A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2-hydroxyglutaric aciduria

Here we describe an 8？month old Yorkshire terrier that presented with episodes of hyperactivity and aggressive behavior. Between episodes, the dog’s behavior and neurologic examinations were normal. A T2 weighted MRI of the brain showed diffuse grey matter hyperintensity and a urine metabolite screen showed elevated 2-hydroxyglutaric acid. We sequenced all 10 exons and intron-exon borders of L2HGDH from the affected dog and identified a homozygous A to G transition in the initiator methionine codon. The first inframe methionine is at p.M183 which is past the mitochondrial targeting domain of the protein. Initiation of translation at p.M183 would encode an N-terminal truncated protein unlikely to be functional.We have identified a mutation in the initiation codon of L2HGDH that is likely to result in a non-functional gene. The Yorkshire terrier could serve as an animal model to understand the pathogenesis of L-2-hydroxyglutaric aciduria and to evaluate potential therapies.L-2 hydroxyglutaric aciduria (L-2-HGA) was first described in 1980 in a young boy with psychomotor retardation and musculoskeletal dystrophy [1]. This rare autosomal recessive inherited disease is characterized by an elevated concentration of L-2-hydroxyglutaric acid in plasma, cerebrospinal fluid, and urine [1]. In human patients, the clinical features are mild psychomotor delay, followed by progressive cerebellar ataxia, dysarthria, moderate to severe mental deterioration and in some cases seizures [2,3]. Magnetic resonance imaging (MRI) of L-2-HGA patients shows abnormal signal in the peripheral subcortical white matter, basal ganglia and dentate nuclei. Also, cerebellar atrophy is present. The distribution of signal abnormalities in the MRI of L-2-HGA patients is distinct and differentiates it from other diseases [4,5].In 2004, mutations in L2HGDH were shown to cause human L-2-HGA [3,6]. L2HGDH is comprised of 10 exons which encode a protein of 463 amino acids that contains a N-terminal mitochon