2-Hydroxyglutaric aciduria
| 2-Hydroxyglutaric aciduria |
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2-hydroxyglutaric aciduria is a group of rare neurometabolic disorders characterized by the significantly elevated levels of hydroxyglutaric acid in ones urine. It is either autosomal recessive or autosomal dominant.
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.[1]
It is associated with L2HGDH, which encodes L-2-hydroxyglutarate dehydrogenase.[2] 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.[3]
D-2-hydroxyglutaric aciduria
The D2 form is rare, with symptoms including macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness.[4]
It is caused by recessive mutations in D2HGDH[5] (type I) or by dominant gain-of-function mutations in IDH2[6] (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.[7] It is caused by recessive mutations in SLC25A1 encoding the mitochondrial citrate carrier.[8]
See also
References
- ^ Seijo-Martinez M, Navarro C, Castro del Rio M, Vila O, Puig M, Ribes A, Butron M (2005). "L-2-hydroxyglutaric aciduria: clinical, neuroimaging, and neuropathological findings". Arch Neurol. 62 (4): 666–670. doi:10.1001/archneur.62.4.666. PMID 15824270.
- ^ Topçu M, Jobard F, Halliez S, et al. (November 2004). "L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1". Hum. Mol. Genet. 13 (22): 2803–11. doi:10.1093/hmg/ddh300. PMID 15385440.
- ^ Van Schaftingen, E.; Rzem, R.; Veiga-da-Cunha, M. (2009-04-01). "L: -2-Hydroxyglutaric aciduria, a disorder of metabolite repair". Journal of Inherited Metabolic Disease. 32 (2): 135–142. doi:10.1007/s10545-008-1042-3. ISSN 1573-2665. PMID 19020988.
- ^ Nyhan WL, Shelton GD, Jakobs C, Holmes B, Bowe C, Curry CJ, Vance C, Duran M, Sweetman L (1995). "D-2-hydroxyglutaric aciduria". J Child Neurol. 10 (2): 137–142. doi:10.1177/088307389501000216. PMID 7782605.
- ^ Struys EA, Salomons GS, Achouri Y, Van Schaftingen E, Grosso S, Craigen WJ, Verhoeven NM, Jakobs C (Jan 2005). "Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria". Am J Hum Genet. 76 (2): 358–60. doi:10.1086/427890. PMC 1196381. PMID 15609246.
- ^ Kranendijk M, Struys EA, van Schaftingen E, et al. (2010). "IDH2 mutations in patients with D-2-hydroxyglutaric aciduria". Science. 330 (6002): 336. doi:10.1126/science.1192632. PMID 20847235.
- ^ Muntau A, Röschinger W, Merkenschlager A, van der Knaap MS, et al. (2000). "Combined D-2- and L-2-hydroxyglutaric aciduria with neonatal onset encephalopathy: a third biochemical variant of 2-hydroxyglutaric aciduria?". Neuropediatrics. 31 (3): 137–40. doi:10.1055/s-2000-7497. PMID 10963100.
- ^ Nota B; et al. (2013). "Deficiency in SLC25A1, Encoding the Mitochondrial Citrate Carrier, Causes Combined D-2- and L-2-Hydroxyglutaric Aciduria". The American Journal of Human Genetics. 92 (4): 627–631. doi:10.1016/j.ajhg.2013.03.009. PMID 23561848.