Inborn error of fatty acid beta-oxidation due to medium-chain acyl-CoA dehydrogenase deficiency (ACADM/MCAD). It prevents the energetic use of fatty acids during fasting or exertion, producing hypoketotic hypoglycemia with acidosis and a risk of collapse or sudden death. It has been described in the Cavalier King Charles Spaniel and is inherited in a recessive manner.

Specific to the Cavalier King Charles Spaniel. In genotyping of 162 additional CKCS the variant allele frequency was 23.5%, with 12 additional mutant homozygotes (Christen et al. 2022, PMID 36292732); the variant was not found in 923 control genomes from other breeds.

- Episodes of hypoglycemia after fasting or exercise
- Post-exercise or post-fasting collapse
- Lethargy and weakness
- Risk of sudden death in puppies
- Hypoketotic hypoglycemia and suggestive organic aciduria on laboratory testing

MCAD deficiency was described in the Cavalier King Charles Spaniel from cases of collapse and sudden death in puppies, with biochemistry of hypoketotic hypoglycemia. Molecular studies associated it with a variant of the ACADM gene that reduces enzyme activity, analogous to the human deficiency. Its characterization enabled a carrier genetic test for the breed.

- Test breeding animals before mating
- Do not mate two carriers: 25% risk of affected homozygotes
- A carrier can be mated to a clear animal; test offspring intended for breeding
- Avoid spreading the allele to lines where it does not exist
- In known homozygotes, avoid prolonged fasting and manage exercise

Differential diagnosis with other causes of collapse and sudden death in the Cavalier (degenerative mitral valve disease, syncopal collapse, epilepsy) and with other beta-oxidation errors. Laboratory findings of hypoketotic hypoglycemia and the acylcarnitine profile are suggestive; the genetic test confirms carrier status. Management of homozygotes includes avoiding fasting and offering frequent carbohydrate-rich meals.

1. Christen M, Bongers J, Mathis D, Jagannathan V, Quintana RG, Leeb T. (2022) ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency. Genes (Basel) 13:1847. PMID: 36292732