Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, England
3Wellcome Centre for Mitochondrial Research, Institute of Ageing and Health, Newcastle University, Newcastle Upon Tyne, England
JAMA Neurol. 2013;70(12):1552-1555. doi:10.1001/jamaneurol.2013.4111.
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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.

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Figure 1.
Serial Brain Magnetic Resonance Imaging From Twin 1

Magnetic resonance findings from twin 1 demonstrating a fluctuating leukoencephalopathy on serial imaging. Initial brain imaging demonstrates 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, arrows). Repeat imaging nearly 2 years later revealed resolution of the cortical and thalamic lesions (F-H).

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Figure 2.
Bilateral Optic Atrophy in Twin 1

Marked global thinning of the peripapillary retinal nerve fiber layer is seen in twin 1. Optical coherence tomographic measurements were obtained with the Topcon 3D OCT-2000 platform (Topcon Medical Systems). 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): red <1%, yellow 1%-5%, and green 5%-95%. I indicates inferior; N, nasal; S, superior; T, temporal.

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