2-Hydroxyglutaric aciduria

Presentation

The signs/symptoms of this condition are consistent with the following:

• Intellectual disability,
• Muscular hypotonia
• Encephalitis
• Seizures
• Aphasia

Cause

Diagnosis

Classification

2-hydroxyglutaric aciduria is an organic aciduria, and because of the stereoisomeric property of 2-hydroxyglutarate different variants of this disorder are distinguished:

L-2-hydroxyglutaric aciduria

The L-2 form is more common, severe, and mainly affects the central nervous system. The basal ganglia are affected, and cystic cavitations in the white matter of the brain are common, beginning in infancy. This form is chronic, with early symptoms such as hypotonia, tremors, and epilepsy declining into spongiform leukoencephalopathy, muscular choreodystonia, mental retardation, and psychomotor regression.

It is associated with L2HGDH, which encodes L-2-hydroxyglutarate dehydrogenase. L-2-hydroxyglutarate is produced by promiscuous action of malate dehydrogenase on 2-oxoglutarate, and L-2-hydroxyglutarate dehydrogenase is an example of a metabolite repair enzyme that oxidizes L-2-hydroxyglutarate back to 2-oxoglutarate.

D-2-hydroxyglutaric aciduria

The D2 form is rare, with symptoms including macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness. It is caused by recessive mutations in D2HGDH (type I) or by dominant gain-of-function mutations in IDH2 (type II).

Combined D-2- and L-2-hydroxyglutaric aciduria

The combined form is characterized by severe early-onset epileptic encephalopathy and absence of developmental progress. It is caused by recessive mutations in SLC25A1 encoding the mitochondrial citrate carrier.

Treatment

The treatment of 2-Hydroxyglutaric aciduria is based on seizure control, the prognosis depends on how severe the condition is.

References

References

1. Reference, Genetics Home. "2-hydroxyglutaric aciduria".
2. "L-2-hydroxyglutaric aciduria {{!}} Genetic and Rare Diseases Information Center (GARD) – an NCATS Program".
3. "2-hydroxyglutaric aciduria: MedlinePlus Genetics".
4. (2012). "Progress in understanding 2-hydroxyglutaric acidurias". Journal of Inherited Metabolic Disease.
5. (2005). "L-2-hydroxyglutaric aciduria: clinical, neuroimaging, and neuropathological findings". Arch. Neurol..
6. (November 2004). "L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1". Hum. Mol. Genet..
7. (2009-04-01). "L: -2-Hydroxyglutaric aciduria, a disorder of metabolite repair". Journal of Inherited Metabolic Disease.
8. (1995). "D-2-hydroxyglutaric aciduria". J. Child Neurol..
9. (Jan 2005). "Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria". Am J Hum Genet.
10. (2010). "IDH2 mutations in patients with D-2-hydroxyglutaric aciduria". Science.
11. (2000). "Combined D-2- and L-2-hydroxyglutaric aciduria with neonatal onset encephalopathy: a third biochemical variant of 2-hydroxyglutaric aciduria?". Neuropediatrics.
12. Nota B. (2013). "Deficiency in SLC25A1, Encoding the Mitochondrial Citrate Carrier, Causes Combined D-2- and L-2-Hydroxyglutaric Aciduria.". The American Journal of Human Genetics.
13. "D-2-hydroxyglutaric aciduria". OrphaNet: The portal for rare diseases and orphan drugs.