An Inherited Disorder of Isoleucine Catabolism Causing Accumulation of α-Methylacetoacetate and α-Methyl-β-hydroxybutyrate, and Intermittent Metabolic Acidosis

Abstract

ExtractAt least 15 apparently inherited disorders of branched chain amino acid catabolism are now known; the 12th in chronological order of discovery is described in this report. It is a partial defect of the pathway of isoleucine oxidation beyond the level of oxidative decarboxylation and prior to the oxidation of propionate. The impairment of isoleucine catabolism appears to be situated at the "thiolase" reaction which converts a-methylacetoacetyl coenzyme A (CoA) to propionyl-CoA and acetyl-CoA. Two pedigrees (B and M) were investigated in detail. A third (S pedigree) has been brought to our attention for analysis of metabolites in urine but we have not performed additional studies in the latter. Each propositus was ascertained because of intermittent, odorless metabolic acidosis usually precipitated by intercurrent infection. Lethargy and coma occurred frequently during the periods of acidosis. One M sib, also presumably affected, died abroad in such an episode. Symptoms can be ameliorated by a low protein diet and careful attention to the management of intercurrent illness.A large excess of a-methyl-|8-hydroxybutyrate and a seemingly smaller excess of a-methylacetoacetate is present at all times in the urine of the three propositions. The M and S propositi also excrete i\f-tiglylglycine. The amounts of these unusual metabolites increase severalfold during acidosis and after a dietary load of L-isoleucine (75 mg/kg, 3 times daily for 2 days). The urine also contains butanone, particularly during acidosis. The amount of propionate and of glycine and other amino acids in blood and urine is always normal in our patients. Oxidation of L-isoleucine-U-14 G to GO 2 by cultured skin fibroblasts is about 45% of normal in the B propositus. The precise nature and location of the enzyme defect awaits clarification.Studies of family members reveal that presumed obligate heterozygotes excrete a small excess of a-methyl-8-hydroxybutyrate at all times; the amount can be increased by L-isoleucine feeding. The condition is apparently inherited in autosomal recessive fashion. It is likely that more than one form of mutant allele is responsible for the condition, as it is found in the three different pedigrees described here. Speculation

Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency.

“…3KTD patients present with intermittent ketoacidotic episodes and urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine (1)(2)(3)(4).…”

3-Oxothiolase Activities and [14C]-2-Methylbutanoic Acid Incorporation in Cultured Fibroblasts from 13 Cases of Suspected 3-Oxothiolase Deficiency

“…W.G.138 cells, also originally stud ied by Da u m et at. (3), clearly have abnormal thiolase activity. The mu tant allele may therefore be different in th e cell lines W.G .…”

“…These cells were from th e original proband J.B., who led Da um et at. (1,3) to suggest that the absen ce ofthiolase activity was the cause of the symptoms. These authors showed that W.G.…”

“…Measurement of I-p4C]-2-methylbutanoic acid incorporation in cultured fibroblasts adds important information in stud ying possible defects of the isoleucine catabolic pathway. (Pediatr Res 28: 518-522, 1990) by Daum et al ( I) , Since then , a number of cases have been reported, with a somewhat varying patt ern of organic aciduria, but genera lly excretion of 2-methyl-3-hydroxybutyric acid and tiglylglycine (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). In some of these cases, a defect in th e mit ochondrial short chain-length-specific thiolase (EC 2.3.1.9) (McKusick 20375) has been observed (7,(9)(10)(11)(12).…”

Identification of a novel exonic mutation at -13 from 5' splice site causing exon skipping in a girl with mitochondrial acetoacetyl-coenzyme A thiolase deficiency.

“…Mitochondrial acetoacetyl-CoA thiolase (T2,' EC 2.3.1.9) deficiency (,3-ketothiolase deficiency, 2-methylacetoacetic aciduria, McKusick 203750) is an inborn error of isoleucine and ketone body catabolism characterized by intermittent ketoacidotic episodes and urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine (1)(2)(3)(4). Fibroblasts from one patient with this disorder lacked the T2 protein because of a defect in its biosynthesis (5).…”