L-2-Hydroxyglutaric Aciduria

L-2-hydroxyglutaric aciduria is an inherited metabolic disorder that causes the accumulation of L-2-hydroxyglutaric acid in the brain, resulting in spongiform changes mainly affecting the gray matter of certain brain areas.


The resulting symptomatology of L-2-hydroxyglutaric aciduria is extensive and includes mild motor and neurological defects in the early stages of the dog's life. Over time, symptoms worsen and signs of ataxia, tremors, seizures, hyperreflexia and coordination problems of the throat, tongue or facial muscles appear. The first clinical signs usually appear between 6 months and 1 year of age, although late-onset cases have also been reported.

Disease Management

Currently, no cure has been found for L-2-hydroxyglutaric aciduria in dogs. However, symptomatic treatment and palliative care may help to improve the animal's quality of life. The use of phenobarbitone or other anticonvulsants such as levetiracetam may help to control seizure activity in affected dogs. However, further research is still needed to determine the effectiveness of anticonvulsant therapy in these cases.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the dog, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected dog must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

L-2-hydroxyglutaric aciduria is a metabolic disease in dogs caused by the accumulation of L-2-hydroxyglutaric acid, a toxic metabolite. This accumulation occurs due to deficiency of the enzyme L-2-hydroxyglutarate dehydrogenase, which is responsible for breaking down L-2-hydroxyglutaric acid and converting it into a Krebs cycle intermediate. The L2HGDH gene encodes the L-2-hydroxyglutarate enzyme, and certain mutations in this gene have been linked to the disease. In the Yorkshire Terrier breed, a specific mutation (c.1A>G) has been detected in the L2HGDH gene that has been linked to L-2-hydroxyglutaric aciduria. This mutation affects the translation initiation codon and its effect on the protein is not entirely clear. It could result in a complete absence of the protein or, alternatively, there could be another translation initiation site that produces a different protein. In the Staffordshire Bull Terrier breed, a causative mutation (c.1298_1300delinsCTT) in the same gene has also been identified, however, this variant is not currently covered in our test.

Most affected breeds

  • Staffordshire Bull Terrier
  • West Highland Terrier
  • Yorkshire Terrier


Farias FH, Zeng R, Johnson GS,et al. A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2-hydroxyglutaric aciduria. BMC Vet Res. 2012 Jul 26;8:124.

Penderis J, Calvin J, Abramson C,et al. L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model. J Med Genet. 2007 May;44(5):334-40.

Sanchez-Masian DF, Artuch R, Mascort J,et al. L-2-hydroxyglutaric aciduria in two female Yorkshire terriers. J Am Anim Hosp Assoc. 2012 Sep-Oct;48(5):366-71.

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