In 1961, Childs et al published the earliest clinical report of a patient who was ultimately found to be affected by a deficiency of propionyl coenzyme A (CoA) carboxylase (ie, propionic acidemia).
These authors noted a series of severe ketoacidotic episodes in the child that were precipitated by protein ingestion (specifically, methionine and threonine administration) but manifested by marked elevations in plasma and urinary glycine levels. Because of these observations, the disease was given the name ketotic hyperglycinemia, a phenomenological term that inadvertently drew investigators’ efforts toward a defect in glycine metabolism and delayed elucidation of the biochemical basis. The clinical hallmark of the disease is severe ketoacidosis of an episodic nature.
In 1969, Hsia et al described the underlying defect in propionate carboxylation that occurs in patients with ketotic hyperglycinemia.
Simultaneously, Morrow et al described the concurrence of methylmalonic acidemia and ketotic hyperglycinemia; thus, although the condition had been previously considered a single disorder, it was subsequently recognized on clinical grounds to be composed of least 2 different diseases.
In 1971, subsequent studies by Hsia et al of the original patient’s sister demonstrated a specific defect in propionyl CoA carboxylase.
The study also delineated propionic acidemia from methylmalonic acidemia as a distinct biochemical disorder. Subsequent work led to further delineation of another disorder, initially called multiple carboxylase deficiency, which includes deficiency of propionyl CoA carboxylase activity in addition to defects in other carboxylases.
The defect may be present at either of 2 different gene loci. One locus, on chromosome 13, controls synthesis of the α subunit of the tetrameric enzyme apoprotein; the second locus, on chromosome 3, controls synthesis of the β subunit. The 2 types of mutations are categorized as PCCA and PCCB (also PCCC) complementation groups,
distinguishable from each other by complementation studies of cultured fibroblasts in vitro.