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

Area of Science:

• Veterinary Neurology
• Metabolic Disorders
• Canine and Feline Genetics

Background:

• L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare metabolic disorder.
• Investigating the genetic basis of L-2-HGA in felines is crucial for understanding its pathophysiology and developing targeted therapies.

Observation:

• A 7-month-old domestic longhair cat presented with a 4-month history of paroxysmal seizure-like episodes, abnormal behavior, and neurological deficits.
• Brain MRI revealed multifocal T2-weighted hyperintensities in the grey matter of the prosencephalon, mesencephalon, and metencephalon.
• Elevated urinary L-2-hydroxyglutaric acid levels confirmed the diagnosis of L-2-HGA.

Findings:

• Whole-genome sequencing identified a private homozygous variant (XM_023255678.1:c.1301A>G) in the L2HGDH gene, predicted to cause a His434Arg amino acid change (XP_023111446.1:p.His434Arg).
• This variant in L-2-hydroxyglutarate dehydrogenase is classified as causative for the observed neurological signs, based on existing knowledge of L2HGDH variants in humans and dogs.
• The cat achieved seizure control for 16 months with anticonvulsant therapy (levetiracetam and phenobarbitone).

Implications:

• This research elucidates the genetic etiology of L-2-HGA in a feline model, expanding the known spectrum of this metabolic disorder.
• The findings contribute to the understanding of L2HGDH gene function and its role in neurological health across species.
• This case highlights the importance of advanced genetic analysis in diagnosing rare metabolic diseases in veterinary medicine.