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L-2-hydroxyglutaric aciduria is a primarily neurological form of 2-hydroxyglutaric aciduria (see this term) characterized by psychomotor retardation, cerebellar ataxia and variable macrocephaly or epilepsy.
ORPHA:79314Classification level: Disorder
Exact prevalence and incidence of this disorder are not known but about 140 cases have been reported to date. The disorder appears to be pan-ethnic with cases reported worldwide.
Onset is often insidious in the first year of life. Presenting symptoms include motor retardation and epilepsy. The disease course is progressive leading to mental deterioration such as speech difficulties and motor deficits such as loss of independent walking. Most reported patients had macrocephaly. Other signs include hypotonia in the early stages and spasticity later in the course of the disease, extrapyramidal symptoms and behavioral disorders. An increased incidence of brain tumors has also been reported.
L-2-hydroxyglutaric aciduria is thought to be caused by mutations in the L2HGDH gene (14q22.1) L-encoding mitochondrial 2-hydroxyglutarate dehydrogenase. More than 70 different mutations have been identified to date. However, several affected families did not have identifiable mutations in this gene.
Urinary organic acid screening reveals a massive increase of 2HG, and subsequent chiral differentiation is needed establish the biochemical diagnosis of L-2-hydroxyglutaric aciduria. Diagnosis may be delayed due to the slowly progressive course of the disorder and is based on magnetic resonance imaging (MRI) or computed tomography (CT) findings, biochemical testing, and mutational analysis of the L2HGDH gene. MRI and CT findings are typically subcortical and paraventricular hyperintensities. Varying degrees of subcortical leukoencephalopathy and cerebellar atrophy have been observed.
Urinary organic acid screening does not allow differentiation between L-2-hydroxygluratic acid and D-2-hydroxyglurac acid. Therefore, this differentiation has to be performed subsequently by a specialized laboratory.
Prenatal diagnosis can be performed by mutational analysis and by the measurement of L-2-hydroxyglutaric acid in amniotic fluid.
L-2-hydroxyglutaric aciduria follows an autosomal recessive pattern of inheritance.
Management and treatment
There is currently no specific treatment for L-2-hydroxyglutaric aciduria. Supportive and symptomatic measures are therefore recommended.
Prognosis is poor but most patients reach adulthood.
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