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.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.
"The five affected proteins which play an important role in ATP production: are succinyl-CoA ligase subunit beta (SUCLA2), aconitate hydratase (ACO2), aspartate aminotransferase (GOT2), fumarate hydratase (FH1), and succinyl-CoA:3-ketoacid-coenzyme A transferase 1 (SCOT). Low levels of these proteins are related to seizures, such as depletion of SUCLA2 , deficiency of FH1  and mutations on genes that codes for ACO2 and SCOT  . Furthermore , a low level of GOT2 was described in the hippocampus of TLE patients . "
[Show abstract][Hide abstract]ABSTRACT: Long-term structural and functional changes in the hippocampus have been identified as the primary physiopathological basis for temporal lobe epilepsy. These changes include reactive gliosis and granule cell axonal sprouting within the dentate gyrus. The intimate mechanisms of these changes are beginning to be revealed. Here, we show the possibility of using laser capture microdissection (LCM) to isolate the dentate granular cell layer of Wistar rats submitted to the pilocarpine model of epilepsy. Using two-dimensional gel electrophoresis (2-D PAGE) and mass spectrometry for laser-captured cells, we identified molecular events that could be altered as part of the epileptic pathogenic process. According to our results, eight proteins related to energy metabolism were differentially expressed between both the control and pilocarpine-treated animals. These results provide, for the first time, new molecular insights into the altered protein profile of the epileptogenic dentate gyrus and can contribute to a better understanding of the phenomena involved in the genesis and maintenance of the epileptic state.
Full-text · Article · Dec 2013 · Neuroscience Letters
"It has been reported that a mutation in the human m-aconitase gene ACO2 causes infantile cerebellar-retinal degeneration . Therefore, we examined whether reduction of Acon induces cell death in the Drosophila larval brain. "
[Show abstract][Hide abstract]ABSTRACT: Aconitase catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid (TCA) cycle, and its deficiency in humans is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. Here we investigated the effect of gene knockout and knockdown of the mitochondrial aconitase Acon in Drosophila. Acon-knockout flies were homozygous lethal, indicating that Acon is essential for viability. RNA interference-generated Acon-knockdown flies exhibited a variety of phenotypes, such as reduced locomotor activity, a shortened lifespan, and increased cell death in the developing brain. Metabolomic analysis revealed that acetyl-CoA, citrate/isocitrate, and cis-aconitate were significantly increased, while most metabolites of glycolysis and the TCA cycle were reduced. Reduced ATP and increased triacylglyceride suggested that lipids were used as an energy source because of the impaired glycolysis and TCA cycle. The Acon-knockdown model should facilitate further understanding of the pathophysiology of m-aconitase deficiency in humans.
Full-text · Article · Feb 2013 · Biochemical and Biophysical Research Communications