3-Hydroxymethylglutaryl CoA (HMG-CoA) Lyase is an enzyme which catalyzes the last step of ketogenesis from fatty acids, and thus plays a major role in fatty acid catabolism. This enzyme also plays a vital role in the breakdown of the amino acid leucine. The actual reaction catalyzed by the enzyme is the divalent cation-dependent cleavage of HMG-CoA to form acetyl-CoA and acetoacetate. A deficiency of this enzyme results in the inability of the body to metabolize fatty acids as well as proteins properly. Lack of ketones leads to hypoglycemia and organic acids build up in the blood causing acidemia. The effect is prominent during periods of fasting, where HMG-CoA accumulates to dangerous levels, particularly in tissues of the central nervous system. Usually, the symptoms of HL Deficiency occur within the first year of life and affected children present with signs and symptoms typical of metabolic disorders. These include vomiting, lethargy, hypotonia, developmental delays, encephalopathy, seizures, and hepatomegaly. If left untreated, the condition can get severe, resulting in coma, followed by death. HL deficiency is relatively common in Arabic populations but seems to be rare in Europe. In Saudi Arabia, HL Deficiency has been reported to be the most common organic acidemia.
Symptoms of hypoglycemia, metabolic acidosis, low bicarbonate levels, hyperammonemia, and reduced ketones in urine point towards HL Deficiency. However, diagnosis can only be confirmed either through serum or urine organic acid analysis through high resolution chromatography and spectrometry, measurement of enzyme activity in leukocytes or fibroblasts, or genetic testing. Urine or blood culture may also be required in order to rule out Reye Syndrome, a disorder in children with similar symptoms, but caused due to infection.