L-2-hydroxyglutaric aciduria in Staffordshire bull terrier (L-2-HGA)

L-2-HGA (L-2-hydroxyglutaric aciduria) is a neurometabolic disease causing various clinical neurological problems, including psychomotor retardation, seizures (like epilepsy) or ataxia (observed as "shaky walking", muscle stiffness). Aciduria disease is characterized by accumulation of L-2-hydroxyglutaric acid in urine, plasma and coeliolymph. The disease affects Staffordshire bull terriers.

In a healthy organism L-2-hydroxyglutarate is normally metabolized to the alpha-ketoglutarate. Dogs affected by L-2-HGA accumulate L-2-droxyglutarate in their bodies. This leads to central nervous system damage. Clinical symptoms usually appear from 6 months to one year (but may occur much later). Clinical symptoms of L-2-HGA disease, described in the first paragraph, are not fully specific for L-2-HGA disease. These symptoms may accompany some other diseases such as primary epilepsy, brain tumors or meningitis. L-2-HGA disease can be proved only by MRI examination (magnetic resonance). That allows distinguishing L-2-HGA from other diseases with similar clinical symptoms. L-2-HGA affected dogs demonstrated a highly conserved MRI pattern of bilaterally symmetrical regions of hyperintensity on T2-weighted images of certain areas of the brain (thalamus, hypothalamus, dentate nucleus, basal ganglia, dorsal area of the brain strain and cerebellar nuclei and gyres). These changes are related to metabolic or toxic disorder of gray matter.

Easier way, how to diagnose L-2-HGA disease is to do specific molecular genetic test. This test demonstrates presence or absence of causal mutations causing L-2-HGA disease. The disease is caused by double substitution (c.1297T → C, C c.1299C → T) in exon 10 of L2HGDH gene coding L2-hydroglutaric dehydrogenase enzyme. Double substitution leads to double amino acid replacement: leucine to proline in position 433 and histidine to tyrosine in position 434 (Penderis et al. 2008). Presence or absence of the double substitution is analyzed using DNA sequencing.

L-2-HGA in Staffordshire bull terrier is inherited as an autosomal recessive trait. That means the disease affects dogs with P/P (positive / positive) genotype only. The dogs with P/N (positive /negative) genotype are clinically without any symptom. They are genetically considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended.

Molecular genetic test is highly reliable. It is possible to distinguish affected dogs, healthy carrier dogs and healthy dogs. We recommend testing all individuals which will be included in the breeding.

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References:

Penderis J., Clavin J., Abramson C., Jakobs C., Pettitt L., Binns M. M., Vehoeven N. M., O´Driscoll E., Platt S. R., Mellerexh C. S.: L-2-hydroxyglutaric aciduria: characterisation of the molecular defect in a spontaneous canine model. J Med Genet 2007;44:334-340.