Screened for by all state newborn screening (NBS) programs in the United States, mitochondrial
acetoacetyl-coenzyme A thiolase (T2), or β-ketothiolase, deficiency is a rare autosomal recessive disorder that causes
ketoacidosis and
hypoglycemia/
hyperglycemia. Outcomes vary from normal development to severe
cognitive impairment or even death after an acute episode of
ketoacidosis. The classical biochemical profile of
T2 deficiency is a result of null mutations in both alleles of the ACAT1 gene and consists of persistently increased urinary excretion of
ketones, characteristic organic
acids, and
tiglylglycine as well as abnormal blood or plasma
acylcarnitine profiles in acute and stable conditions. Early diagnosis and aggressive management can prevent further episodes of
ketoacidosis and lead to normal development. We report the cases of 3 children, all subsequently found to have mutations predicted to be associated with no residual T2 enzymatic activity, but only 1 was identified by NBS in Minnesota since 2001. To our knowledge, this is the first description of compound heterozygotes for null mutations associated with no enzymatic activity exhibiting normal urinary organic
acid, blood, and plasma
acylcarnitine profiles when clinically well, thereby explaining the false-negative NBS results. We suggest that
T2 deficiency may be underrecognized, because the incidence of
T2 deficiency in Minnesota, on the basis of these 3 cases, is 1 in 232 000, higher than the reported <1 in 1 million incidence. Our cases emphasize that
T2 deficiency must be considered in patients who present with
ketoacidosis disproportionately severe to the triggering illness despite normal NBS results or nonspecific biochemical findings in blood and urine during asymptomatic periods.