J Clin Neurol.  2012 Sep;8(3):230-234. 10.3988/jcn.2012.8.3.230.

Leber's Hereditary Optic Neuropathy with Olivocerebellar Degeneration due to G11778A and T3394C Mutations in the Mitochondrial DNA

• Nakaso K
• Adachi Y
• Fusayasu E
• Doi K
• Imamura K
• Yasui K
• Nakashima

• KMID: 2287596
• DOI: http://doi.org/10.3988/jcn.2012.8.3.230

Abstract

BACKGROUND
Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of "LHON plus" have been reported.
CASE REPORT
The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations.
CONCLUSIONS
These results suggest that the combination of G11778A and T3394C mutations leads to an atypical LHON phenotype.

Keyword

Leber's hereditary optic neuropathy; Leber's hereditary optic neuropathy plus; mitochondria; inferior olivary nucleus; G11778A; T3394C

MeSH Terms

Adult
Atrophy
Brain
Cerebellar Ataxia
Cerebellum
DNA, Mitochondrial
Dysarthria
Gait
Humans
Mitochondria
Mitochondrial Diseases
Olivary Nucleus
Optic Atrophy, Hereditary, Leber
Optic Nerve
Orbit
Paralysis
Phenotype
DNA, Mitochondrial

Figure

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  Fig. 1 Pedigree of the family. The arrow indicates the proband.

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  Fig. 2 MRI findings of the orbit and brain (A-D: III-1; E-H: II-2). A: T1-weighted orbital MRI [repetition time (TR)/echo time (TE)=670/14 ms] showing atrophy of the bilateral optic nerves (arrows). B: Sagittal section of the T1-weighted brain MRI (TR/TE=670/14 ms) showing severe atrophy of the cerebellum (arrowhead) and hypointensities of the bilateral inferior olivary nucleus (arrow). C: T1-weighted brain MRI (TR/TE=670/14 ms) showing severe atrophy of the cerebellum and symmetric hypointensities of the bilateral inferior olivary nucleus (white arrow). D: T2-weighted brain MRI (TR/TE=3600/96 ms) showing symmetric hyperintensities of the bilateral inferior olive (black arrow). E: T1-weighted orbital MRI (TR/TE=670/14 ms) of II-2 showing atrophy of the bilateral optic nerves. F: Sagittal section of the T1-weighted brain MRI (TR/TE=670/14 ms) of I-1 showing mild atrophy of the brain stem and cerebellum (arrowhead). G and H: T2-weighted brain MRI (TR/TE=3600/96 ms) showing mild atrophy of the brain stem and cerebellum without degeneration of the inferior olivary nucleus.

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  Fig. 3 Analysis of the T3394C mutation in the mtDNA. Sequence data (A) and PCR-RFLP data (B) showing the homoplasmic T3394C mutation of mtDNA in both I-1 and II-1. The PCR product (176 bp) was digested using HaeIII to 97- and 79-bp fragments in CTL, but the T3394C mutation induced a new restriction site for HaeIII, and the 97-bp fragments were not observed in I-1 and II-1. CTL: control, mtDNA: mitochondrial DNA, PCR: polymerase chain reaction, RFLP: restriction fragment length polymorphism.

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  Fig. 4 Analysis of the G11778A mutation in the mtDNA. Sequence data (A) and PCR-RFLP data (B) showing the heteroplasmic G11778A mutation of mtDNA in both I-1 and II-1. The PCR product (2001 bp) was digested by Tsp45I to 1410- and 591-bp fragments in CTL, but the G11778A mutation induced a new restriction site for Tsp45I, and a portion of the 1410-bp fragment was further digested to 1212- and 188-bp fragments in I-1 and II-1. C: Semiquantitative analysis of G11778A heteroplasmy. The upper panel shows standard samples including 0%, 10%, 30%, 60%, 90%, and 100% of the G11778A mutation. The lower panel shows the data from III-1 and II-2. CTL: control, mtDNA: mitochondrial DNA, PCR: polymerase chain reaction, RFLP: restriction fragment length polymorphism.

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