L-2-hydroxyglutaric aciduria

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Transverse T2-weighted MRI image through the midbrain of the Yorkshire terrier with L-2-HGA, showing the symmetric hyperintensity of the cerebrum and brainstem characteristic of the disease[1]

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[2].

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[3]

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[4][5].

L-2-hydroxyglutarate induces oxidative stress and inhibits mitochondrial creatine kinase in the cerebellum[6][7]. 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[8]. 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[9].

A case of L-2-HGA was also reported in a West Highland White Terrier with clinical and MRI characteristics of the disease[10].

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[11]. 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.


  1. Farias FH et al (2012) A L2HGDH initiator methionine codon mutation in a Yorkshire terrier with L-2-hydroxyglutaric aciduria. BMC Vet Res 8:124
  2. Sanchez-Masian DF et al (2012) L-2-hydroxyglutaric aciduria in two female Yorkshire terriers. J Am Anim Hosp Assoc 48(5):366-371
  3. Abramson CJ et al (2003) L-2-Hydroxyglutaric aciduria in staffordshire bull terriers. J Vet Intern Med 17:551–556
  4. Rzem R et al (2004) A gene encoding a putative FAD‐dependent L‐2‐hydroxyglutarate dehydrogenase is mutated in L‐2‐hydroxyglutaric aciduria. Proc Natl Acad Sci USA 1011:6849–6854
  5. Rzem R et al (2006) The gene mutated in L‐2‐hydroxyglutaric aciduria encodes L‐2‐hydroxyglutarate dehydrogenase. Biochimie 88:113–116
  6. Latini A et al (2003) Induction of oxidative stress by L-2-hydroxyglutaric acid in rat brain. J Neurosci Res 74:103–110
  7. da Silva CG et al (2003) l-2-Hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats. Int J Dev Neurosci 21:217–224
  8. Van Schaftingen E et al (2009) L-2-Hydroxyglutaric aciduria, a disorder of metabolite repair. J Inherit Metab Dis 32:135–142
  9. Penderis J et al (2007) L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model. J Med Genet 44:334–340
  10. Garosi LS et al (2005) L-2-hydroxyglutaric aciduria in a West Highland white terrier. Vet Rec 156:145–147
  11. Scurrell E et al (2008) Neuropathological findings in a Staffordshire bull terrier with l-2-hydroxyglutaric aciduria. J Comp Pathol 138(2-3):160-164