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J Inherit Metab Dis. 2019 Mar;42(2):264-275. doi: 10.1002/jimd.12022. Epub 2019 Jan 28.

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

Author information

1
Unit of Human Biology and Genetics, The Triangle Regional Research and Development Center, Kafr Qari, Israel.
2
Unit of Nature Science, Beit-Berl Academic College, Beit-Berl, Israel.
3
Department of Pediatrics, Oklahoma University Health Sciences Center, Oklahoma City, OK 73104, USA.
4
Department of Biochemistry and Molecular Biology, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.
5
Unit of Muscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesu' Children's Research Hospital, Rome, Italy.
6
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.
7
Department of Pediatrics, Oakland University William Beaumont School of Medicine, Rochester, Michigan.
8
Division of Child Neurology, University Children's Hospital Zurich, Zurich, Switzerland.
9
Department of Pediatrics, Medical University of Graz, Graz, Austria.
10
Department of Pediatric Neurology, University Children's Hospital Basel and University Children's Hospital, Bern, Switzerland.
11
Molecular Neurosciences, Developmental Neuroscience, UCL Institute of Child Health, London, UK.
12
German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
13
Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
14
Rappaport Faculty of Medicine, Technion- Israel Institute of Technology, Haifa, Israel.
15
Institute of Medical Genetics, Emek Medical Center, Afula, Israel.
16
Child Neurology and Development Center, Hillel-Yaffe Medical Center, Hadera, Israel.
17
Department of Pediatrics B, Emek Medical Center, Afula, Israel.

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.

KEYWORDS:

ACO2 gene; aconitase; infantile cerebellar retinal degeneration (ICRD); neurodegenerative disorder; optic atrophy; tricarboxylic acid cycle

PMID:
30689204
DOI:
10.1002/jimd.12022

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