Infantile Presentation of Leber Hereditary Optic Neuropathy “Plus” Disease

A 3-year-old boy was evaluated in the emergency department with a 2-month history of intractable vomiting. He also experienced an episode of ataxia 3 months before presentation. Examination revealed dehydration and global hypotonia. Metabolic workup showed elevated plasma alanine and elevated plasma alanine/lysine ratio, suggestive of mitochondrial dysfunction. Ophthalmologic examination demonstrated visual acuities of 20/20 in the right eye (Allen Chart) and counting fingers in the left eye. A left afferent pupillary defect was present. The patient exhibited an esotropia with full extraocular movements. Fundus examination revealed a hyperemic right optic disc, whereas the left disc was pale (Fig. 1).FIG. 1.: At initial presentation, the right optic disc appears hyperemic, whereas the left disc is pale.Brain MRI demonstrated hyperintense signal bilaterally in the subthalamic nuclei and posterior medulla, with the latter showing restricted diffusion (Fig. 2). Genetic testing showed a homoplasmic mitochondrial 11778G>A mutation and 2 homoplasmic mitochondrial secondary mutations at the 4216T>C and 4917A>G locations. Treatment with oral coenzyme Q (ubiquinol) was initiated at 90 mg twice a day.FIG. 2.: Brain MRI. Axial scans show hyperintensities (arrows) in the subthalamic nuclei on T2 (A) and fluid-attenuated inversion recovery (FLAIR) (B) images. Similar hyperintensities are seen in the medulla on T2 (C) and FLAIR (D) sequences.The patient was stable for 3.5 years but then developed left-sided weakness. Neurological assessment revealed left-sided lower-limb weakness, dystonia, foot clonus, and extensor plantar response. Gait assessment demonstrated left foot circumduction, in-toeing, and guarded left arm position. MRI showed progressive changes (Fig. 3), and the patient was prescribed oral citrulline at 1,150 mg three times a day.FIG. 3.: Brain MRI 3.5 years after initial evaluation. A. Hyperintensities are seen in the lentiform nuclei (arrows) on T2 imaging, and these lesions demonstrate central hypointensity (arrows) on fluid-attenuated inversion recovery image (FLAIR) sequences (B). Areas of increased signal are seen in the dorsal midbrain on T2 (C) and FLAIR (D) scans.Neurological testing 1.5 years later demonstrated dysarthria, right-sided facial droop, and dystonia. Visual acuities were stable and the funduscopic appearance was unchanged. On optical coherence tomography, peripapillary retinal nerve fiber layer thickness was 121 µm in the right eye and 72 µm in the left eye (Fig. 4). Increased signal was found in the putamen bilaterally, left posterior globus pallidus, and bilateral cerebral peduncles on T2 and fluid-attenuated inversion recovery image MRI.FIG. 4.: Five years after initial presentation, the right optic disc remains hyperemic, the left disc pale. Retinal nerve fiber layer measurements confirm increased thickness in the right eye and thinning in the left eye. OD, right eye; OS, left eye.Children with Leber hereditary optic neuropathy (LHON) often experience milder disease than adults. Barboni et al (1) identified 3 subcategories of LHON with childhood onset: acute bilateral, slowly progressive, and subclinical/acute unilateral disease. Those with acute bilateral childhood onset of disease were more likely to experience visual recovery compared to those with adult onset. Majander et al (2) also noted a more favorable disease course in children presenting with LHON younger than 12 years, irrespective of subcategory or mutation type. Our patient falls into the subclinical/acute unilateral disease category because he was not initially suspected of having vision loss. Although Majander et al (2) noted significant diagnostic delays among children with subclinical disease presentation, our patient's optic atrophy was quickly identified as being LHON related, likely secondary to his other neurological findings and suspicion for mitochondrial disease. LHON can be associated with other neurological abnormalities, termed LHON “plus” disease. Nikoskelainen et al (3) reported a 59% prevalence rate of neurological abnormalities associated with LHON. Neurological manifestations include postural tremor, motor disorders, Parkinsonism with dystonia, peripheral neuropathy, cerebellar ataxia, anarthria, spasticity, and encephalopathy. LHON “plus” disease with childhood onset has been described infrequently. To the best of our knowledge, few pediatric patients with the 11778G>A LHON mutation have been reported with atypical Leigh-like or mainly dystonia-involving presentations, as found in our patient (4). Most cases with optic atrophy and dystonia have been found to harbor mitochondrial mutations at the 11696G>A, 14459G>A, or 14596T>A positions (5). MRI in these patients typically demonstrates deep gray matter lesions. The basal ganglia are believed to be especially vulnerable to injury in mitochondrial disease due to high energy requirements and increased free radical formation (6). Age, sex, environmental factors, and type of primary mitochondrial mutation ultimately affect the disease course in patients with LHON. Furthermore, additional mitochondrial mutations have been proposed to act as LHON disease modifiers, including those at positions 4216, 4917, 13708, 15257, and 15812. The 4216T>C and 4917A>G (haplogroup T) mutations, as present in our patient, have been found with equal frequency in both patients with LHON and controls. Although Torroni et al (7) found that haplogroup T does not seem to play a role in potentiating LHON disease expression, various studies have shown increased frequency of the 4216T>C mutation among young migraine and stroke sufferers, and patients with Parkinson disease, multiple sclerosis, and Wolfram disease (7,8). In our patient, due to early onset and a severe LHON “plus” course, the question arises as to whether his secondary mitochondrial mutations contributed to the disease process and age of disease manifestation.

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