Stéphanie Paquay1,2, Agnès Bourillon3, Samia Pichard1, Jean-François Benoist3, Pascale de Lonlay4,5, Dries Dobbelaere6, Alain Fouilhoux7, Nathalie Guffon7, Isabelle Rouvet8, François Labarthe9, Karine Mention6, Guy Touati10, Vassili Valayannopoulos4,11, Hélène Ogier de Baulny1, Monique Elmaleh-Bergès12, Cécile Acquaviva-Bourdain13, Christine Vianey-Saban13, Manuel Schiff14,15. 1. Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France. 2. Pediatric Neurology, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium. 3. Biochemistry, Hôpital Robert Debré, APHP, Paris, France. 4. Reference Center for Inborn Errors of Metabolism, Hôpital Necker, APHP, Paris, France. 5. Université Paris-Descartes, Sorbonne Paris Cité, Paris, France. 6. Reference Center for Inherited Metabolic Diseases in Child and Adulthood, University Children's Hospital Jeanne de Flandre, Lille, France. 7. Reference Center for Inherited Metabolic Diseases, Hôpital Femme-Mère-Enfant, CHU Lyon, Lyon, France. 8. Centre de Biotechnologie Cellulaire et Biothèque, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, CHU Lyon, Lyon, France. 9. Department of Pediatrics, CHRU Tours, Tours, France. 10. Department of Pediatrics, CHU Toulouse, Toulouse, France. 11. Sanofi-Genzyme, Cambridge, MA, USA. 12. Child Radiology, Hôpital Robert Debré, APHP, Paris, France. 13. Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, CHU Lyon, Lyon, France. 14. Reference Center for Inborn Errors of Metabolism, Robert Debré University Hospital, 48 Bd Sérurier, Paris, F-75935 Cedex 19, France. manuel.schiff@aphp.fr. 15. UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. manuel.schiff@aphp.fr.
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.
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-deficientpatient 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-deficientpatients 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: Peter M van Hasselt; Sacha Ferdinandusse; Glen R Monroe; Jos P N Ruiter; Marjolein Turkenburg; Maartje J Geerlings; Karen Duran; Magdalena Harakalova; Bert van der Zwaag; Ardeshir A Monavari; Ilyas Okur; Mark J Sharrard; Maureen Cleary; Nuala O'Connell; Valerie Walker; M Estela Rubio-Gozalbo; Maaike C de Vries; Gepke Visser; Roderick H J Houwen; Jasper J van der Smagt; Nanda M Verhoeven-Duif; Ronald J A Wanders; Gijs van Haaften Journal: N Engl J Med Date: 2014-11-13 Impact factor: 91.245
Authors: Mustafa S Pir; Halil I Bilgin; Ahmet Sayici; Fatih Coşkun; Furkan M Torun; Pei Zhao; Yahong Kang; Sebiha Cevik; Oktay I Kaplan Journal: Nucleic Acids Res Date: 2022-01-07 Impact factor: 16.971