Biochemical characterization on muscle tissue of a novel biallelic ACO2 mutation in an infant with progressive encephalopathy.

Autor: Ricci FS; Division of Child and Adolescent Neuropsychiatry, Department of Public Health and Pediatric Sciences University of Turin Turin Italy., Stanga S; Department of Neuroscience 'Rita Levi Montalcini' Neuroscience Institute Cavalieri Ottolenghi, University of Turin Turin Italy., Mezzanotte M; Department of Neuroscience 'Rita Levi Montalcini' Neuroscience Institute Cavalieri Ottolenghi, University of Turin Turin Italy., Marinaccio C; Division of Child and Adolescent Neuropsychiatry, Department of Child Care and Pathology Children Hospital 'Regina Margherita' Turin Italy., D'Alessandro R; Division of Child and Adolescent Neuropsychiatry, Department of Child Care and Pathology Children Hospital 'Regina Margherita' Turin Italy., Somà A; Division of Child and Adolescent Neuropsychiatry, Department of Public Health and Pediatric Sciences University of Turin Turin Italy., Sottemano S; Division of Child and Adolescent Neuropsychiatry, Department of Public Health and Pediatric Sciences University of Turin Turin Italy., Conio A; Pediatric Intensive Care Unit, Anesthesia, Resuscitation and Emergency Department University of Turin Turin Italy., Morana G; Neuroradiology Unit, Department of Neuroscience 'Rita Levi Montalcini' University of Turin Turin Italy., Spada M; Division of Child and Adolescent Neuropsychiatry, Department of Child Care and Pathology Children Hospital 'Regina Margherita' Turin Italy., Boido M; Department of Neuroscience 'Rita Levi Montalcini' Neuroscience Institute Cavalieri Ottolenghi, University of Turin Turin Italy., Mongini TE; Division of Neurology 1, Department of Neuroscience 'Rita Levi Montalcini' University of Turin Turin Italy.
Jazyk: angličtina
Zdroj: JIMD reports [JIMD Rep] 2023 Dec 15; Vol. 65 (1), pp. 3-9. Date of Electronic Publication: 2023 Dec 15 (Print Publication: 2024).
DOI: 10.1002/jmd2.12400
Abstrakt: The ACO2 gene encodes the mitochondrial protein aconitate hydratase, which is responsible for catalyzing the interconversion of citrate into isocitrate in the tricarboxylic acid (TCA) cycle. Mitochondrial aconitase is expressed ubiquitously, and deficiencies in TCA-cycle enzymes have been reported to cause various neurodegenerative diseases due to disruption of cellular energy metabolism and development of oxidative stress. We investigated a severe early infantile-onset neurometabolic syndrome due to a homozygous novel variant in exon 13 of the ACO2 gene. The in vitro pathogenicity of this variant of unknown significance was demonstrated by the loss of both protein expression and its enzymatic activity on muscle tissue sample taken from the patient. The patient presented with progressive encephalopathy soon after birth, characterized by hypotonia, progressive severe muscle atrophy, and respiratory failure. Serial brain magnetic resonance imaging showed progressive abnormalities compatible with a metabolic disorder, possibly mitochondrial. Muscle biopsy disclosed moderate myopathic alterations and features consistent with a mitochondriopathy albeit nonspecific. The course was characterized by progressive worsening of the clinical and neurological picture, and the patient died at 5 months of age. This study provides the first report on the validation in muscle from human subjects regarding in vitro analysis for mitochondrial aconitase activity. To our knowledge, no prior reports have demonstrated a correlation of phenotypic and diagnostic characteristics with in vitro muscle enzymatic activity of mitochondrial aconitase in humans. In conclusion, this case further expands the genetic spectrum of ACO2 variants and defines a complex case of severe neonatal neurometabolic disorder.
Competing Interests: The authors declare no conflicts of interest.
(© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)
Databáze: MEDLINE
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