Alternative titles; symbols
SNOMEDCT: 238004006; ORPHA: 832;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p13.1 | Succinyl CoA:3-oxoacid CoA transferase deficiency | 245050 | Autosomal recessive | 3 | OXCT1 | 601424 |
A number sign (#) is used with this entry because of evidence that succinyl-CoA:3-oxoacid-CoA transferase deficiency (SCOTD) is caused by homozygous or compound heterozygous mutation in the OXCT1 gene (601424) on chromosome 5p13.
Ketone bodies are major vectors of energy transfer from the liver to extrahepatic tissues and are the main source of lipid-derived energy for the brain. Mitchell et al. (1995) reviewed medical aspects of ketone body metabolism, including the differential diagnosis of abnormalities. As the first step of ketone body utilization, succinyl-CoA:3-oxoacid CoA transferase (SCOT, or OXCT1; EC 2.8.3.5) catalyzes the reversible transfer of CoA from succinyl-CoA to acetoacetate.
By study of cultured fibroblasts and postmortem tissue from a black male infant who died at age 6 months from severe intermittent ketoacidosis, Tildon and Cornblath (1972) found no measurable succinyl-CoA:3-ketoacid CoA-transferase activity. Other causes of ketoacidosis in the neonate include diabetes mellitus, type I glycogen storage disease (232200), propionic acidemia (606054), methylmalonic aciduria (251000), and lactic acidosis (245400). Other cases of succinyl-CoA:3-ketoacid-CoA transferase deficiency were described by Spence et al. (1973) and Middleton et al. (1987). Different clinical severity was demonstrated.
Perez-Cerda et al. (1992) reported the offspring of a consanguineous couple who had autosomal recessive OXCT deficiency. The affected girl had tachypnea, metabolic acidosis, and ketonuria at the age of 36 hours, and responded promptly to treatment. At the age of 4 years, the girl showed satisfactory psychomotor and physical development but had some episodes of ketosis, vomiting, and tachypnea associated with fasting, infections, stress, or prolonged physical exertion. Kassovska-Bratinova et al. (1996) cited reports of 6 patients in whom autosomal recessive deficiency of OXCT led to sustained hyperketonemia and episodes of severe ketoacidosis.
Snyderman et al. (1998) reported SCOT deficiency in the child of a consanguineous Pakistani couple. At 15 months of age, he was physically and developmentally normal, but had experienced several episodes of severe ketoacidosis requiring admission. SCOT activity was 8% of normal. Elevated levels of beta-hydroxybutyric acid and acetoacetic acid were detected in the urine. The authors suggested that instead of being very rare, this condition may be underdiagnosed.
Baric et al. (2001) reported a new case of SCOT deficiency who presented at 6 months of age with lethargy and severe metabolic acidosis. She had had only 1 other episode and had normal physical and psychomotor development, despite only 1% of normal enzyme activity.
Hori et al. (2013) reported a 7-month-old boy of Mexican origin with SCOT deficiency confirmed by genetic analysis that identified a homozygous mutation in the PXCT1 gene (601424.0007). The patient had recurrent ketoacidotic episodes in association with recurrent infections beginning at age 7 months. He then had permanent ketosis. Patient fibroblasts showed less than 10% residual OXCT1 activity and lack of detectable protein on immunoblot analysis.
Fukao et al. (1996) described prenatal diagnosis of SCOT deficiency in a fetus whose sib represented the first case of SCOT deficiency identified in Japan (Sakazaki et al., 1995). In the fetus, SCOT activity was not detected in either chorionic villi or cultured amniocytes. No elevated accumulation of 3-hydroxybutyrate or acetoacetate was detected in the amniotic fluid of the fetus.
The transmission pattern of SCOTD in the patient reported by Perez-Cerda et al. (1992) and Kassovska-Bratinova et al. (1996) was consistent with autosomal recessive inheritance.
To screen for mutations in the patient reported by Perez-Cerda et al. (1992), Kassovska-Bratinova et al. (1996) amplified and cloned cDNA fragments containing the entire OXCT coding sequence from the patient and her consanguineous parents. They found the patient to be homozygous for a nonsense mutation (S283X; 601424.0001), which proved incompatible with normal enzyme function.
Fukao et al. (2000) reported 3 novel missense mutations in the SCOT gene in 3 patients with SCOT deficiency. One of the mutations (V221M; 601424.0006) is associated with a detectable level of SCOT protein in fibroblasts and with a mild clinical course.
Berry et al. (2001) reported an additional case of SCOT deficiency who presented at 4 days of age with hypoglycemia, ketoacidosis, and coma. The hypoglycemic tendency was observed only in the first month of life. Nine percent residual SCOT activity and undetectable cross-reactive protein were noted in fibroblasts, and the patient was found to be homozygous for a G234E mutation (601424.0004). By 7 years of age, recurrent episodes of ketoacidosis superimposed on persistent hyperketonemia had resulted in over 25 hospitalizations requiring IV fluid, glucose, and sodium bicarbonate therapy. He had normal growth but developmental delay and attention deficit-hyperactivity disorder. Berry et al. (2001) concluded that the presence of hypoglycemia does not exclude the diagnosis of SCOT deficiency in infancy.
Baric, I., Sarnavka, V., Fumic, K., Maradin, M., Begovic, D., Ruiter, J. P. N., Wanders, R. J. A. A new case of succinyl-CoA:acetoacetate transferase deficiency: favourable course despite very low residual activity. J. Inherit. Metab. Dis. 24: 81-82, 2001. [PubMed: 11286388] [Full Text: https://doi.org/10.1023/a:1005671109585]
Berry, G. T., Fukao, T., Mitchell, G. A., Mazur, A., Ciafre, M., Gibson, J., Kondo, N., Palmieri, M. J. Neonatal hypoglycaemia in severe succinyl-CoA:3-oxoacid CoA-transferase deficiency. J. Inherit. Metab. Dis. 24: 587-595, 2001. [PubMed: 11757586] [Full Text: https://doi.org/10.1023/a:1012419911789]
Fukao, T., Mitchell, G. A., Song, X.-Q., Nakamura, H., Kassovska-Bratinova, S., Orii, K. E., Wraith, J. E., Besley, G., Wanders, R. J. A., Niezen-Koning, K. E., Berry, G. T., Palmieri, M., Kondo, N. Succinyl-CoA:3-ketoacid CoA transferase (SCOT): cloning of the human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations. Genomics 68: 144-151, 2000. [PubMed: 10964512] [Full Text: https://doi.org/10.1006/geno.2000.6282]
Fukao, T., Song, X.-Q., Watanabe, H., Hirayama, K., Sakazaki, H., Shintaku, H., Imanaka, M., Orii, T., Kondo, N. Prenatal diagnosis of succinyl-coenzyme A:3-ketoacid coenzyme A transferase deficiency. Prenatal Diag. 16: 471-474, 1996. [PubMed: 8844009] [Full Text: https://doi.org/10.1002/(SICI)1097-0223(199605)16:5<471::AID-PD898>3.0.CO;2-E]
Hori, T., Fukao, T., Murase, K., Sakaguchi, N., Harding, C. O., Kondo, N. Molecular basis of two-exon skipping (exons 12 and 13) by c.1248+5g-a in OXCT1 gene: study on intermediates of OXCT1 transcripts in fibroblasts. Hum. Mutat. 34: 473-480, 2013. [PubMed: 23281106] [Full Text: https://doi.org/10.1002/humu.22258]
Kassovska-Bratinova, S., Fukao, T., Song, X.-Q., Duncan, A. M. V., Chen, H. S., Robert, M.-F., Perez-Cerda, C., Ugarte, M., Chartrand, C., Vobecky, S., Kondo, N., Mitchell, G. A. Succinyl CoA:3-oxoacid CoA transferase (SCOT): human cDNA cloning, human chromosomal mapping to 5p13, and mutation detection in a SCOT-deficient patient. Am. J. Hum. Genet. 59: 519-528, 1996. [PubMed: 8751852]
Middleton, B., Day, R., Lombes, A., Saudubray, J. M. Infantile ketoacidosis associated with decreased activity of succinyl-CoA:3-ketoacid CoA-transferase. J. Inherit. Metab. Dis. 10 (suppl. 2): 273-275, 1987.
Mitchell, G. A., Kassovska-Bratinova, S., Boukaftane, Y., Robert, M.-F., Wang, S. P., Ashmarina, L., Lambert, M., Lapierre, P., Potier, E. Medical aspects of ketone body metabolism. Clin. Invest. Med. 18: 193-216, 1995. [PubMed: 7554586]
Perez-Cerda, C., Merinero, B., Sanz, P., Jimenez, A., Hernandez, C., Garcia, M. J., Ugarte, M. A new case of succinyl-CoA:acetoacetate transferase deficiency. J. Inherit. Metab. Dis. 15: 371-373, 1992. [PubMed: 1405472] [Full Text: https://doi.org/10.1007/BF02435979]
Sakazaki, H., Hirayama, K., Murakami, S., Yonezawa, S., Shintaku, H., Sawada, Y., Fukao, T., Watanabe, H., Orii, T., Isshiki, G. A new Japanese case of succinyl-CoA:3-ketoacid CoA-transferase deficiency. J. Inherit. Metab. Dis. 18: 323-325, 1995. [PubMed: 7474899] [Full Text: https://doi.org/10.1007/BF00710423]
Snyderman, S. E., Sansaricq, C., Middleton, B. Succinyl-CoA:3-ketoacid CoA-transferase deficiency. Pediatrics 101: 709-711, 1998. [PubMed: 9521962] [Full Text: https://doi.org/10.1542/peds.101.4.709]
Spence, M. W., Murphy, M. G., Cook, H. W., Ripley, B. A., Embil, J. A. Succinyl CoA:3-ketoacid CoA transferase deficiency: a 'new' phenotype? (Abstract) Pediat. Res. 7: 394 only, 1973.
Tildon, J. T., Cornblath, M. Succinyl-CoA: 3-ketoacid CoA-transferase deficiency. A cause for ketoacidosis in infancy. J. Clin. Invest. 51: 493-498, 1972. [PubMed: 4258782] [Full Text: https://doi.org/10.1172/JCI106837]