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Leber hereditary optic neuropathy (LHON) sometimes occurs with dystonia1 in association with mitochondrial DNA (mtDNA) mutations in complex I.2 We describe a patient with LHON plus dystonia who had a severe complex I respiratory defect with no pathological mtDNA mutation, implying a mitochondrial abnormality of nuclear origin.
The proband was healthy until age 17 years when she developed progressive right sided weakness followed 5 years later by a left hemiparesis with involuntary posturing of the left arm and leg. Intelligence was average, and she finished grade 6 at school. Her parents were unrelated, and she had five healthy siblings.
Neuro-ophthalmological examination at age 23 documented excellent afferent and efferent visual functioning with no Kaiser-Fleischer ring. Optic discs were hyperaemic and slightly elevated with peripapillary telangiectasias in both eyes (fig 1A and B). She had modest right sided weakness, diffuse hyper-reflexia greater on the right, bilateral Babinski signs, and dystonic posturing on the right while walking.
On return 21 months later, she reported that the vision of both eyes had declined 9 months previously. Visual acuity was 20/100 in both eyes with poor colour vision in both eyes, a mild left afferent pupillary defect, and bilateral optic atrophy with no residual hyperaemia or peripapillary telangiectasias (fig 1C). Gait was somewhat worse, and she was modestly dysarthric. Vision did not improve during 18 months of follow up.
Normal laboratory studies included haemogram, liver and renal function, serum lactate, pyruvate, and 24 hour urine copper excretion. Cerebral spinal fluid (CSF) lactic acid was slightly elevated (2.8 mm/l with normal range 0.6–2.2 mm/l), and brain MRI revealed abnormalities in both basal ganglia (fig 1D).
After signing informed consent, the proband, her mother and father, and four siblings had blood drawn for DNA extraction, polymerase chain reaction amplification, and sequencing of the entire mitochondrial genomic coding region as previously described.3 Sequence results were compared to Mitomap (www.mitomap.org/mitomap/mitoseq.html), the human mitochondrial genome database (www.genpat.uu.se/mtDB), GenBank (www.ncbi.nlm.nih.gov/Genbank/index.html), and a normal control group of 119 people with no medical problems, who share similar ethnicity with the proband. Mitochondrial respiratory function in complexes I, III, IV, and V was assessed in the proband and one unaffected sibling using a previously described flow cytometric functional analysis method.3,4
The proband, her siblings, and their mother had one mtDNA sequence variant recognised as a polymorphism in the Japanese population,5 which was not present in the 119 normal controls of similar ethnicity. Thirteen previously reported homoplasmic mtDNA polymorphisms were detected in the proband, her family, and the control group. The proband, but not her unaffected brother, had a severe respiratory defect in complex I (fig 1E, F, and G).
This young woman’s initial examination was significant for normal vision with hyperaemic optic discs, pseudopapilloedema, and peripapillary telangiectasias. She went on to develop bilateral optic nerve injury typical of LHON. She also had progressive basal ganglion and upper motor neuron disease culminating in bilateral spasticity, a broad based and unsteady gait, dystonia, and dysarthria. Her clinical course, elevated CSF lactate, normal urinary copper excretion, and severe complex I respiratory defect imply a mitochondrial mechanism for optic nerve and brain injury.
Mitochondrial complex I dysfunction in the absence of a pathological mtDNA mutation provides presumptive evidence of a mitochondrial abnormality of nuclear origin. Complex I dysfunction has been identified in patients with sporadic focal dystonia,6 and at least one familial generalised dystonia syndrome had a defined nuclear mutation affecting a mitochondrial protein.7 Other patients with LHON plus dystonia have had complex I mtDNA mutation(s), so this patient broadens the genetic circumstance in which the phenotype may be expected.