Evidence that 2-methylacetoacetate induces oxidative stress in rat brain

Leipnitz, Guilhian; Seminotti, Bianca; Amaral, Alexandre Umpierrez; Fernandes, Carolina Gonçalves; Dutra-Filho, Carlos Severo

doi:10.1007/s11011-010-9204-z

Cited by 7 publications

(4 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several patients with T2 deficiency developed chronic neurological impairment, mainly extrapyramidal, independent of frank ketoacidosis (Buhaş et al, ; Fukao et al, ; Paquay et al, ). In vitro studies indicate that 2MAA and 2M3HB exert neurotoxic effects (Leipnitz et al, ; Rosa et al, ). Therefore, accumulated isoleucine‐catabolic metabolites may contribute to neurological impairment in patients with T2 deficiency (Fukao et al, ; Paquay et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…However, an increasing body of evidence indicates that chronic neurological impairment, mainly extrapyramidal manifestations, can exist independent of frank ketoacidosis even in patients with T2 deficiency confirmed at the molecular level (Buhaş et al, 2013;Fukao et al, 2018;Paquay et al, 2017). In vitro studies indicate that 2MAA and 2M3HB exert neurotoxic effects (Leipnitz et al, 2010;Rosa et al, 2005).…”

Section: Biochemical and Laboratory Significancementioning

confidence: 99%

See 1 more Smart Citation

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

et al. 2019

View full text Add to dashboard Cite

Mitochondrial acetoacetyl‐CoA thiolase (T2, encoded by the ACAT1 gene) deficiency is an inherited disorder of ketone body and isoleucine metabolism. It typically manifests with episodic ketoacidosis. The presence of isoleucine‐derived metabolites is the key marker for biochemical diagnosis. To date, 105 ACAT1 variants have been reported in 149 T2‐deficient patients. The 56 disease‐associated missense ACAT1 variants have been mapped onto the crystal structure of T2. Almost all these missense variants concern residues that are completely or partially buried in the T2 structure. Such variants are expected to cause T2 deficiency by having lower in vivo T2 activity because of lower folding efficiency and/or stability. Expression and activity data of 30 disease‐associated missense ACAT1 variants have been measured by expressing them in human SV40‐transformed fibroblasts. Only two variants (p.Cys126Ser and p.Tyr219His) appear to have equal stability as wild‐type. For these variants, which are inactive, the side chains point into the active site. In patients with T2 deficiency, the genotype does not correlate with the clinical phenotype but exerts a considerable effect on the biochemical phenotype. This could be related to variable remaining residual T2 activity in vivo and has important clinical implications concerning disease management and newborn screening.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Biochemical and Laboratory Significancementioning

confidence: 99%

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Evidence supports a direct neurotoxic mechanism in T2D. A metabolite that is specific to T2D, 2‐methylacetoacetate, can induce oxidative stress in rat cerebral cortex . Also, hereditary deficiency of the preceding enzyme of isoleucine degradation, 2‐methyl‐3‐hydroxybutyryl‐CoA dehydrogenase, has been associated with choreoathetoid movements and abnormal basal ganglia imaging.…”

Section: Discussionmentioning

confidence: 99%

A treatable new cause of chorea: Beta‐ketothiolase deficiency

et al. 2013

View full text Add to dashboard Cite

“…Does accumulation of 2M3HB and 2AcAc result in basal ganglia lesions, leading to extrapyramidal manifestation? There are only a few reports about a direct influence of these compounds on brain function [79,80]. They showed that these compounds inhibited aerobic energy metabolism in the TCA cycle and the mitochondrial respiratory chain and induced oxidative stress in rat brain cortex in vitro.…”

Section: Neurological Manifestationmentioning

confidence: 99%

Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency

et al. 2018

View full text Add to dashboard Cite

Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency (OMIM #203750, *607809) is an inborn error of metabolism that affects isoleucine catabolism and ketone body metabolism. This disorder is clinically characterized by intermittent ketoacidotic crises under ketogenic stresses. In addition to a previous 26-case series, four series of T2-deficient patients were recently reported from different regions. In these series, most T2-deficient patients developed their first ketoacidotic crises between the ages of 6 months and 3 years. Most patients experienced less than three metabolic crises. Newborn screening (NBS) for T2 deficiency is performed in some countries but some T2-deficient patients have been missed by NBS. Therefore, T2 deficiency should be considered in patients with severe metabolic acidosis, even in regions where NBS for T2 deficiency is performed. Neurological manifestations, especially extrapyramidal manifestations, can occur as sequelae to severe metabolic acidosis; however, this can also occur in patients without any apparent metabolic crisis or before the onset of metabolic crisis.

show abstract

Evidence that 2-methylacetoacetate induces oxidative stress in rat brain

Cited by 7 publications

References 31 publications

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency

A treatable new cause of chorea: Beta‐ketothiolase deficiency

Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency

Contact Info

Product

Resources

About