Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D,
Gérard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I,
Amiel J, Rio M, Kaplan J, Munnich A, Rötig A, Rozet JM, Besmond C. Mutations in
the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or
syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med
Genet. 2014Dec;51(12):834-8.
Abstract
BACKGROUND:
Inherited optic neuropathy has been ascribed to mutations in
mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial
DNA-encoded respiratory enzyme genes or nuclear genes of poorly known
mitochondrial function. However, the disease causing gene remains unknown in
many families.
METHODS:
We used exome sequencing in order to identify the gene
responsible for isolated or syndromic optic atrophy in five patients from three
independent families.
RESULTS:
We found homozygous or compound heterozygous missense and
frameshift mutations in the gene encoding mitochondrial aconitase (ACO2), a
tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into
isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to
complement the respiratory growth of a yeast aco1-deletion strain.
Retrospective studies using patient-derived cultured skin fibroblasts revealed
various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic
activity.
CONCLUSIONS:
Our study shows that autosomal recessive ACO2 mutations can
cause either isolated or syndromic optic neuropathy. This observation
identifies ACO2 as the second gene responsible for non-syndromic autosomal
recessive optic neuropathies and provides evidence for a genetic overlap
between isolated and syndromic forms, giving further support to the view that
optic atrophy is a hallmark of defective mitochondrial energy supply.
Inspired by a colleague's sibship of 4 homozygotes and 3 heterozygotes.
Spiegel R, Pines O, Ta-Shma A, Burak E, Shaag A, Halvardson J, Edvardson S, Mahajna M, Zenvirt S, Saada A, Shalev S, Feuk L, Elpeleg O. Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2. Am J Hum Genet. 2012 Mar 9;90(3):518-23.
ReplyDeleteAbstract
Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.