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

Abstract

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.

A novel missense variant in the L2HGDH gene in a cat with L‐2‐hydroxyglutaric aciduria and multicystic cerebral lesions

“… 3 , 4 , 7 , 8 , 9 , 10 In our cat as in the previously reported cats and dogs, the changes affected mainly the gray matter, cerebellar nuclei, cerebellar cortex, thalamus and colliculi in a bilateral and symmetrical manner. 5 , 6 Additionally, our cat had multicystic lesions affecting the subcortical white matter bilaterally, a feature that has not been reported in dogs or cats with L2HGA before. Subcortical cystic degeneration has been described in a few cases of L2HGA in humans, mostly as a late manifestation.…”

“…Unlike our cat, that died shortly after diagnosis, the two previously reported cats responded well to treatment with phenobarbital, having good seizure control. 5 , 6 The poor outcome combined with the multicystic lesions identified on MRI may indicate that the nonsense variant identified in our cat causes a more severe phenotype than the previously reported p.His434Arg missense variant. 5 In humans, limited phenotypic variation has been reported among the multiple genetic variants.…”

“…Age of onset was 7 months in our case compared to 14 months and 3 months in previously reported cases. 5 , 6 In humans, L2HGA causes only neurological signs, including psychomotor retardation, cerebellar ataxia, macrocephaly and seizures. 1 , 2 In Staffordshire bull terriers, the most common clinical signs include gait abnormalities and behavioral changes, with seizure‐like episodes observed in two‐thirds of the cases.…”

“…It is caused by genetic variants affecting the L2HGDH gene encoding L‐2‐hydroxyglutarate dehydrogenase and has an autosomal recessive mode of inheritance. 1 , 2 , 3 , 4 , 5 , 6 , 7 Disease‐causing variants have been reported in humans, dogs (Staffordshire bull terrier, Yorkshire terrier) and 1 cat. 1 , 2 , 3 , 4 , 5 The clinical signs and magnetic resonance imaging (MRI) findings in dogs and cats with L2HGA have been reported previously.…”

“… 1 , 2 , 3 , 4 , 5 , 6 , 7 Disease‐causing variants have been reported in humans, dogs (Staffordshire bull terrier, Yorkshire terrier) and 1 cat. 1 , 2 , 3 , 4 , 5 The clinical signs and magnetic resonance imaging (MRI) findings in dogs and cats with L2HGA have been reported previously. 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 Our purpose was to describe a novel candidate disease‐causing variant for L2HGA in a cat with previously unreported MRI findings and a fatal outcome.…”