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D-2-hydroxyglutaric aciduria 1(D2HGA1)

MedGen UID:
463405
Concept ID:
C3152055
Disease or Syndrome
Synonym: D2HGA1
 
Gene (location): D2HGDH (2q37.3)
 
Monarch Initiative: MONDO:0024554
OMIM®: 600721

Definition

D-2-hydroxyglutaric aciduria is a neurometabolic disorder first described by Chalmers et al. (1980). Clinical symptoms include developmental delay, epilepsy, hypotonia, and dysmorphic features. Mild and severe phenotypes were characterized (van der Knaap et al., 1999). The severe phenotype is homogeneous and is characterized by early infantile-onset epileptic encephalopathy and, often, cardiomyopathy. The mild phenotype has a more variable clinical presentation. Genetic Heterogeneity of D-2-Hydroxyglutaric Aciduria D-2-hydroxyglutaric aciduria-2 (D2HGA2; 613657) is caused by heterozygous mutation in the mitochondrial isocitrate dehydrogenase-2 gene (IDH2; 147650) on chromosome 15q26. [from OMIM]

Additional description

From MedlinePlus Genetics
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).  https://medlineplus.gov/genetics/condition/2-hydroxyglutaric-aciduria

Clinical features

From HPO
Glutaric aciduria
MedGen UID:
75695
Concept ID:
C0268594
Disease or Syndrome
The concentration of glutaric acid in the urine, normalized for urine concentration, is above the upper limit of normal.
D-2-hydroxyglutaric aciduria
MedGen UID:
322192
Concept ID:
C1833429
Disease or Syndrome
An increased concentration of 2-hydroxyglutaric acid in the urine.
Aortic regurgitation
MedGen UID:
8153
Concept ID:
C0003504
Disease or Syndrome
An insufficiency of the aortic valve, leading to regurgitation (backward flow) of blood from the aorta into the left ventricle.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
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.
Tonic seizure
MedGen UID:
82855
Concept ID:
C0270844
Disease or Syndrome
A tonic seizure is a type of motor seizure characterized by unilateral or bilateral limb stiffening or elevation, often with neck stiffening.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Subependymal cysts
MedGen UID:
318876
Concept ID:
C1833431
Anatomical Abnormality
Cerebral cysts, usually located in the wall of the caudate nucleus or in the caudothalamic groove. They are found in up to 5.2% of all neonates, using transfontanellar ultrasound in the first days of life.
Multifocal cerebral white matter abnormalities
MedGen UID:
371562
Concept ID:
C1833434
Finding
Infantile encephalopathy
MedGen UID:
343542
Concept ID:
C1856408
Finding
Encephalopathy with onset in the infantile period.
Lateral ventricle dilatation
MedGen UID:
383904
Concept ID:
C1856409
Pathologic Function
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.
Infantile spasms
MedGen UID:
854616
Concept ID:
C3887898
Disease or Syndrome
Infantile spasms represent a subset of "epileptic spasms". Infantile Spasms are epileptic spasms starting in the first year of life (infancy).
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Myoclonic seizure
MedGen UID:
1385980
Concept ID:
C4317123
Sign or Symptom
A myoclonic seizure is a type of motor seizure characterized by sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Elevated CSF D-2-hydroxyglutaric acid concentration
MedGen UID:
1052927
Concept ID:
CN376759
Finding
The concentration of D-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF) is above the upper limit of normal.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Inspiratory stridor
MedGen UID:
146165
Concept ID:
C0677600
Sign or Symptom
Inspiratory stridor is a high pitched sound upon inspiration that is generally related to laryngeal abnormalities.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Professional guidelines

PubMed

Gibson KM, ten Brink HJ, Schor DS, Kok RM, Bootsma AH, Hoffmann GF, Jakobs C
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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
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Korman SH, Salomons GS, Gutman A, Brooks R, Jakobs C
Neuropediatrics 2004 Jun;35(3):151-6. doi: 10.1055/s-2004-817905. PMID: 15248096
van der Knaap MS, Jakobs C, Hoffmann GF, Nyhan WL, Renier WO, Smeitink JA, Catsman-Berrevoets CE, Hjalmarson O, Vallance H, Sugita K, Bowe CM, Herrin JT, Craigen WJ, Buist NR, Brookfield DS, Chalmers RA
Ann Neurol 1999 Jan;45(1):111-9. doi: 10.1002/1531-8249(199901)45:1<111::aid-art17>3.0.co;2-n. PMID: 9894884

Diagnosis

Bellad A, Holla VV, Kumari R, Kamble N, Yadav R, Pandey A, Pal PK, Muthusamy B
Acta Neurol Belg 2023 Dec;123(6):2315-2323. Epub 2023 Jun 28 doi: 10.1007/s13760-023-02318-7. PMID: 37378753
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Anghileri E, Bertolino N, Salsano E, Antelmi L, Carpinelli P, Castellotti B, Zucca I, Gellera C, Bisogno R, Caccia C, Cuccarini V
Brain Res 2016 Oct 1;1648(Pt A):506-511. Epub 2016 Aug 16 doi: 10.1016/j.brainres.2016.08.013. PMID: 27543339
Struys EA
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Sugita K, Kakinuma H, Okajima Y, Ogawa A, Watanabe H, Niimi H
Brain Dev 1995 Mar-Apr;17(2):139-41; discussion 144-5. doi: 10.1016/0387-7604(94)00123-f. PMID: 7625550

Therapy

Srinivasan A, Zhou Y, Scordino T, Prabhu S, Wierenga A, Simon G, Wierenga KJ, Thompson J, Shah R, Sinha AA
Pediatr Hematol Oncol 2020 Aug;37(5):431-437. Epub 2020 Mar 13 doi: 10.1080/08880018.2020.1737284. PMID: 32166993

Prognosis

Peng W, Ma XW, Yang X, Zhang WQ, Yan L, Wang YX, Liu X, Wang Y, Feng ZC
BMC Med Genet 2018 Sep 14;19(1):167. doi: 10.1186/s12881-018-0675-9. PMID: 30217188Free PMC Article
Vissers LE, Fano V, Martinelli D, Campos-Xavier B, Barbuti D, Cho TJ, Dursun A, Kim OH, Lee SH, Timpani G, Nishimura G, Unger S, Sass JO, Veltman JA, Brunner HG, Bonafé L, Dionisi-Vici C, Superti-Furga A
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J Inherit Metab Dis 2008 Dec;31 Suppl 2:S275-9. Epub 2008 Apr 14 doi: 10.1007/s10545-008-0855-4. PMID: 18415700

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
Anghileri E, Bertolino N, Salsano E, Antelmi L, Carpinelli P, Castellotti B, Zucca I, Gellera C, Bisogno R, Caccia C, Cuccarini V
Brain Res 2016 Oct 1;1648(Pt A):506-511. Epub 2016 Aug 16 doi: 10.1016/j.brainres.2016.08.013. PMID: 27543339
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
Korman SH, Salomons GS, Gutman A, Brooks R, Jakobs C
Neuropediatrics 2004 Jun;35(3):151-6. doi: 10.1055/s-2004-817905. PMID: 15248096
van der Knaap MS, Jakobs C, Hoffmann GF, Nyhan WL, Renier WO, Smeitink JA, Catsman-Berrevoets CE, Hjalmarson O, Vallance H, Sugita K, Bowe CM, Herrin JT, Craigen WJ, Buist NR, Brookfield DS, Chalmers RA
Ann Neurol 1999 Jan;45(1):111-9. doi: 10.1002/1531-8249(199901)45:1<111::aid-art17>3.0.co;2-n. PMID: 9894884

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