Abstract
Aconitase 2 (ACO2) encodes the mitochondrial aconitase (ACO2), an enzyme catalyzing interconversion of citrate into isocitrate in the Krebs cycle. ACO2 mutations have been initially associated with infantile cerebellar-retinal degeneration combining optic atrophy, retinal degeneration, severe encephalopathy, epilepsy, and cerebellar ataxia 1-3 ; subsequently, ACO2 mutations have also been associated with milder presentations including isolated optic atrophy 2 or cerebellar ataxia without optic atrophy. 4 We report here a patient presenting with a novel ACO2 phenotype associating optic atrophy with spastic paraplegia. Methods Mini-exome sequencing by exon capture (TruSight One Sequencing Panel kit-Montpellier NGS platform) was performed in a patient with familial syndromic optic atrophy. Written informed consent was obtained. Aconitase enzymatic activity was measured as previously described. 5 Case report A now 56-year-old white lady issued from a nonconsanguineous union presented because of severe optic atrophy and spastic paraplegia. Her symptoms had been slowly progressive since infancy and associated with delayed motor (walking at about 3 years) and mental development. An ophthalmologist (C.H.) first examined her at the age of 38 years because of her visual problems. She came to the neurologic clinic at the age of 49 years because of aggravation of the spastic paraplegia, requiring a walking aid. She currently presents with mild cognitive involvement allowing a relatively autonomous life with a sheltered social work. Her sister (not directly examined) has a similar but more severe clinical presentation with visual problems, spasticity, and mental retardation. Cerebral MRI showed mild vermian cerebellar atrophy and nonspecific T2 and fluid-attenuated inversion recovery hyperintensities in cerebellar dentate nuclei and supratentorial white matter (figure, AD). Neurologic examination revealed severe visual impairment, mild upper limb ataxia, diffuse hyperreflexia, and severe spastic paraplegia with bilateral extensor plantar reflex. Ophthalmological evaluation confirmed the presence of bilateral optic atrophy without retinal involvement, globally stable since first examination at the age of 38 years. Visual acuity was severely reduced (right eye: counts the fingers at 30 cm; left eye: counts the fingers at 1 m). The patient did not present any signs of peripheral neuropathy, and the EMG was normal. Mini-exome analysis identified compound heterozygous mutations in the ACO2 gene (c.2135C>T [p.(Pro712Leu)] 4 ; c.940+5G>C) in the patient and her