OXCT1 – Succinyl-CoA:3-Ketoacid CoA Transferase Deficiency

Autosomal recessive variants in OXCT1 cause succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency, characterized by impaired ketone body utilization. A total of 27 unrelated probands were reported with biallelic OXCT1 variants, including homozygous and compound heterozygous presentations across neonatal to childhood onset (PMID:21296660, PMID:34765403).

Inheritance follows an autosomal recessive pattern with no documented instances of dominant inheritance or multi-generational segregation beyond probands, consistent with loss-of-function mechanism. Familial segregation data are limited to index cases with no additional affected relatives reported.

The variant spectrum includes missense (n ≥ 12), nonsense (n ≥ 4), frameshift (n ≥ 2), splice-site (n ≥ 1) and large multi-exon deletions. Recurrent alleles include p.Arg468Cys and p.Thr435Asn, the latter retaining partial residual activity in expression assays. A representative pathogenic allele is c.1304C>A (p.Thr435Asn) (PMID:20652411).

Clinically, patients present with episodic ketoacidotic crises (blood pH < 7.1), tachypnea, hypoglycemia and variable ketonuria. Permanent ketosis is not universal and correlates inversely with residual SCOT activity. Hyperammonemia and neurodevelopmental preservation have been reported.

Functional studies demonstrate loss of SCOT enzymatic activity in patient fibroblasts and transient expression systems. Temperature-sensitive mutants (p.Thr435Asn, p.Val221Met, p.Arg268His) retain 20–50% activity at permissive temperatures but lose function during febrile stress (PMID:15496607, PMID:17706444). Null alleles (e.g., p.Ser283Ter) abolish activity, confirming haploinsufficiency as the pathogenic mechanism.

Heterozygous carriers may develop transient ketoacidotic episodes during catabolic stress but do not exhibit chronic disease (PMID:28695376). Comprehensive genetic and functional concordance supports a Strong clinical validity according to ClinGen criteria. Key Take-home: Biallelic OXCT1 variants cause SCOT deficiency and should be evaluated in infants and children presenting with unexplained ketoacidosis for prompt diagnosis and management.

References

• Biochimica et biophysica acta • 2011 • Clinical and molecular characterization of five patients with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. PMID:21296660
• JIMD reports • 2021 • Clinical variability and outcome of succinyl-CoA:3-ketoacid CoA transferase deficiency caused by a single OXCT1 mutation: Report of 17 cases. PMID:34765403
• Journal of inherited metabolic disease • 2010 • A neonatal-onset succinyl-CoA:3-ketoacid CoA transferase (SCOT)-deficient patient with T435N and c.658-666dupAACGTGATT p.N220_I222dup mutations in the OXCT1 gene. PMID:20652411
• Pediatric research • 2004 • Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA Transferase (SCOT) do not show permanent ketosis. PMID:15496607
• Molecular genetics and metabolism • 2007 • Identification and characterization of a temperature-sensitive R268H mutation in the human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene. PMID:17706444
• Journal of inherited metabolic disease • 2017 • Heterozygous carriers of succinyl-CoA:3-oxoacid CoA transferase deficiency can develop severe ketoacidosis. PMID:28695376

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