L2HGDH Missense Variant in a Cat with L-2-Hydroxyglutaric Aciduria

Genes (Basel). 2021 May 1;12(5):682. doi: 10.3390/genes12050682.


A 7-month-old, spayed female, domestic longhair cat with L-2-hydroxyglutaric aciduria (L-2-HGA) was investigated. The aim of this study was to investigate the clinical signs, metabolic changes and underlying genetic defect. The owner of the cat reported a 4-month history of multiple paroxysmal seizure-like episodes, characterized by running around the house, often in circles, with abnormal behavior, bumping into obstacles, salivating and often urinating. The episodes were followed by a period of disorientation and inappetence. Neurological examination revealed an absent bilateral menace response. Routine blood work revealed mild microcytic anemia but biochemistry, ammonia, lactate and pre- and post-prandial bile acids were unremarkable. MRI of the brain identified multifocal, bilaterally symmetrical and T2-weighted hyperintensities within the prosencephalon, mesencephalon and metencephalon, primarily affecting the grey matter. Urinary organic acids identified highly increased levels of L-2-hydroxyglutaric acid. The cat was treated with the anticonvulsants levetiracetam and phenobarbitone and has been seizure-free for 16 months. We sequenced the genome of the affected cat and compared the data to 48 control genomes. L2HGDH, coding for L-2-hydroxyglutarate dehydrogenase, was investigated as the top functional candidate gene. This search revealed a single private protein-changing variant in the affected cat. The identified homozygous variant, XM_023255678.1:c.1301A>G, is predicted to result in an amino acid change in the L2HGDH protein, XP_023111446.1:p.His434Arg. The available clinical and biochemical data together with current knowledge about L2HGDH variants and their functional impact in humans and dogs allow us to classify the p.His434Arg variant as a causative variant for the observed neurological signs in this cat.

Keywords: Felis catus; animal model; metabolism; metabolite repair; neurology; precision medicine; seizure.

Publication types

  • Case Reports

MeSH terms

  • Alcohol Oxidoreductases / genetics*
  • Animals
  • Anticonvulsants / administration & dosage
  • Anticonvulsants / therapeutic use
  • Brain Diseases, Metabolic, Inborn / drug therapy
  • Brain Diseases, Metabolic, Inborn / genetics
  • Brain Diseases, Metabolic, Inborn / pathology
  • Brain Diseases, Metabolic, Inborn / veterinary*
  • Cat Diseases / drug therapy
  • Cat Diseases / genetics*
  • Cat Diseases / pathology
  • Cats
  • Female
  • Genetic Testing / veterinary
  • Levetiracetam / administration & dosage
  • Levetiracetam / therapeutic use
  • Mutation, Missense


  • Anticonvulsants
  • Levetiracetam
  • Alcohol Oxidoreductases

Supplementary concepts

  • 2-Hydroxyglutaricaciduria