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2-hydroxyglutaric aciduria(D2L2AD)

MedGen UID:
412535
Concept ID:
C2746066
Disease or Syndrome
Synonym: D2L2AD
SNOMED CT: 2-hydroxyglutaric aciduria (698870008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Monarch Initiative: MONDO:0016001
Orphanet: ORPHA19

Definition

Combined D,L-2-HGA causes severe brain abnormalities that become apparent in early infancy. Affected infants have severe seizures, weak muscle tone (hypotonia), and breathing and feeding problems. They usually survive only into infancy or early childhood.

L-2-HGA particularly affects a region of the brain called the cerebellum, which is involved in coordinating movements. As a result, many affected individuals have problems with balance and muscle coordination (ataxia). Additional features of L-2-HGA can include delayed development, seizures, speech difficulties, and an unusually large head (macrocephaly). Typically, signs and symptoms of this disorder begin during infancy or early childhood. The disorder worsens over time, usually leading to severe disability by early adulthood.

The main features of D-2-HGA are delayed development, seizures, weak muscle tone (hypotonia), and abnormalities in the largest part of the brain (the cerebrum), which controls many important functions such as muscle movement, speech, vision, thinking, emotion, and memory. Researchers have described two subtypes of D-2-HGA, type I and type II. The two subtypes are distinguished by their genetic cause and pattern of inheritance, although they also have some differences in signs and symptoms. Type II tends to begin earlier and often causes more severe health problems than type I. Type II may also be associated with a weakened and enlarged heart (cardiomyopathy), a feature that is typically not found with type I.

2-hydroxyglutaric aciduria is a condition that causes progressive damage to the brain. The major types of this disorder are called D-2-hydroxyglutaric aciduria (D-2-HGA), L-2-hydroxyglutaric aciduria (L-2-HGA), and combined D,L-2-hydroxyglutaric aciduria (D,L-2-HGA). [from MedlinePlus Genetics]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGV2-hydroxyglutaric aciduria
Follow this link to review classifications for 2-hydroxyglutaric aciduria in Orphanet.

Professional guidelines

PubMed

Phua YL, D'Annibale OM, Karunanidhi A, Mohsen AW, Kirmse B, Dobrowolski SF, Vockley J
Mol Genet Metab 2024 Jul;142(3):108495. Epub 2024 May 15 doi: 10.1016/j.ymgme.2024.108495. PMID: 38772223
Steenweg ME, Jakobs C, Errami A, van Dooren SJ, Adeva Bartolomé MT, Aerssens P, Augoustides-Savvapoulou P, Baric I, Baumann M, Bonafé L, Chabrol B, Clarke JT, Clayton P, Coker M, Cooper S, Falik-Zaccai T, Gorman M, Hahn A, Hasanoglu A, King MD, de Klerk HB, Korman SH, Lee C, Meldgaard Lund A, Mejaski-Bosnjak V, Pascual-Castroviejo I, Raadhyaksha A, Rootwelt T, Roubertie A, Ruiz-Falco ML, Scalais E, Schimmel U, Seijo-Martinez M, Suri M, Sykut-Cegielska J, Trefz FK, Uziel G, Valayannopoulos V, Vianey-Saban C, Vlaho S, Vodopiutz J, Wajner M, Walter J, Walter-Derbort C, Yapici Z, Zafeiriou DI, Spreeuwenberg MD, Celli J, den Dunnen JT, van der Knaap MS, Salomons GS
Hum Mutat 2010 Apr;31(4):380-90. doi: 10.1002/humu.21197. PMID: 20052767
Gibson KM, ten Brink HJ, Schor DS, Kok RM, Bootsma AH, Hoffmann GF, Jakobs C
Pediatr Res 1993 Sep;34(3):277-80. doi: 10.1203/00006450-199309000-00007. PMID: 8134166

Recent clinical studies

Etiology

Cansever MS, Zubarioglu T, Oruc C, Kiykim E, Gezdirici A, Neselioglu S, Erel O, Yalcinkaya C, Aktuglu-Zeybek C
Metab Brain Dis 2019 Feb;34(1):283-288. Epub 2018 Nov 29 doi: 10.1007/s11011-018-0354-8. PMID: 30499066
Faiyaz-Ul-Haque M, Al-Sayed MD, Faqeih E, Jamil M, Saeed A, Amoudi MS, Kaya N, Abalkhail H, Al-Abdullatif A, Rashed M, Al-Owain M, Peltekova I, Zaidi SH
Ann Saudi Med 2014 Mar-Apr;34(2):107-14. doi: 10.5144/0256-4947.2014.107. PMID: 24894778Free PMC Article
Patay Z, Mills JC, Löbel U, Lambert A, Sablauer A, Ellison DW
AJNR Am J Neuroradiol 2012 May;33(5):940-3. Epub 2012 Jan 12 doi: 10.3174/ajnr.A2869. PMID: 22241392Free PMC Article
Aghili M, Zahedi F, Rafiee E
J Neurooncol 2009 Jan;91(2):233-6. Epub 2008 Oct 18 doi: 10.1007/s11060-008-9706-2. PMID: 18931888
Hoffmann GF, Gibson KM, Trefz FK, Nyhan WL, Bremer HJ, Rating D
Eur J Pediatr 1994;153(7 Suppl 1):S94-100. doi: 10.1007/BF02138786. PMID: 7957396

Diagnosis

Reijngoud DJ
J Inherit Metab Dis 2018 May;41(3):309-328. Epub 2018 Jan 9 doi: 10.1007/s10545-017-0124-5. PMID: 29318410Free PMC Article
Eguchi M, Ozaki E, Yamauchi T, Ohta M, Higaki T, Masuda K, Imoto I, Ishii E, Eguchi-Ishimae M
Am J Med Genet A 2018 Feb;176(2):351-358. Epub 2017 Dec 19 doi: 10.1002/ajmg.a.38578. PMID: 29265763
Aghili M, Zahedi F, Rafiee E
J Neurooncol 2009 Jan;91(2):233-6. Epub 2008 Oct 18 doi: 10.1007/s11060-008-9706-2. PMID: 18931888
Struys EA
J Inherit Metab Dis 2006 Feb;29(1):21-9. doi: 10.1007/s10545-006-0317-9. PMID: 16601864
Nyhan WL, Shelton GD, Jakobs C, Holmes B, Bowe C, Curry CJ, Vance C, Duran M, Sweetman L
J Child Neurol 1995 Mar;10(2):137-42. doi: 10.1177/088307389501000216. PMID: 7782605

Therapy

Phua YL, D'Annibale OM, Karunanidhi A, Mohsen AW, Kirmse B, Dobrowolski SF, Vockley J
Mol Genet Metab 2024 Jul;142(3):108495. Epub 2024 May 15 doi: 10.1016/j.ymgme.2024.108495. PMID: 38772223
Geoerger B, Schiff M, Penard-Lacronique V, Darin N, Saad SM, Duchon C, Lamazière A, Desmons A, Pontoizeau C, Berlanga P, Ducassou S, Yen K, Su M, Schenkein D, Ottolenghi C, De Botton S
Nat Med 2023 Jun;29(6):1358-1363. Epub 2023 May 29 doi: 10.1038/s41591-023-02382-9. PMID: 37248298
Mühlhausen C, Salomons GS, Lukacs Z, Struys EA, van der Knaap MS, Ullrich K, Santer R
J Inherit Metab Dis 2014 Sep;37(5):775-81. Epub 2014 Apr 1 doi: 10.1007/s10545-014-9702-y. PMID: 24687295
Gökçen C, Isikay S, Yilmaz K
BMJ Case Rep 2013 Jun 6;2013 doi: 10.1136/bcr-2013-009512. PMID: 23749824Free PMC Article
Seijo-Martínez M, Navarro C, Castro del Río M, Vila O, Puig M, Ribes A, Butron M
Arch Neurol 2005 Apr;62(4):666-70. doi: 10.1001/archneur.62.4.666. PMID: 15824270

Prognosis

Jović NJ, Kosać A, Koprivsek K
Srp Arh Celok Lek 2014 May-Jun;142(5-6):337-41. doi: 10.2298/sarh1406337j. PMID: 25033591
Patay Z, Mills JC, Löbel U, Lambert A, Sablauer A, Ellison DW
AJNR Am J Neuroradiol 2012 May;33(5):940-3. Epub 2012 Jan 12 doi: 10.3174/ajnr.A2869. PMID: 22241392Free PMC Article
Aghili M, Zahedi F, Rafiee E
J Neurooncol 2009 Jan;91(2):233-6. Epub 2008 Oct 18 doi: 10.1007/s11060-008-9706-2. PMID: 18931888
Moroni I, Bugiani M, D'Incerti L, Maccagnano C, Rimoldi M, Bissola L, Pollo B, Finocchiaro G, Uziel G
Neurology 2004 May 25;62(10):1882-4. doi: 10.1212/01.wnl.0000125335.21381.87. PMID: 15159502
Hoffmann GF, Gibson KM, Trefz FK, Nyhan WL, Bremer HJ, Rating D
Eur J Pediatr 1994;153(7 Suppl 1):S94-100. doi: 10.1007/BF02138786. PMID: 7957396

Clinical prediction guides

Geoerger B, Schiff M, Penard-Lacronique V, Darin N, Saad SM, Duchon C, Lamazière A, Desmons A, Pontoizeau C, Berlanga P, Ducassou S, Yen K, Su M, Schenkein D, Ottolenghi C, De Botton S
Nat Med 2023 Jun;29(6):1358-1363. Epub 2023 May 29 doi: 10.1038/s41591-023-02382-9. PMID: 37248298
Cansever MS, Zubarioglu T, Oruc C, Kiykim E, Gezdirici A, Neselioglu S, Erel O, Yalcinkaya C, Aktuglu-Zeybek C
Metab Brain Dis 2019 Feb;34(1):283-288. Epub 2018 Nov 29 doi: 10.1007/s11011-018-0354-8. PMID: 30499066
Eguchi M, Ozaki E, Yamauchi T, Ohta M, Higaki T, Masuda K, Imoto I, Ishii E, Eguchi-Ishimae M
Am J Med Genet A 2018 Feb;176(2):351-358. Epub 2017 Dec 19 doi: 10.1002/ajmg.a.38578. PMID: 29265763
Pop A, Williams M, Struys EA, Monné M, Jansen EEW, De Grassi A, Kanhai WA, Scarcia P, Ojeda MRF, Porcelli V, van Dooren SJM, Lennertz P, Nota B, Abdenur JE, Coman D, Das AM, El-Gharbawy A, Nuoffer JM, Polic B, Santer R, Weinhold N, Zuccarelli B, Palmieri F, Palmieri L, Salomons GS
J Inherit Metab Dis 2018 Mar;41(2):169-180. Epub 2017 Dec 13 doi: 10.1007/s10545-017-0106-7. PMID: 29238895Free PMC Article
Jović NJ, Kosać A, Koprivsek K
Srp Arh Celok Lek 2014 May-Jun;142(5-6):337-41. doi: 10.2298/sarh1406337j. PMID: 25033591

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