Early Onset Leber Hereditary Optic Neuropathy Associated with Two Mitochondrial Mutations in ND4 and Cytochrome B

1. Leo Sheck^1,2
2. Stephen J Best²
3. Andrea L Vincent¹

¹Department of Ophthalmology, New Zealand National eye Centre, Faculty of Medical and Health Sciences, University of Auckland,
²Department of Ophthalmology, Greenlane Clinical Centre, Auckland District Health Board

Purpose
To report a case of Leber hereditary optic neuropathy (LHON) associated with two mitochondrial mutations, including one novel variant.

Methods
Routine history, clinical examination and visual fields were performed. Biological samples were obtained from the proband and family members for mitochondrial DNA sequencing by PCR and bidirectional fluorescent sequencing. The proband also underwent ECG, serum electrolytes, creatinine, creatine kinase, urine organic acid profile, and brain MRI.

Results
A 12-year-old boy presented with painless vision loss in the left eye over one month. Visual acuity measured 6/4.8 right eye, 6/38 left eye, with a left afferent pupil defect, and significant pallor of the left optic disc on fundus examination. Automated visual field (VF) testing showed a diffuse loss of field in left eye. Brain MRI was normal. Initial screening of the 8 most common LHON mutations was negative, but subsequently complete mitochondrial sequencing identified two homoplasmic changes in the proband's DNA - m.11253T>C resulting in p.ND4:Ile165Thr, and m.14970A>G resulting in p.CYTB:Tyr75Cys. The unaffected proband's mother and maternal grandmother were also homoplasmic for these changes. The m.11253T>C is previously reported causing LHON associated with Parkinsons disease. The m.14970A>G variant is novel and this nucleotide is conserved across species, the substitution results in the disruption of a ligand binding site, and Polyphen protein prediction deems this variant as 'probably damaging".

Conclusions
The presence of the novel Cytochrome B variant,m.14970A>G, possibly increases the pathogenicity of the ND4 mutation, resulting in an earlier onset of symptoms in LHON.