HMG-CoA lyase deficiency is a rare genetic disorder characterized by the deficiency of an enzyme that is necessary for the synthesis of ketone bodies and metabolism of leucine, an essential amino acid. Thus, patients present with severe and potentially life-threatening hypoglycemia, metabolic acidosis without ketosis, hyperammonemia, and even coma when introduced to dietary protein. The diagnosis may be difficult to attain, which is why a comprehensive workup is vital.
3-Hydroxy-3-Methylglutaryl (or HMG) CoA lyase deficiency is an autosomal recessive genetic disorder that is rarely encountered in clinical practice, although several reports have stressed a rather high prevalence in certain parts of the world such as Saudi Arabia and Portugal    . The pathogenesis and the clinical presentation arise from the inability of the affected patients to synthesize ketone bodies, on one hand, (which are one of the primary source of energy during fasting) and degrade one of the essential amino acids leucine    . As a result, excessive accumulation of ammonia (hyperammonemia), metabolic acidosis and hypoketotic hypoglycemia develop during the first year of life    . These metabolic changes induce symptoms when infants are introduced to dietary protein for the first time, or during prolonged fasting (eg. viral infections)  . Nausea, vomiting, lethargy and hypotonia are most important symptoms, whereas respiratory distress and coma are reported in severe cases  . Hypoglycemic crises are strikingly similar to severe stages of Reye's syndrome, and can lead to irreversible neurological sequelae (psychomotor retardation, epilepsy), cardiomyopathy, pancreatitis, or even death, as mortality rates are estimated at 20% according to certain reports     . For this reason, prompt recognition is vital in preventing complications. Some individuals, on the other hand, in whom the daily diet contains limited amounts of fat and protein, may be completely asymptomatic for a prolonged period of time .
The role of a properly obtained patient history (primarily from the parents due to the young age of the patient) is vital in recognizing the typical signs and symptoms of HMG-CoA lyase deficiency. Physicians should inquire about dietary habits, the amount of protein and fat intake on a daily basis, and evaluate if patients were predisposed to metabolic crises by fasting states, such as recent infections or profound physical activity  . As soon as clinical criteria suggest a hypoglycemic state, serum glucose levels must be measured, followed by a detailed laboratory workup. Urinalysis (specifically gas chromatography-mass spectrometry, or GC/MS), however, is used as a definite method for recognizing HMG-CoA lyase deficiency, during which detection of organic acids - 3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-hydroxyisovaleric acids (leucine metabolites), provides important clues to the diagnosis   . Further confirmation can be achieved through more advanced studies that evaluate the enzymatic activity of HMG-CoA lyase and genetic testing. The HMGCL gene, for whom dozens of mutations have been described, is located on chromosome 1  .