title: Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis.
abstract: Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects ketone body and isoleucine catabolism. Neurological impairment may occur secondary to ketoacidotic episodes. However, we observed neuromotor abnormalities without ketoacidotic events in two T2-deficient families. We hypothesized that the neurological signs were related to the genetic defect and may occur independently of ketoacidotic episodes. We therefore conducted a retrospective review on a French T2-deficient patient series searching for neuromotor impairment.
  
  
  
  In total, 26 cases were retrospectively analysed for clinical, biological and neuroimaging data.
  
  
  
  Neurological findings were observed for 6/26 (23%) patients. Among these, two had never experienced ketoacidotic episodes, though they developed extrapyramidal signs with putamen involvement. Two of the other four patients developed neurological abnormalities before the first ketoacidotic crisis, with putamen involvement in one case. The third patient developed extrapyramidal symptoms more than 10 years after the initial decompensation with globus pallidus involvement. The last patient developed extrapyramidal signs immediately after a severe ketoacidotic crisis with putaminal lesions.
  
  
  
  Most T2-deficient patients achieved normal neurodevelopment. However, on account of the role of T2 in isoleucine catabolism, these patients are potentially exposed to accumulation of toxic isoleucine-derived metabolites, which may contribute to neurological impairment. Our findings confirm previous observations that neurological symptoms in T2 deficiency may occur unrelated to ketoacidosis. The role of protein restriction as a preventive measure against neurological symptoms could not be established in this study and deserves further evaluation. Long-term follow-up data on children diagnosed by newborn screening may clarify the pathogenesis of this neurometabolic association.
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France.|Pediatric Neurology, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Paquay
authors.affiliation: Biochemistry, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Bourillon
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Pichard
authors.affiliation: Biochemistry, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Benoist
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Hôpital Necker, APHP, Paris, France.|Université Paris-Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.affiliation: Reference Center for Inherited Metabolic Diseases in Child and Adulthood, University Children's Hospital Jeanne de Flandre, Lille, France.
authors.forename: Dries
authors.initials: D
authors.lastname: Dobbelaere
authors.affiliation: Reference Center for Inherited Metabolic Diseases, Hôpital Femme-Mère-Enfant, CHU Lyon, Lyon, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Fouilhoux
authors.affiliation: Reference Center for Inherited Metabolic Diseases, Hôpital Femme-Mère-Enfant, CHU Lyon, Lyon, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Guffon
authors.affiliation: Centre de Biotechnologie Cellulaire et Biothèque, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, CHU Lyon, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rouvet
authors.affiliation: Department of Pediatrics, CHRU Tours, Tours, France.
authors.forename: François
authors.initials: F
authors.lastname: Labarthe
authors.affiliation: Reference Center for Inherited Metabolic Diseases in Child and Adulthood, University Children's Hospital Jeanne de Flandre, Lille, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Mention
authors.affiliation: Department of Pediatrics, CHU Toulouse, Toulouse, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Touati
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Hôpital Necker, APHP, Paris, France.|Sanofi-Genzyme, Cambridge, MA, USA.
authors.forename: Vassili
authors.initials: V
authors.lastname: Valayannopoulos
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Ogier de Baulny
authors.affiliation: Child Radiology, Hôpital Robert Debré, APHP, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Elmaleh-Bergès
authors.affiliation: Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, CHU Lyon, Lyon, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva-Bourdain
authors.affiliation: Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, CHU Lyon, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vianey-Saban
authors.affiliation: Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France. manuel.schiff@aphp.fr.|UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. manuel.schiff@aphp.fr.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schiff
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000172:deficiency*; D000102:Acetyl-CoA C-Acyltransferase / Q000172:deficiency* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000378:metabolism*; D001479:Basal Ganglia / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007532:Isoleucine / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism; D007662:Ketosis / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D015997:Neonatal Screening / Q000379:methods; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D007657:Ketone Bodies; D007532:Isoleucine; D000102:Acetyl-CoA C-Acyltransferase; D000101:Acetyl-CoA C-Acetyltransferase