Background
Holocarboxylase synthetase (HCS) was identified as a distinct inborn error of metabolism in 1980, after about a decade of reports of children presenting with curious metabolic derangements indicating abnormal function of several carboxylase enzymes: 3-methylcrotonyl-CoA carboxylase (3MCC), pyruvate carboxylase (PC), acetyl-CoA carboxylase (ACC), and propionyl-CoA carboxylase (PCC). Several children became critically ill, ultimately succumbing to complications of severe metabolic acidosis, but there were signs that supplementation with pharmacologic doses of biotin (vitamin B7) could improve patient outcomes. [1, 2] By 1980, Roth et al put a name to the disorder that was unified by deficient activity of HCS, the enzyme involved in binding biotin to apocarboxylases (3MCC, PC, ACC, PCC), and thus allowing for the generation of active form of the enzymes (ie, holocarboxylases). [3] Genetic etiology, phenotypic variety, and long-term outcomes have been elicited over the years, further characterizing the nature of this rare disorder of biotin metabolism.
Pathophysiology
Biotin (vitamin B7) serves as a key coenzyme to carboxylases, enzymes that catalyze the addition of a carboxyl group to a unique substrate. Holocarboxylase synthetase (HCS) is the enzyme that binds biotin to the inactive form of carboxylases (apocarboxylases) into the active form (holocarboxylases) that can perform its role in metabolic pathways (see figure below). The five carboxylases are 3-methylcrotonyl-CoA carboxylase (3MCC), pyruvate carboxylase (PC), cytosolic and mitochondrial acetyl-CoA carboxylase (ACC 1 and 2, respectively), and propionyl-CoA carboxylase (PCC). Each of the four holocarboxylases serves a distinct purpose in metabolism: 3MCC is involved in the catabolism of the amino acid leucine; PC catalyzes a crucial step in gluconeogenesis; ACC is key to fatty acid synthesis; and PCC is required for metabolism of branched chain amino acids and odd-chain fatty acids. Biotin is then released from the enzymes via biotinidase, so that it can be recycled. [4] In recent years, it has become evident that beyond its enzymatic role describe above, HCS plays a regulatory role in the utilization of biotin, although how this contributes to the overall mechanism of disease continues to be explored. [5]
There are 2 inborn errors of biotin metabolism: holocarboxylase synthetase deficiency and biotinidase deficiency. Both result in deficient activity of all carboxylases, thus “multiple carboxylase deficiency,” however their presentations typically differ by age of onset, with biotinidase deficiency tending to present later in life, although variability does exist. [4, 6, 7] Holocarboxylase synthetase deficiency (HCSD) is an autosomal recessive disorder due to biallelic pathogenic variants in HLCS. Due to the multiple carboxylase deficiency that results, patients develop characteristic biochemical abnormalities, namely metabolic ketolactic acidosis, organic aciduria, with elevations of lactic acid, 3-hydroxyisovaleric acid, 3-methylcrotonic acid, 3-methylcrotonylglycine, 3-hydroxypropionic acid, and methylcitric acid, elevated C3 and C5-OH on acylcarnitine analysis, and hyperammonemia due to secondary inhibition of the urea cycle. [4, 6, 8, 9] If patients are left untreated, these abnormalities result in critical illness similar to that seen in other organic acidurias and often lead to neonatal death.
Epidemiology
Frequency
Holocarboxylase synthetase deficiency (HCSD) is a very rare inborn error of metabolism, with an estimated prevalence at birth of 1 in 200,000. [8] There are reports of increased prevalence in certain regions, namely Japan and the Faroe Islands.
Mortality/Morbidity
Without treatment, HCSD is fatal. With treatment, morbidity depends on the length of delay in diagnosis and the extent of damage incurred from severe metabolic acidosis.
Sex
HCSD is inherited in an autosomal recessive manner, therefore it affects males and females at an equal rate.
Age
Clinical onset of HCSD typically occurs before 3 months of age, although variability exists. [6] With the advent of newborn screening, the majority of infants in the US are identified prior to onset of symptoms.
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Urea cycle. Compounds that comprise the urea cycle are numbered sequentially, beginning with carbamyl phosphate. At the first step (1), the first waste nitrogen is incorporated into the cycle; also at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (4); the reaction is mediated by argininosuccinate (ASA) synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
