Tags

Type your tag names separated by a space and hit enter

Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis.
J Inherit Metab Dis 2017; 40(3):415-422JI

Abstract

BACKGROUND

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.

METHODS

In total, 26 cases were retrospectively analysed for clinical, biological and neuroimaging data.

RESULTS

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.

CONCLUSIONS

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+Show Affiliations

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.Biochemistry, Hôpital Robert Debré, APHP, Paris, France.Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France.Biochemistry, Hôpital Robert Debré, APHP, Paris, France.Reference Center for Inborn Errors of Metabolism, Hôpital Necker, APHP, Paris, France. Université Paris-Descartes, Sorbonne Paris Cité, Paris, France.Reference Center for Inherited Metabolic Diseases in Child and Adulthood, University Children's Hospital Jeanne de Flandre, Lille, France.Reference Center for Inherited Metabolic Diseases, Hôpital Femme-Mère-Enfant, CHU Lyon, Lyon, France.Reference Center for Inherited Metabolic Diseases, Hôpital Femme-Mère-Enfant, CHU Lyon, Lyon, France.Centre de Biotechnologie Cellulaire et Biothèque, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, CHU Lyon, Lyon, France.Department of Pediatrics, CHRU Tours, Tours, France.Reference Center for Inherited Metabolic Diseases in Child and Adulthood, University Children's Hospital Jeanne de Flandre, Lille, France.Department of Pediatrics, CHU Toulouse, Toulouse, France.Reference Center for Inborn Errors of Metabolism, Hôpital Necker, APHP, Paris, France. Sanofi-Genzyme, Cambridge, MA, USA.Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France.Child Radiology, Hôpital Robert Debré, APHP, Paris, France.Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, CHU Lyon, Lyon, France.Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, CHU Lyon, Lyon, France.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28255778

Citation

Paquay, Stéphanie, et al. "Mitochondrial acetoacetyl-CoA Thiolase Deficiency: Basal Ganglia Impairment May Occur Independently of Ketoacidosis." Journal of Inherited Metabolic Disease, vol. 40, no. 3, 2017, pp. 415-422.
Paquay S, Bourillon A, Pichard S, et al. Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis. J Inherit Metab Dis. 2017;40(3):415-422.
Paquay, S., Bourillon, A., Pichard, S., Benoist, J. F., de Lonlay, P., Dobbelaere, D., ... Schiff, M. (2017). Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis. Journal of Inherited Metabolic Disease, 40(3), pp. 415-422. doi:10.1007/s10545-017-0021-y.
Paquay S, et al. Mitochondrial acetoacetyl-CoA Thiolase Deficiency: Basal Ganglia Impairment May Occur Independently of Ketoacidosis. J Inherit Metab Dis. 2017;40(3):415-422. PubMed PMID: 28255778.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis. AU - Paquay,Stéphanie, AU - Bourillon,Agnès, AU - Pichard,Samia, AU - Benoist,Jean-François, AU - de Lonlay,Pascale, AU - Dobbelaere,Dries, AU - Fouilhoux,Alain, AU - Guffon,Nathalie, AU - Rouvet,Isabelle, AU - Labarthe,François, AU - Mention,Karine, AU - Touati,Guy, AU - Valayannopoulos,Vassili, AU - Ogier de Baulny,Hélène, AU - Elmaleh-Bergès,Monique, AU - Acquaviva-Bourdain,Cécile, AU - Vianey-Saban,Christine, AU - Schiff,Manuel, Y1 - 2017/03/02/ PY - 2016/10/10/received PY - 2017/01/24/accepted PY - 2017/01/23/revised PY - 2017/3/4/pubmed PY - 2017/8/25/medline PY - 2017/3/4/entrez SP - 415 EP - 422 JF - Journal of inherited metabolic disease JO - J. Inherit. Metab. Dis. VL - 40 IS - 3 N2 - BACKGROUND: 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. METHODS: In total, 26 cases were retrospectively analysed for clinical, biological and neuroimaging data. RESULTS: 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. CONCLUSIONS: 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. SN - 1573-2665 UR - https://www.unboundmedicine.com/medline/citation/28255778/Mitochondrial_acetoacetyl_CoA_thiolase_deficiency:_basal_ganglia_impairment_may_occur_independently_of_ketoacidosis_ L2 - https://doi.org/10.1007/s10545-017-0021-y DB - PRIME DP - Unbound Medicine ER -