Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects: Delineation of an emerging neurometabolic syndrome

Abstract

Mitochondrial aconitase is the second enzyme in the tricarboxylic acid (TCA) cycle catalyzing the interconversion of citrate into isocitrate and encoded by the nuclear gene ACO2. A homozygous pathogenic variant in the ACO2 gene was initially described in 2012 resulting in a novel disorder termed “infantile cerebellar retinal degeneration” (ICRD, OMIM#614559). Subsequently, additional studies reported patients with pathogenic ACO2 variants, further expanding the genetic and clinical spectrum of this disorder to include milder and later onset manifestations. Here, we report an international multicenter cohort of 16 patients (of whom 7 are newly diagnosed) with biallelic pathogenic variants in ACO2 gene. Most patients present in early infancy with severe truncal hypotonia, truncal ataxia, variable seizures, evolving microcephaly, and ophthalmological abnormalities of which the most dominant are esotropia and optic atrophy with later development of retinal dystrophy. Most patients remain nonambulatory and do no acquire any language, but a subgroup of patients share a more favorable course. Brain magnetic resonance imaging (MRI) is typically normal within the first months but global atrophy gradually develops affecting predominantly the cerebellum. Ten of our patients were homozygous to the previously reported c.336C>G founder mutation while the other six patients were all compound heterozygotes displaying 10 novel mutations of whom 2 were nonsense predicting a deleterious effect on enzyme function. Structural protein modeling predicted significant impairment in aconitase substrate binding in the additional missense mutations. This study provides the most extensive cohort of patients and further delineates the clinical, radiological, biochemical, and molecular features of ACO2 deficiency.

Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy

“…Neurological examination revealed normal findings apart from visual deficits described above. Especially, there were no signs of cerebellar ataxia or cognitive deficits reported before in carriers of biallelic ACO2 mutations 5,[9][10][11]13,14 . Laboratory tests found increased levels of ferritin (79 µg/dl; norm: 3-30) with normal levels of iron and transferrin.…”

“…However, its amino acid sequence is 96.5% identical to the sequence of the same enzyme from pig (pdb entry 1b0j). Therefore, we used this structure as a template to predict the structure of human ACO2 14 . The structure was predicted using the homology-modelling software MODELLER 46 .…”

“…To date, a number of families or isolated patients with mutations in the Aconitase 2 (ACO2) gene were described, clinically presenting with neurodegenerative or metabolic disease of variable severity. ACO2-linked pathologies are inherited as an autosomal recessive trait, as all described patients carry homozygous or compound heterozygous missense or frameshift mutations, respectively 5,[9][10][11][12][13][14] .…”

Gene Therapy to the Retina and the Cochlea

“…Other disease genes with multiple affected areas include many of the retinal disease genes that cause optic atrophy such as MECR and ACO2 which are also associated with cerebellar defects and ataxias (Heimer et al, 1993;Sharkia et al, 2019). In other cases, these disorders also have a deafness component, for example in the case of TIMM8A, which is associated with deafness-dystonia-optic neuropathy syndrome (Tranebjaerg, 1993).…”

Spectrum of movement disorders in mitochondrial diseases

“…Finally, it is worth mentioning some rare complex forms due to mitochondrial enzymes deficiencies, such as Aconitase 2 (ACO2) deficiency reported in severe encephalopathy with hypotonia, athetosis, seizures, optic atrophy, and retinal and cerebellar degeneration or defect of the epimerase encoded by NAXE that results in children with ataxia, cerebellar edema, spinal myelopathy, and skin lesions [118,119] .…”