Knowledge on rare diseases and orphan drugs

Over 30 cases have been reported to date.

Neonatal onset occurs in half of patients, presenting with a first ketoacidotic attack 2-4 days after birth. Patients with later onset present with an initial episode of ketoacidosis between 6-20 months of age. Initial episodes are often severe, and further episodes may be triggered by metabolic stress, infection or extended periods of fasting. Symptoms include tachypnea, vomiting, lethargy, hypotonia, and, in severe cases, coma. Episode intensity and frequency is variable and severe attacks are potentially fatal. Patients are generally healthy and develop normally between episodes, but infants may present with failure to thrive and poor feeding prior to diagnosis. Cardiomegaly has developed in two cases and may lead to congestive heart failure.

This disease is caused by mutations in the OXCT1 gene (5p13) that encodes the mitochondrial enzyme, succinyl-CoA:3-oxoacid CoA transferase, essential for ketone body metabolism in all extrahepatic tissue. Over 30 different mutations to OXCT1 have been identified, all leading to the accumulation of ketone bodies and ketoacidosis during periods of catabolic stress. Partial loss-of-function mutations have been identified that also lead to severe ketoacidosis, but without permanent ketosis.

Permanent ketosis or persistent ketouria are pathognomic features; however, some mild cases may not present with these signs. Patients display metabolic acidosis during crises and both serum and urinalysis reveal high levels of ketones, pH levels between 6.8 and 7.12, and HCO3 levels between 3-8 mmol/L may be observed. There is no characteristic organic acid or acylcarnitine profile. The ratio of free fatty acids to total ketone bodies becomes less than 0.3 during a short fast and this may lead one to suspect the disease. Enzyme activity assays using fibroblasts, lymphocytes or platelets reveal a lack, or great reduction, of functional succinyl-CoA:3-oxoacid CoA transferase.

Differential diagnoses include physiological ketosis (e.g. ketoacidosis due to significant catabolism due to rotavirus infection) and ketoacidosis due to beta-ketothiolase deficiency or monocarboxylate transporter 1 deficiency.

Prenatal diagnosis by enzyme activity assays is possible using cultured amniocytes.

The pattern of inheritance is autosomal recessive and genetic counseling should be offered to affected families. There is a 25% risk of disease transmission to offspring where both parents are unaffected carriers.

Ketoacidotic crises must be treated immediately with intravenous fluid therapy including enough glucose, even when patients show normo- or hyper-glycemia, to suppress ketogenesis. Treatment of metabolic acidosis using sodium bicarbonate is controversial. Minimal usage of sodium bicarbonate is recommended. Patients must avoid prolonged fasting. A fat-rich diet which induces ketogenesis should be avoided. Protein restriction may be not necessary, because the effect of prevention of ketoacidosis is not proven. Home monitoring of urinary ketones helps parents to follow the patient's condition. Carbohydrate-rich food or drink should immediately be provided if ketone levels are higher than usual. If patients become weak or vomit, intravenous glucose infusions should be considered. There is no recommended medication for the chronic phase. The use of oral sodium bicarbonate and L-carnitine have been reported in the literature, but the effect of prevention of ketoacidosis attack is not proven. Affected females should be closely monitored during pregnancy and delivery.

Risk of premature death is highest during the neonatal and infantile period due to severe episodes of ketoacidosis. However, the frequency and severity of ketoacidosis decreases after 10 years of age; thus, beyond this period, life expectancy maybe as good as in the general population. Normal growth and development is expected when proper treatment and diet are followed.

Last update: February 2020 - Expert reviewer(s): Pr Toshiyuki FUKAO - Dr Hideki MATSUMOTO