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

Rajech Sharkia, Klaas J Wierenga, Amit Kessel, Abdussalam Azem, Enrico Bertini, Rosalba Carrozzo, Alessandra Torraco, Paola Goffrini, Camilla Ceccatelli Berti, M Eileen McCormick, Barbara Plecko, Andrea Klein, Lucia Abela, Holger Hengel, Ludger Schöls, Stavit Shalev, Morad Khayat, Muhammad Mahajnah, Ronen Spiegel

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJournal of Inherited Metabolic Disease
DOIs
Publication statusE-pub ahead of print - Dec 27 2018

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Genes
Aconitate Hydratase
Autosomal Dominant Optic Atrophy
Retinal Dystrophies
Genetic Databases
Esotropia
Microcephaly
Retinal Degeneration
Mutation
Muscle Hypotonia
Citric Acid Cycle
Missense Mutation
Enzymes
Ataxia
Heterozygote
Citric Acid
Cerebellum
Atrophy
Seizures
Language

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Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects : Delineation of an emerging neurometabolic syndrome. / Sharkia, Rajech; Wierenga, Klaas J; Kessel, Amit; Azem, Abdussalam; Bertini, Enrico; Carrozzo, Rosalba; Torraco, Alessandra; Goffrini, Paola; Berti, Camilla Ceccatelli; McCormick, M Eileen; Plecko, Barbara; Klein, Andrea; Abela, Lucia; Hengel, Holger; Schöls, Ludger; Shalev, Stavit; Khayat, Morad; Mahajnah, Muhammad; Spiegel, Ronen.

In: Journal of Inherited Metabolic Disease, 27.12.2018.

Research output: Contribution to journalArticle

Sharkia, R, Wierenga, KJ, Kessel, A, Azem, A, Bertini, E, Carrozzo, R, Torraco, A, Goffrini, P, Berti, CC, McCormick, ME, Plecko, B, Klein, A, Abela, L, Hengel, H, Schöls, L, Shalev, S, Khayat, M, Mahajnah, M & Spiegel, R 2018, 'Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects: Delineation of an emerging neurometabolic syndrome', Journal of Inherited Metabolic Disease. https://doi.org/10.1002/jimd.12022
Sharkia, Rajech ; Wierenga, Klaas J ; Kessel, Amit ; Azem, Abdussalam ; Bertini, Enrico ; Carrozzo, Rosalba ; Torraco, Alessandra ; Goffrini, Paola ; Berti, Camilla Ceccatelli ; McCormick, M Eileen ; Plecko, Barbara ; Klein, Andrea ; Abela, Lucia ; Hengel, Holger ; Schöls, Ludger ; Shalev, Stavit ; Khayat, Morad ; Mahajnah, Muhammad ; Spiegel, Ronen. / Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects : Delineation of an emerging neurometabolic syndrome. In: Journal of Inherited Metabolic Disease. 2018.
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AU - Sharkia, Rajech

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AU - Kessel, Amit

AU - Azem, Abdussalam

AU - Bertini, Enrico

AU - Carrozzo, Rosalba

AU - Torraco, Alessandra

AU - Goffrini, Paola

AU - Berti, Camilla Ceccatelli

AU - McCormick, M Eileen

AU - Plecko, Barbara

AU - Klein, Andrea

AU - Abela, Lucia

AU - Hengel, Holger

AU - Schöls, Ludger

AU - Shalev, Stavit

AU - Khayat, Morad

AU - Mahajnah, Muhammad

AU - Spiegel, Ronen

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N2 - 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.

AB - 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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