Unripe Akee Fruit & Pivalic Acid Generating Antibiotics- Mimics of Carnitine Deficiency

In the 1950s, researchers noticed that people in Jamaica, who ate the unripe fruit of Akee tree, usually in the cold season, developed a constellation of symptoms comprising vomiting, hypoglycaemia and altered sensorium. The putative component was therefore named "hypoglycin" and later identified as methylenecyclopropane acetic acid (MCPA). It turned out that MCPA inhibited several acyl-coA dehydrogenases, namely those pertaining to isovaleryl-coA, glutaryl-coA and isobutyryl co-A. These fatty acids are complexed to carnitine and therefore lead to secondary carnitine deficiency. Plasma acylcarnitines relevant to these fatty acids are thus raised, accompanied by an increase in urinary dicarboxylic organic acids such as ethylmalonic acid and suberic acid, presumably formed by w-oxidation of the involved fatty acids, given that beta-oxidation is blocked. Thus, subjects eating unripe Akee fruit had features mimicking several disorders that shared defective beta-oxidation of fatty acids as their underlying aetiology, such as medium chain acyl-coA dehydrogenase deficiency and isovaleric acidemia (both of which are screened for in the UK through a heel prick test 5 days after birth in all neonates as part of the national newborn screening programme).

A similar picture can be seen in subjects taking prolonged courses of certain antibiotics (mostly for prophylaxis against recurrent infections). These antibiotics, namely pivmecillinam (widely used in the UK for UTI), pivampicillin (only used in Denmark), and cefditoren pivoxil (Spectracef) all have pivalic acid as one of their metabolites. Pivalic acid is excreted as pivaloylcarnitine, and thus can lead to secondary carnitine deficiency, and the familiar symptoms of nonketotic hypoglycaemia, vomiting and abdominal pain. Prolonged courses of these antibiotics is therefore inadvisable.