Action of the toxin

Hypoglycine A (HGA) and methylenecyclopropylglycine (MCPrG) are not toxic by themselves but become toxic after ingestion and metabolization into harmful compounds. HGA is metabolized into methylenecyclopropylacetyl-CoA (MCPA-CoA) and MCPrG into methylenecyclopropylformyl-CoA (MCPF-CoA) in two steps through two enzymes: branched-chain aminotransferase and branched-chain α-ketoacid dehydrogenase. MCPA-CoA and MCPF-CoA can bind to glycine and carnitine, and it is in this bound form that they are found in the blood or urine.

These toxic metabolites lead to the inhibition of beta-oxidation of fatty acids (in the mitochondria), causing muscle cells to be unable to use lipids as an energy source. More specifically, MCPA-CoA inhibits acyl-CoA dehydrogenase, and MCPF-CoA inhibits enoyl-CoA hydratase, 3-oxoacyl-CoA thiolase, and to a lesser extent, acyl-CoA dehydrogenase. Their ability to use carbohydrates is preserved to some extent. These molecules also interfere, to a lesser extent, with amino acid metabolism.

These biochemical disorders lead to the accumulation of degradation products from energy metabolism (including acylcarnitines) in the blood. The resulting biochemical profile (a significant increase in acylcarnitines in the blood) helps confirm the diagnosis of atypical myopathy.

The muscles most affected are those that work continuously (as they are rich in mitochondria, which are affected by the toxins): the muscles involved in posture, respiration, and the heart. Due to the lack of energy, these muscles degrade and release a molecule called myoglobin into the blood, which tints the urine red (pigmenturia) in equines suffering from atypical myopathy.

In this diagram:

- Metabolites in red are increased in horses affected by atypical myopathy.

- Toxic compounds are represented in blue.

- Metabolic pathways are depicted within yellow ellipses.

- Enzymes are represented in brown.

Legend:

HGA: hypoglycin A; MCPA: methylenecyclopropylacetyl-CoA; CoA: coenzyme A; CPT: carnitin palmitoyltransferase; CACT: carnitin acylcarnitin translocase; MCPF: methylenecyclopropylformyl-CoA; MCPrG: methylenecyclopropylglycine; Interior: inner mitochondrial membrane; Exterior: outer mitochondrial membrane.