The mitochondrial acetoacetyl‐CoA thiolase (T2) deficiency in Japanese patients: urinary organic acid and blood acylcarnitine profiles under stable conditions have subtle abnormalities in T2‐deficient patients with some residual T2 activity

Abstract

Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency is an inborn error of metabolism affecting isoleucine and ketone bodies in the catabolic process. Mutation analysis and expression analysis of mutant cDNAs have facilitated the division of T2-deficient patients into two groups: those with null mutations in either allele (group 1) and those with mutation(s) retaining some residual T2 activity in at least one of two mutant alleles (group II). Among 5 Japanese T2-deficient patients, GK01 belonged to group I and the other patients (GK19, GK19B, GK30 and GK31) to group II. As we have suggested previously, the severity of ketoacidotic episodes in the group II patients was similar to that in the group I patient. However, the urinary organic acid and blood spot acylcarnitine profiles under stable conditions differed between the two groups. The group I patient had typical profiles for the T2 deficiency. In contrast, in all four patients in group II, tiglylglycine was not or was only faintly detected and the 2-methyl-3-hydroxybutyrate levels were less than the cutoff value. Their tiglylcarnitine levels were within the normal range and 2-methyl-3-hydroxy-, butyrylcarnitine was detected just around the cutoff value in our newborn screening pilot test. Hence, these analyses under stable conditions are not reliable for diagnosing the T2 deficiency in the group II patients. The T2 deficiency (group II) can be misdiagnosed as normal if these analyses are performed under nonepisodic conditions and possibly during the newborn screening for inborn errors of metabolism.

The first case of mitochondrial acetoacetyl‐CoA thiolase deficiency identified by expanded newborn metabolic screening in Italy: the importance of an integrated diagnostic approach

“…The H397D mutation changes an amino acid residue that is highly conserved among species. The H397D mutation provokes a null allele in the sense that it causes the total loss of acetoacetyl-CoA thiolase activity for which the potassium ion is critical (Fukao et al 2003, 2008; Haapalainen et al 2007). Such a severe three-dimensional perturbation destabilises the overall integrity of the mutant enzyme (Zhang et al 2004).…”

Development of Urinary Biomarkers for Internal Exposure by Cesium-137 Using a Metabolomics Approach in Mice

“…Tiglylcarnitine was found to be down-regulated in the 137 Cs exposed mice. Tiglylcarnitine is formed during degradation of isoleucine by the action of mitochondrial enzyme acetoacetyl-CoA thiolase and assists in transporting fatty acids (19). A decrease in its levels may be indicative of deficiencies in mitochondria function.…”

Beta-Ketothiolase Deficiency Presenting with Metabolic Stroke After a Normal Newborn Screen in Two Individuals

“…The classic metabolic perturbations seen in this disorder, namely elevations of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine in urine, with C5OH and C5:1 in plasma, may not all be present. This is even more problematic in patients with residual enzyme activity, and during periods of clinical stability (Fukao et al 2003(Fukao et al , 2012Sarafoglou et al 2011). In particular, 2-methylacetoacetic acid is unstable and can be difficult to detect with routinely used methods for organic acid analysis (Korman 2006;Catanzano et al 2010).…”