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Mitochondrial acetoacetyl‐CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis
Author(s) -
Paquay Stéphanie,
Bourillon Agnès,
Pichard Samia,
Benoist JeanFrançois,
Lonlay Pascale,
Dobbelaere Dries,
Fouilhoux Alain,
Guffon Nathalie,
Rouvet Isabelle,
Labarthe François,
Mention Karine,
Touati Guy,
Valayannopoulos Vassili,
Ogier de Baulny Hélène,
ElmalehBergès Monique,
AcquavivaBourdain Cécile,
VianeySaban Christine,
Schiff Manuel
Publication year - 2017
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-017-0021-y
Subject(s) - thiolase , medicine , globus pallidus , putamen , ketoacidosis , pediatrics , basal ganglia disease , ketone bodies , basal ganglia , ketosis , endocrinology , diabetes mellitus , central nervous system , peroxisome , receptor , metabolism , type 1 diabetes
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.