Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency

Abela, Lucia; Spiegel, Ronen; Crowther, Lisa M.; Klein, Andrea; Steindl, Katharina; Papuc, Sorina Mihaela; Joset, Pascal; Zehavi, Yoav; Rauch, Anita; Plecko, Barbara; Simmons, Thomas L.

doi:10.1371/journal.pone.0176363

Cited by 45 publications

(44 citation statements)

References 41 publications

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“…In addition to cerebellar atrophy and ophthalmological abnormalities, the patients also exhibited hypotonia, ataxia, seizure disorder, developmental delay, intellectual disability and hearing loss (Spiegel et al, ). Thereafter, one homozygous (p.Gly259Asp) and five compound heterozygous (p.[Lys736Asn;Lys776Asn], p.[Arg607Cys; Pro712Leu], p.[Gly620Asp;Gly683Val], p.[Val364Ala; Lys776Asnfs*49] and p.[Pro712Leu; Gly279_Glu313del]) mutations of ACO2 were found in patients with similar clinical characteristics to those described by Spiegel (p.Ser112Arg), and one compound heterozygous mutation (p.[Leu74Val; Gly661Val]) in siblings having only ophthalmological abnormalities (Abela et al, ; Marelli et al, ; Metodiev et al, ; Sadat et al, ; Srivastava et al, ). Significant decreases in aconitase activity in patient cells were observed in most cases, and the impaired energy metabolism due to TCA cycle dysfunction was considered to be a major cause of symptoms in ACO2 deficiency.…”

Section: Introductionsupporting

confidence: 59%

Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy

Fukada

Yamada

Eda

et al. 2019

Molec Gen & Gen Med

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Background The tricarboxylic acid (TCA) cycle is a sequence of catabolic reactions within the mitochondrial matrix, and is a central pathway for cellular energy metabolism. Genetic defects affecting the TCA cycle are known to cause severe multisystem disorders. Methods We performed whole exome sequencing of genomic DNA of a patient with progressive cerebellar and cerebral atrophy, hypotonia, ataxia, seizure disorder, developmental delay, ophthalmological abnormalities and hearing loss. We also performed biochemical studies using patient fibroblasts. Results We identified new compound heterozygous mutations (c.1534G > A, p.Asp512Asn and c.1997G > C, p.Gly666Ala) in ACO2, which encodes aconitase 2, a component of the TCA cycle. In patient fibroblasts, the aconitase activity was reduced to 15% of that of the control, and the aconitase 2 level decreased to 36% of that of the control. As such a decrease in aconitase 2 in patient fibroblasts was partially restored by proteasome inhibition, mutant aconitase 2 was suggested to be relatively unstable and rapidly degraded after being synthesized. In addition, the activity of the father‐derived variant of aconitase 2 (p.Gly666Ala), which had a mutation near the active center, was 55% of that of wild‐type. Conclusion The marked reduction of aconitase activity in patient fibroblasts was due to the combination of decreased aconitase 2 amount and activity due to mutations. Reduced aconitase activity directly suppresses the TCA cycle, resulting in mitochondrial dysfunction, which may lead to symptoms similar to those observed in mitochondrial diseases.

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Section: Introductionsupporting

confidence: 59%

Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy

Fukada

Yamada

Eda

et al. 2019

Molec Gen & Gen Med

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“…Of these, seven are newly diagnosed and their presentation and clinical course are illustrated in detail (File S1). One of these patients (E1) has been previously published but with a focus on metabolomic biochemical findings . In addition, we provide an update and follow‐up on the clinical, radiological, and molecular details of the eight previously described patients .…”

Section: Methodsmentioning

confidence: 98%

“…Patients I9 and I10 (two siblings) and patients E2 and E3 (two additional siblings) were diagnosed by whole‐exome sequencing (WES) performed on a research basis. Patient E1 was previously reported and the genetic diagnosis was made by WES performed on a research project on epileptic encephalopathies . In patients A1, A2, and A3 clinical WES was part of the clinical diagnostic evaluation and was performed by the Baylor Miraca Whole Genome Genetics Laboratory (patient A1), Ambry Genetics (patient A2), Gene Dx DNA diagnostic Experts (patient A3).…”

Section: Methodsmentioning

confidence: 99%

“…One of these patients (E1) has been previously published but with a focus on metabolomic biochemical findings. 11 In addition, we provide an update and follow-up on the clinical, radiological, and molecular details of the eight previously described patients. 4 Data were retrospectively collected from the physicians caring for these patients.…”

Section: Patientsmentioning

confidence: 99%

“…Patient E1 was previously reported and the genetic diagnosis was made by WES performed on a research project on epileptic encephalopathies. 11 In patients A1, A2, and A3 clinical WES was part of the clinical diagnostic evaluation and was performed by the Baylor Miraca Whole Genome Genetics Laboratory (patient A1), Ambry Genetics (patient A2), Gene Dx DNA diagnostic Experts (patient A3). Suspected pathogenic variants identified by WES were validated by means of Sanger sequencing.…”

Section: Genetic Analysismentioning

confidence: 99%

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

Sharkia

Wierenga

Kessel

et al. 2019

J of Inher Metab Disea

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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.

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Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2

Blackburn

Schultz

Lahner

et al. 2020

Ann Clin Transl Neurol

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ObjectiveWe describe the clinical characteristics and genetic etiology of several new cases within the ACO2‐related disease spectrum. Mitochondrial aconitase (ACO2) is a nuclear‐encoded tricarboxylic acid cycle enzyme. Homozygous pathogenic missense variants in the ACO2 gene were initially associated with infantile degeneration of the cerebrum, cerebellum, and retina, resulting in profound intellectual and developmental disability and early death. Subsequent studies have identified a range of homozygous and compound heterozygous pathogenic missense, nonsense, frameshift, and splice‐site ACO2 variants in patients with a spectrum of clinical manifestations and disease severities.MethodsWe describe a cohort of five novel patients with biallelic pathogenic variants in ACO2. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated ACO2 variants and compare with those described previously in the literature.ResultsTwo siblings with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities including hyperactivity and depressive symptoms with generalized anxiety. One patient presented with the classic form with cerebellar hypoplasia, ataxia, seizures, optic atrophy, and retinitis pigmentosa. Another unrelated patient presented with ataxia but developed severe progressive spastic quadriplegia. Another patient demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months.InterpretationIn this study, we highlight the importance of recognizing milder forms of the disorder, which may escape detection due to atypical disease presentation.

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Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency

Cited by 45 publications

References 41 publications

Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy

Identification of novel compound heterozygous mutations in ACO2 in a patient with progressive cerebral and cerebellar atrophy

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

Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2

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