ClinVar Genomic variation as it relates to human health

Global developmental delay (present) , Bilateral sensorineural hearing impairment (present) , Appendicular hypotonia (present) , Truncal ataxia (present) , Myoclonic spasms (present) , Downslanted palpebral fissures (present) , Frontal bossing (present) , Arachnoid cyst (present) (less)

In a 3-year-old boy of Afro-Caribbean and East Indian ancestry with truncal ataxia, hypotonia, developmental delay, and hearing loss (ICRD; 614559), Sadat et al. (2016) identified compound heterozygosity for a c.2135C-T transition (c.2135C-T, NM_001098) in exon 17 of the ACO2 gene, resulting in a pro712-to-leu (P712L) substitution, and a c.1819C-T transition in exon 15 of the ACO2 gene, resulting in an arg607-to-cys (R607C; 100850.0016) substitution, both involving highly conserved residues. His unaffected parents were each heterozygous for 1 of the mutations. The P712L variant was present once in the ESP5400 database and 4 times in the ExAC database, with no homozygotes reported, whereas the R607C was not found in either database. Analysis of patient fibroblasts demonstrated an 80% reduction in aconitase enzyme activity compared to control fibroblasts, and mitochondria isolated from patient fibroblasts also showed ACO2 activity that was approximately 20% of control cell activity. Whole-cell aconitase activity was completely restored upon transduction of patient cells with wildtype ACO2. Cellular respiration studies revealed that patient fibroblasts had a significantly lower total respiratory capacity and minimal reserve capacity compared to control cells, operating at 40% less capacity than the maximal respiration rate of control cells. Introduction of wildtype ACO2 into patient fibroblasts completely rescued the cellular respiration defects, indicating that the defects were specific for the observed ACO2 deficiency. In addition, the authors performed qPCR and observed a 50% reduction in mtDNA copy number compared to control cells, and mtDNA levels were restored to control levels with introduction of wildtype ACO2 into patient cells. Western blot analysis of other TCA cycle enzymes and OXPHOS complexes showed increases in the steady-state level of subunits of respiratory chain complex II (SDHA; 600857) and complex III (UQCRC2; 191329), as well as subunits of TCA enzyme succinyl-CoA synthetase (SUCLG1, 611224; SUCLG2, 603922); these increased levels were reduced to normal levels in the rescued cell line, suggesting that these changes were a consequence of ACO2 deficiency. In 2 sisters with severe optic atrophy and spastic paraplegia, Marelli et al. (2018) identified compound heterozygosity for mutations in the ACO2 gene: the previously reported P712L substitution, and a splice site mutation (c.940+5G-C; 100850.0017) in intron 7 of ACO2. RT-PRC analysis of patient fibroblasts demonstrated in-frame skipping of exon 7. No relevant variants were found in other genes causing isolated or syndromic optic atrophy, and their unaffected parents were each heterozygous for 1 of the ACO2 mutations. Analysis of patient fibroblasts showed a 40 to 50% reduction in total aconitase activity; no mtDNA depletion was detected in patient cells. (less)