Neonatal hypoglycaemia in severe succinyl‐CoA:3‐oxoacid CoA‐transferase deficiency

Abstract

Succinyl-CoA: 3-oxoacid CoA-transferase (SCOT) deficiency is an inborn error of ketone body utilization, characterized by intermittent ketoacidotic crises and persistent ketosis. The diagnosis was suspected in a patient who presented with hypoglycaemia, ketoacidosis and coma at 4 days of age. The hypoglycaemic tendency was only observed during the first month of life. A novel macromolecular labelling assay in cultured skin fibroblasts using D-3-hydroxy[3-14C]butyrate supported the diagnosis. Subsequently, 9% residual SCOT activity and undetectable cross-reactive protein were noted in fibroblasts and the patient was found to be homozygous for the G324E SCOT gene mutation. By 7 years of age, recurrent episodes of ketoacidosis superimposed on persistent hyperketonaemia had resulted in over 25 hospitalizations requiring intravenous fluid, glucose and sodium bicarbonate therapy. He has had normal growth but developmental delay and attention deficit-hyperactivity disorder. A continuous intravenous glucose infusion at 38 microlmol (6.8 mg)/kg per min reduced plasma total ketone levels from greater than 1.5 mmol/L to less than 0.5 mmol/L after 48 h. This indicates that patients with SCOT deficiency do not always manifest ketosis with administration of a sufficient amount of carbohydrates, but that even under such conditions hyperketonaemia is difficult to eliminate completely. The presence of hypoglycaemia does not exclude the diagnosis of SCOT deficiency in infancy.

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…SREBP-2, a master transcriptional regulator of cholesterol biosynthesis, and peroxisome proliferator activated receptor (PPAR)-γ are AACS transcriptional activators, and regulate its transcription during neurite development and in the liver (Aguilo et al, 2010; Hasegawa et al, 2012c). Taken together, cytoplasmic ketone body metabolism may be important in select conditions or disease natural histories, but are inadequate to dispose of liver derived ketone bodies, as massive hyperketonemia occurs in the setting of selective impairment of the primary oxidative fate via loss of function mutations to SCOT (Berry et al, 2001; Cotter et al, 2011). …”

“…Tissue-specific loss of SCOT in neurons or skeletal myocytes induces metabolic abnormalities during starvation but is not lethal (Cotter et al, 2013b). In humans, SCOT deficiency presents early in life with severe ketoacidosis, causing lethargy, vomiting, and coma (Berry et al, 2001; Fukao et al, 2000; Kassovska-Bratinova et al, 1996; Niezen-Koning et al, 1997; Saudubray et al, 1987; Snyderman et al, 1998; Tildon and Cornblath, 1972). Relatively little is known at the cellular level about SCOT gene and protein expression regulators.…”

A structural mapping of mutations causing succinyl‐CoA:3‐ketoacid CoA transferase (SCOT) deficiency

“…SCOT-deficient patients, often with neonatal onset, present with recurrent ketoacidosis episodes that could be life-threatening, but with no symptoms between episodes (Niezen-Koning et al 1997 ). The number of reported cases is few, and symptoms, which may vary among individuals, include vomiting, lethargy and tachypnea, as well as unconsciousness caused by severe ketoacidosis (Berry et al 2001 ; Sakazaki et al 1995 ; Snyderman et al 1998 ). Permanent ketosis or ketonuria is a characteristic symptom but may be absent in patients retaining residual SCOT activity (Fukao et al 2010 ; Fukao et al 2011 ; Fukao et al 2004 ).…”

hZnT8 (Slc30a8) Transgenic Mice That Overexpress the R325W Polymorph Have Reduced Islet Zn2+ and Proinsulin Levels, Increased Glucose Tolerance After a High-Fat Diet, and Altered Levels of Pancreatic Zinc Binding Proteins

“…SCOT is a mitochondrial enzyme that catalyzes the reversible transfer of CoA from acetoacetyl-CoA to succinate to form acetoacetate and succinyl-CoA, a reaction in the gluconeogenesis pathway. Physiologically, its enzymatic activity is involved in maintaining the blood glucose level (38). …”