Case suggests combination of genetic mutations leads to atypical LHON

The authors report the case of a 37-year-old man diagnosed with Leber's hereditary optic neuropathy (LHON) with olivocerebellar degeneration due to a heteroplasmic G11778A mutation in mitochondrial (mt) DNA ND4 and a homoplasmic T3394C mutation in the mtDNA NADH dehydrogenase (ND) 1 gene. They conclude that the combination of these mutations leads to an atypical LHON phenotype, inducing not only optic neuropathy but also degeneration of the olivocerebellar projections.

The patient had severe dizziness and double vision. His visual and gait disturbances had first appeared at age 10. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria and cerebellar ataxia.

MRI showed 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.

Although the thyrotropin-releasing drug taltirelin did not relieve his symptoms, adenosine triphosphate disodium reduced his dizziness.

The authors note that the most common mutation of LHON is G11778A in the mtDNA, which causes an arginine to histidine amino acid substitution in ND4. The patient also had the T3394C mutation, characterized as a mutation associated with LHON that is not common in LHON patients. They say that the significance of this mutation in LHON pathogenesis is not fully understood.

They conclude that the results suggest that LHON is not a monogenetic disease and that it requires additional factors to trigger its phenotypic expression. Since G11778A alone seldom induces disturbance in the central nervous system, coexistence with T3394C may play an important role in the appearance of olivocerebellar degeneration.