L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare autosomal-recessive hereditary neurological disease of Yorkshire Terriers, European Yorkshire terriers and Staffordshire Bull Terriers characterized by dementia, generalized tonic-clonic seizures and ataxia due to elevated levels of L-2-hydroxyglutaric acid in urine, blood and cerebrospinal fluid.
L-2-HGA was first described in Staffordshire Bull Terriers in 2003 and showed MRI changes similar to the human disease, with abnormal signal in the peripheral subcortical white matter, basal ganglia and dentate nuclei. Also, cerebellar atrophy was present
The genetic defect results in a L-2-hydroxyglutarate dehydrogenase deficiency, leading to the accumulation of L-2-hydroxyglutarate. L‐2‐hydroxyglutarate is converted into 2‐oxoglutarate (a widely distributed compound formed through deamination of glutamate and formed within the Krebs cycle) by l‐2‐hydroxglutarate dehydrogenase, a flavin adenine dinucleotide‐dependent dehydrogenase linked to mitochondrial membranes.
L-2-hydroxyglutarate induces oxidative stress and inhibits mitochondrial creatine kinase in the cerebellum. Also, L-2-hydroxyglutarate is a structural analog of glutamate, and thus a potential inhibitor of the many biologic processes that involve this key metabolite and neurotransmitter. The exact mechanism by which accumulation of L-2-hydroxyglutaric acid causes brain injury is still unknown.
L-2-hydroxyglutaric acid levels were elevated in urine, cerebrospinal fluid and plasma from affected dogs. The cause of this disease is thought to be a two base pair substitution in exon 10 of L2HGDH gene predicting a two amino acid substitution in Staffordshire bull terriers affected with L-2-HGA.
Clinical signs are variable, with some dogs only showing hyperactivity and aggression, whereas other are more severe with dementia, seizures and ataxia.
Histological findings include marked spongiform changes predominantly affecting the grey matter of the cerebral cortex, thalamus, cerebellum and brainstem. The spongiform changes are characterized by well-demarcated, clear vacuoles located at perineuronal and perivascular sites. Immunohistochemical and ultrastructural examination usually confirms that the affected cells are astrocytes.
Some clinical response has been shown with dietary modification and use of phenobarbital.
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