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L-2-hydroxyglutaric aciduria(L2HGA)

MedGen UID:
341029
Concept ID:
C1855995
Disease or Syndrome
Synonym: L2HGA
SNOMED CT: L-2-hydroxy-glutaric aciduria (237961001); L-2-hydroxyglutaric aciduria (237961001); L-2-HGA (237961001); L-2(OH) glutaric aciduria (237961001)
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).
 
Gene (location): L2HGDH (14q21.3)
 
HPO: HP:0040144
Monarch Initiative: MONDO:0009370
OMIM®: 236792
Orphanet: ORPHA79314

Definition

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).

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.

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.

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. [from MedlinePlus Genetics]

Clinical features

From HPO
L-2-hydroxyglutaric aciduria
MedGen UID:
341029
Concept ID:
C1855995
Disease or Syndrome
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).\n\nThe 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.\n\nL-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.\n\nCombined 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.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Aphasia
MedGen UID:
8159
Concept ID:
C0003537
Mental or Behavioral Dysfunction
An acquired language impairment of some or all of the abilities to produce or comprehend speech and to read or write.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Gliosis
MedGen UID:
4899
Concept ID:
C0017639
Pathologic Function
Gliosis is the focal proliferation of glial cells in the central nervous system.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Abnormal pyramidal sign
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Global brain atrophy
MedGen UID:
66840
Concept ID:
C0241816
Pathologic Function
Unlocalized atrophy of the brain with decreased total brain matter volume and increased ventricular size.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Corpus callosum atrophy
MedGen UID:
96560
Concept ID:
C0431370
Finding
The presence of atrophy (wasting) of the corpus callosum.
Spastic tetraparesis
MedGen UID:
658719
Concept ID:
C0575059
Disease or Syndrome
Spastic weakness affecting all four limbs.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Severe demyelination of the white matter
MedGen UID:
343453
Concept ID:
C1856001
Finding
A severe loss of myelin from nerve fibers in the central nervous system.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Abnormal pyramidal tract morphology
MedGen UID:
892809
Concept ID:
C4021761
Anatomical Abnormality
Any structural abnormality of the pyramidal tract, whose chief element, the corticospinal tract, is the only direct connection between the brain and the spinal cord. In addition to the corticospinal tract, the pyramidal system includes the corticobulbar, corticomesencephalic, and corticopontine tracts.
L-2-hydroxyglutaric acidemia
MedGen UID:
854752
Concept ID:
C3888081
Disease or Syndrome
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Term Hierarchy

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

Conditions with this feature

L-2-hydroxyglutaric aciduria
MedGen UID:
341029
Concept ID:
C1855995
Disease or Syndrome
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).\n\nThe 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.\n\nL-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.\n\nCombined 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.
D,L-2-hydroxyglutaric aciduria
MedGen UID:
1802316
Concept ID:
C5574940
Disease or Syndrome
Combined D-2- and L-2-hydroxyglutaric aciduria (D-2-HG and L-2-HG) is an autosomal recessive neurometabolic disorder characterized by neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development resulting in early death. Brain imaging shows abnormalities including enlarged ventricles, delayed myelination, and germinal layer cysts (summary by Muntau et al., 2000). See also isolated L-2-hydroxyglutaric aciduria (236792) and isolated D-2-hydroxyglutaric aciduria (see 600721).

Professional guidelines

PubMed

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

Dilber B, Havalı C, Eroglu N, Aydın K, Şahin S, Cansu A
Childs Nerv Syst 2020 Jul;36(7):1545-1548. Epub 2019 Dec 19 doi: 10.1007/s00381-019-04466-9. PMID: 31858216
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
Nota B, Struys EA, Pop A, Jansen EE, Fernandez Ojeda MR, Kanhai WA, Kranendijk M, van Dooren SJ, Bevova MR, Sistermans EA, Nieuwint AW, Barth M, Ben-Omran T, Hoffmann GF, de Lonlay P, McDonald MT, Meberg A, Muntau AC, Nuoffer JM, Parini R, Read MH, Renneberg A, Santer R, Strahleck T, van Schaftingen E, van der Knaap MS, Jakobs C, Salomons GS
Am J Hum Genet 2013 Apr 4;92(4):627-31. doi: 10.1016/j.ajhg.2013.03.009. PMID: 23561848Free 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

Diagnosis

Dilber B, Havalı C, Eroglu N, Aydın K, Şahin S, Cansu A
Childs Nerv Syst 2020 Jul;36(7):1545-1548. Epub 2019 Dec 19 doi: 10.1007/s00381-019-04466-9. PMID: 31858216
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
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

Therapy

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
Işikay S
BMJ Case Rep 2013 Jun 7;2013 doi: 10.1136/bcr-2013-010164. PMID: 23749865Free PMC Article
Gökçen C, Isikay S, Yilmaz K
BMJ Case Rep 2013 Jun 6;2013 doi: 10.1136/bcr-2013-009512. PMID: 23749824Free PMC Article
Rogers RE, Deberardinis RJ, Klesse LJ, Boriack RL, Margraf LR, Rakheja D
Pediatr Dev Pathol 2010 Sep-Oct;13(5):408-11. Epub 2010 Jan 11 doi: 10.2350/09-12-0768-CR.1. PMID: 20064066
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

Dilber B, Havalı C, Eroglu N, Aydın K, Şahin S, Cansu A
Childs Nerv Syst 2020 Jul;36(7):1545-1548. Epub 2019 Dec 19 doi: 10.1007/s00381-019-04466-9. PMID: 31858216
Jović NJ, Kosać A, Koprivsek K
Srp Arh Celok Lek 2014 May-Jun;142(5-6):337-41. doi: 10.2298/sarh1406337j. PMID: 25033591
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
Sass JO, Jobard F, Topçu M, Mahfoud A, Werlé E, Cure S, Al-Sannaa N, Alshahwan SA, Bataillard M, Cimbalistiene L, Grolik C, Kemmerich V, Omran H, Sztriha L, Tabache M, Fischer J
J Inherit Metab Dis 2008 Dec;31 Suppl 2:S275-9. Epub 2008 Apr 14 doi: 10.1007/s10545-008-0855-4. PMID: 18415700
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

Clinical prediction guides

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
Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK
J Inherit Metab Dis 1980;3(4):109-12. doi: 10.1007/BF02312543. PMID: 6787330

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