Beta-ketothiolase deficiency (ORPHA:134)
A rare, genetic organic aciduria affecting ketone body metabolism and the catabolism of isoleucine and characterized by intermittent ketoacidotic episodes associated with vomiting, dyspnea, tachypnoea, hypotonia, lethargy and coma, with an onset during infancy and usually ceasing by adolescence.
Epidemiology
The estimated birth prevalence ranges between 1/100,000 to 230,000 worldwide.
Clinical description
Children often appear normal at birth with disease presentation typically between the ages of 5 months to 2 years; however, presentation may occur anywhere between birth and childhood. The onset of symptoms usually occurs in the form of a ketoacidotic crisis, most often brought on by stress, fasting, acute illness and/or infections (i.e. gastroenteritis), and rarely by increased dietary protein intake. An acetone or fruity odor on the breath often signals ketoacidosis. These episodes are associated with vomiting, dyspnea, lethargy and unconsciousness, and can lead to coma and death if not treated. Neurological sequelae (such as developmental delay) following severe episodes are common. Rarely, patients present with signs of metabolic encephalopathy (hypotonia, dysarthria, chorea, developmental delay). The occurrence of developmental delay or neurological manifestations before a first ketoacidotic crisis, however, is rare. The frequency of episodes decreases with age, eventually stopping before adolescence. In between episodes, patients are often asymptomatic.
Etiology
This disease is caused by mutations (over 100 described) in the gene, ACAT1 (11q22.3). This gene encodes the enzyme acetyl-CoA acetyltransferase which, when its activity is reduced or absent, impairs the breakdown of isoleucine and acetoacetyl- CoA, hampering the utilization of ketone bodies and leading to toxic accumulations of isoleucine derived acyl-CoA esters in the body.
Diagnostic methods
Most patients are diagnosed by demonstrating metabolic acidosis and ketosis, by urinary organic acid analysis (2-methyl-3-hydroxybutyrate (the most reliable marker), 2- methylacetoacetate and tiglylglycine), or by acylcarnitine analysis during metabolic decompensation. Diagnosis can be confirmed by cultured fibroblast enzyme assays (reduced potassium-dependent acetoacetyl-CoA thiolase activity) and molecular genetic testing. Computed tomography of the brain may reveal basal ganglia lesions that have been reported in some patients. Newborn screening programs are available in certain countries including the U.S. and Australia.
Differential diagnosis
The differential diagnosis includes sepsis, other organic acidurias, HSD10 disease and succinyl-CoA:3-ketoacid CoA transferase deficiency, and other conditions that cause ketoacidosis in childhood.
Antenatal diagnosis
In families with a known disease causing mutation, prenatal testing is possible by molecular genetic testing or enzyme activity assays using cultured amniocytes.
Genetic counseling
The pattern of inheritance is autosomal recessive. The risk of inheriting the disease is 25% where both parents are unaffected carriers.
Management and treatment
During a ketoacidotic crisis, intravenous fluids with glucose and electrolytes should be administered immediately. Bicarbonate (initially as 1mmol/kg over 10 minutes followed by continuous infusion) should be given to treat acidosis. Carnitine supplementation may be helpful. Dialysis is effective but usually not necessary. Unconscious patients and those with severe dyspnea may require mechanical ventilation. Long-term management involves avoidance of fasting (and intravenous glucose in cases of fever or vomiting) and, in children, a mildly restricted protein intake (1.5-2g/kg/day), avoidance of fat-rich (ketogenic) diet, and L-carnitine therapy in those with low carnitine levels. Avoidance of isoleucine overload might prevent neurological complications, but currently there is no evidence to support this.
Prognosis
The prognosis is often good if detected early and treated properly so as to prevent ketoacidotic attacks.

                            Last update: 
                            March 2020


                            - Expert reviewer(s): 
                            Pr Toshiyuki FUKAO  - Dr Hideo SASAI