Clinical and molecular characterization of five patients with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency

Abstract

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inborn error of ketone body metabolism and causes episodic ketoacidosis. We report clinical and molecular analyses of 5 patients with SCOT deficiency. Patients GS07, GS13, and GS14 are homozygotes of S405P, L327P, and R468C, respectively. GS17 and GS18 are compound heterozygotes for S226N and A215V, and V404F and E273X, respectively. These mutations have not been reported previously. Missense mutations were further characterized by transient expression analysis of mutant cDNAs. Among 6 missense mutations, mutants L327P, R468C, and A215V retained some residual activities and their mutant proteins were detected in immunoblot analysis following expression at 37°C. They were more stable at 30°C than 37°C, indicating their temperature sensitive character. The R468C mutant is a distinct temperature sensitive mutant which retained 12% and 51% of wild-type residual activities at 37 and 30°C, respectively. The S226N mutant protein was detected but retained no residual activity. Effects of missense mutations were predicted from the tertiary structure of the SCOT molecule. Main effects of these mutations were destabilization of SCOT molecules, and some of them also affected catalytic activity. Among 5 patients, GS07 and GS18 had null mutations in both alleles and the other three patients retained some residual SCOT activities. All 5 developed a first severe ketoacidotic crisis with blood gas pH <7.1, and experienced multiple ketoacidotic decompensations (two of them had seven such episodes). In general, the outcome was good even following multiple ketoacidotic events. Permanent ketosis or ketonuria is considered a pathognomonic feature of SCOT deficiency. However, this condition depends not only on residual activity but also on environmental factors.

Thin endometrium transcriptome analysis reveals a potential mechanism of implantation failure

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Mitochondrial proteomic analysis reveals deficiencies in oxygen utilization in medullary thick ascending limb of Henle in the Dahl salt-sensitive rat

“…Since reduction of acetoacetyl-CoA and succinate reduce ATP production (16), the reduced SCOT in SS mitochondria would also be expected to reduce the efficiency of O 2 utilization. Various diseases associated with SCOT deficiency such as errors of ketone body metabolism result in episodic ketoacidosis (15).…”

Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp374

“…Accordingly, SCOT protein is abundant in normal heart, kidney, brain, and muscle and nearly undetectable in normal liver. Hereditary SCOT deficiency leads to ketoacidosis, and patients often present with elevated levels of ketone bodies in serum, especially when undernourished (8,19).Studies of diabetic hearts have demonstrated that mitochondrial SCOT activity is decreased compared with that observed in normal hearts (12). Furthermore, Turko et al determined that the decreased SCOT catalytic activity that occurs in the…”

“…Accordingly, SCOT protein is abundant in normal heart, kidney, brain, and muscle and nearly undetectable in normal liver. Hereditary SCOT deficiency leads to ketoacidosis, and patients often present with elevated levels of ketone bodies in serum, especially when undernourished (8,19).…”