Succinyl CoA:3-Ketoacid CoA Transferase (SCOT) Deficiency - A Comprehensive Update

Introduction

Ketones are a type of chemical produced by the liver when fat breaks down. The ketones are a source of energy to the heart and the brain during fasting, long periods of exercise, or insufficient carbohydrates. Low levels of ketone do not harm the body, but a high level of ketones leads to ketoacidosis. Succinyl CoA: 3 - ketoacid CoA transferase enables the catabolism of ketones. The malfunctioning enzyme causes a build-up of new ketone bodies leading to ketoacidosis. Other causes of ketoacidosis in neonates include diabetes mellitus, type 1 glycogen storage disease, propionic acidemia, methylmalonic aciduria, and lactic acidosis.

What Is the Epidemiology of SCOT?

The age of onset is in the first four to five days or within two years of life. Since the disease is an inherited condition, family history increases the risk of developing the disease. Around 20 cases worldwide have been reported in the literature. However, the difficulty in diagnosing the disease may cause underreporting.

What Is the Cause of SCOT Deficiency?

SCOT deficiency is an autosomal recessive (2 copies of abnormal gene present) metabolic disorder. OXCT1 gene mutations cause SCOT deficiency. When the SCOT enzyme functionality is reduced, the body’s ability to break down ketone gets hampered, causing decreased energy production and high levels of ketone in the blood. Ketoacidosis attacks occur if the enzyme is partially affected by a mutation in the gene, but ketonemia is not persistent. However, ketoacidosis attacks and ketonemia are seen if the enzyme is fully compromised.

What Is the Mode of Action of the SCOT Enzyme?

SCOT catalyzes the activation of acetoacetate and succinyl CoA to acetoacetyl CoA. Enzyme conversion marks the first step in ketolysis for ATP (adenosine triphosphate) formation. Therefore, the cycle is not initiated if the SCOT enzyme is deficient. SCOT enzyme is found abundantly in the heart, brain, and muscle tissue but can also be seen in other peripheral tissue.

What Are the Functions of the SCOT Enzyme?

Energy is supplied through an alternate mechanism for the utilization of the body. In addition, SCOT is an essential enzyme for tumor development. A tumor cell that escapes the immune system uses a ketolytic route for making acetyl CoA in its mitochondria with the help of the SCOT enzyme. This energy generated enables the tumor cell to grow and differentiate.

What Are the Signs and Symptoms of SCOT Deficiency?

Ketoacidosis attack precedes hypoglycemia.

The signs and symptoms present are

• Extreme tiredness (lethargy).

• Appetite loss.

• Vomiting.

• During the febrile period, symptom manifestations are more pronounced due to the heat susceptibility of the SCOT enzyme.

• Loose motions.

• Rapid breathing.

• Tachycardia (increased heart rate).

• Seizures.

• Hypotonia is seen in acute conditions (weak muscle tone).

• Loss of consciousness.

• Metabolic acidosis.

• Hypoglycemia is seen in most patients, but in some cases, hyperglycemia is detected.

• Permanent ketosis if the enzyme is fully affected.

• The ketoacidosis later progresses to a coma.

Long-term effects

• Obesity.

• Cardiomegaly leading to congestive heart failure.

• Brain damage due to energy depletion manifests as psychomotor retardation.

• Metabolic syndrome.

• Atherosclerosis.

Ketoacidosis attacks are seen in the first four days of life or maybe late-onset. The condition is asymptomatic until a ketoacidosis attack occurs. The frequency and severity of ketoacidosis attacks reduce after ten years of life.

What Is SCOT-t?

Recent studies have isolated germ cell-specific scot-t genes in humans. The new gene exhibited slight structural changes compared to the original. The scot-t gene is localized in the midpiece of spermatozoa where mitochondria are present. This gene generates energy for spermatozoa and sperm mobility through ketolysis. Mutations to the gene lead to infertility among males. Further studies are required to analyze the gene.

How Is the SCOT Deficiency Diagnosed?

• Ketones in the blood remain elevated even when the patient is healthy.

• Urine gas chromatography-mass spectrometry shows elevated ketones in the blood.

• A urine ketone dipstick test is used to check for ketonuria. A chemical-coated dipstick is immersed in urine to react with ketone bodies leading to color change. However, this test is not useful in detecting mild ketosis.

• The ratio of free fatty acids to ketone bodies reducing below 0.3 during a short fast can cause suspicion of metabolic disorder.

• Genetic testing of OXCT1 is done to detect the disease; genomic sequencing is a confirmatory test.

• Enzyme assay of fibroblast or lymphocytes reveals a reduced enzyme level.

• Sanger sequencing using PCR (polymerase chain reaction) analyzes mutations in OXCT-1 gene.

• Skin biopsy is done to detect the SCOT enzyme in the fibroblasts of peripheral tissue.

• Prenatal diagnosis is possible by using cultured amniocytes.

• Genetic counseling is advised to expectant parents if there is any family history of the condition.

The condition is diagnosed late, leading to difficulties in treatment.

How Is SCOT Deficiency Managed?

Early management include

• Avoidance of prolonged fasting.

• Change the diet plan with carbohydrate-rich food and avoid food with high fat or limit protein content to prevent ketoacidosis. In addition, the intake of carnitine supplements is advised.

Weekly evaluation and monitoring during the febrile period are essential.

• In patients with hemodynamic stabilization, oral rehydration is sufficient.

• In very sick patients, hypoglycemia control is through IV ten percent Dextrose, and a good infusion of normal saline does dehydration correction.

• Sodium bicarbonate is used if pH drops below seven.

• Mechanical ventilation.

• Correction of metabolic acidosis.

• Seizure control.

• Peritoneal dialysis.

• Home monitoring of patients with urine dipstick test.

• If metabolic acidosis does not resolve with treatment, sepsis is suspected.

• Most patients with severe ketoacidosis recover without any functional disability. However, in some cases, there will be a neurological or psychomotor disability. In untreated cases, morbidity might be an outcome.

What Is the Differential Diagnosis for SCOT Deficiency?

• Physiological ketosis (caused by rotavirus).

• Beta-keto thiolase deficiency-keto thiolase or mitochondrial acetoacetyl-CoA thiolase plays a role in ketone body metabolism. It is an inherited disorder. The symptoms include hypoglycemia and ketosis. SCOT and beta-keto thiolase deficiency have similar clinical and biochemical presentations. Therefore, the conditions can be differentiated by enzymatic assay or molecular analysis.

• Pediatric diabetic ketoacidosis is a serious complication caused by insulin deficiency leading to diabetes mellitus. The symptoms include hyperglycemia, metabolic acidosis, and ketosis. The presence of diabetes-associated antibodies helps differentiate from SPOT.

SPOT deficiency may mimic conditions like lactic acidosis or salicylate ingestion.

Conclusion

Early diagnosis and management help prevent serious complications and improve prognosis in the initial few years of life. Then, as the child grows, the frequency and severity of the condition reduces.