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At a glance

It is a rare neurometabolic inborn error manifesting as progressive neurodegenerative disorder with psychomotor retardation. It is characterized by increased hydroxyglutaric acid in the urine. The clinical presentation is characterized by mental retardation, moderate to severe seizures, muscular dystonia, encephalitis, and dysphagia.


Three types of this disorder have been reported based on the stereoisometric characteristics of 2-hydroxyglutaric acid and consist of the following:

  • L-2-Hydroxyglutaric Aciduria: The most common presentation. It is characterized clinically with severe central nervous system (CNS) features that include generalized hypotonia, tremors, and severe epilepsy. The disease evolves into spongiform leukoencephalopathy, muscular choreodystonia, mental retardation, and psychomotor regression.

  • D-2-Hydroxyglutaric Aciduria: Rare variant of the disease that is characterized by macrocephaly, cardiomyopathy, mental retardation, generalized hypotonia, and cortical blindness. It is the result of a recessive mutation in the D2HGDH Type 1 gene or a dominant mutation in the IDH2.

  • L-2-Hydroxyglutaric Aciduria and D-2-Hydroxyglutaric Aciduria: Clinically defined as a combined variant that is characterized by severe early-onset epileptic encephalopathy with failure to growth. It is caused by a recessive mutation in the SLC25A1 gene encoding the mitochondrial citrate carrier.


The incidence is unknown but approximately 20 cases have been reported.

Genetic inheritance

It is presumed inherited either as an autosomal recessive trait or an autosomal dominant pattern.

Clinical aspects

The enzymatic defect causing this progressive neurometabolic disorders is yet to be found. L-2-Hydroxyglutaric acid is a stereoisomer of D-2-hydroxyglutaric acid. Elevated levels of L-2-hydroxyglutaric acid are found in the urine, cerebrospinal fluid (CSF), and, to a lesser degree, in the serum. Plasma and CSF levels of lysine are elevated in some of these patients. In most patients, the initial symptoms are a delay of speech, unsupported walk, and febrile seizures within the first 2 years of life. Over the following years, mental retardation associated to cerebellar ataxia with or without dystonia, pyramidal signs, and seizures develop. However, onset can be as early as neonatal age or as late as adolescent age. The oldest patient reported with this disorder was 57 years old. MRI scans reveal a consistent pattern with symmetrical subcortical leukoencephalopathy and cerebellar atrophy (vermis more than hemispheres). Furthermore, pathologic changes can—although inconsistently—be detected in the dentate nuclei, putamina, and globus pallidus.

Anesthetic considerations

Macrocephaly is a common feature but no other facial anomalies have been reported, so airway management should not be affected. Keep in mind that these patients may be taking antiseizure medication, and potential interaction with other drugs and altered hepatic metabolism can occur.

Other conditions to be considered

  • Canavan Syndrome (Canavan-van Bogaert-Bertrand Disease): Progressive leukodystrophy caused by spongy degeneration of ...

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