L-2-Hydroxyglutaric aciduria in two Palestinian siblings with a novel mutation in the L2HGDH gene

L-2-Hydroxyglutaric aciduria is a rare autosomal recessive neurometabolic disorder caused by
deficiency of L-2-hydroxyglutarate dehydrogenase. This enzyme catalyses the conversion of L-2-
hydroxyglutarate to alpha-ketoglutarate and its deficiency causes accumulation of L-2-
hydroxyglutarate which is s toxic to the brain leading to the leukoencephalopathy.
We report a novel mutation in the L2HGDH gene in two siblings with L-2-Hydroxyglutaric aciduria
and describe clinical phenotype. They presented with developmental delay, cerebellar ataxia, tremor
and speech regression. Urine organic acid analysis revealed massive excretion of 2-Hydroxyglutaric
acid. Brain magnetic resonance imaging showed the characteristic leukodystrophy involving the
subcortical cerebral white matter and dentate nucleus, sparing the basal ganglia. Genetic analysis of
L2HGDH gene showed that they were homozygous for the novel mutation chr14:50,750, 731
c.560_561insATTG (p.C187XfsX1) in exon 5 of L2HGDH gene. Both patients showed symptomatic
response to riboflavin and levocarnitine therapy.
Conclusion: This report further expands the genetic spectrum of L-2-HGA and suggests a successful
response to treatment with levocarnitine and riboflavin