Introduction
Enantiomeric d,l-2-hydroxyglutaric acid and its origin
The diagnosis of 2-hydroxyglutaric aciduria
d-2-hydroxyglutaric aciduria type I and II (MIM# 600721 and MIM# 613657)
Clinical manifestations of D-2-HGA
Symptoms | D-2-HGA type I | D-2-HGA type II | |
---|---|---|---|
Number of patients | 14 | 19 | |
Age onset (yr) | Mean | 1 | ¼ |
Range | 0-6 | 0-2 | |
Signs during disease | Developmental delay | 78 (11 pts.) | 100 (19 pts.) |
(% of type I or type II) | - 3 pts. unaffected | - 0 pts. unaffected | |
- 5 pts. mild | - 2 pts. mild | ||
- 3 pts. moderate | - 6 pts. moderate | ||
- 3 pts. severe | - 11 pts. severe | ||
Hypotonia | 57 (8 pts.) | 89 (17 pts.) | |
Seizures | 29 (4 pts.) | 79 (15 pts.) | |
Cardiomyopathy | 0 | 47 ( 9 pts.) | |
- 7 pts. dilated | |||
- 1 pt. hypertrophic | |||
- 1 pt. unknown | |||
Alive (yr) | Mean age | 8 (n = 3) | 8.4 (n = 10) |
Range | 5, 7, 12 | 2.8-19 | |
Died (yr) | Mean age | 3 weeks* (n = 1) | 6.5 (n = 9) |
Range | - | 0.3-22 | |
Unknown | n = 10 | - |
D2HGDH mutations: the molecular basis of D-2-HGA type I
IDH2 mutations: the molecular basis of D-2-HGA type II
D-2-HGA | Remarks | References |
---|---|---|
Type I (n = 26) | 1 patient affected with comorbid Sanfilippo syndrome type C | |
Type II (n = 24) | 15 published pts. | |
9 unpublished pts.* | ||
Undifferentiated (n = 43) | DNA unavailable for D2HGDH and IDH2 sequencing | |
18 published pts. | ||
25 unpublished pts.* | ||
Unknown (n = 2) | D-2-HGA type I and type II were excluded: no mutations detected in D2HGDH or IDH2
| Kranendijk et al 2010b
|
Combined | Increased D-2-HG and L-2-HG | |
D,L-2-HGA (n = 11) | 6 published pts. | |
5 unpublished pts.* | ||
Skeletal dysplasia (n = 6) | 3 published pts. | |
3 unpublished pts.* |
Metabolism in D-2-HGA
D-2-HGDH fib. (pmol h-1 mg prot.-1) | D-2-HGDH lyb. (pmol h-1 mg prot.-1) | IDH2wt/R140Q lyb. (pmol h-1 mg prot.-1) | |
---|---|---|---|
mean (n); range | mean (n); range | mean (n); range | |
Controls | 456 (5); 247-665 | 1409 (5); 273-2545 | 1800 (5); 1400-2100 |
D-2-HGA type I | 22 (5); 0-41 | 12 (2); 2, 21 | 1900 (2); 1900, 1900 |
D-2-HGA type II | 338 (14); 204-634 | 1062 (4); 570-1503 | 14400 (5); 12000-18800 |
Urine (mmol/mol creat.) | Plasma (μmol/L) | CSF (μmol/L) | Lymphoblasts (nmol/mg prot.) | |
---|---|---|---|---|
mean (n); range | mean (n); range | mean (n); range | mean (n); range | |
Controls | 6 (18); 2.8-17 | 0.7 (10); 0.3-0.9 | 0.1 (10); 0.07-0.3 | 0.11 (5); 0.06-0.13 |
D-2-HGA type I | 969 (20); 103-2414 | 68 (7); 26-123 | 13 (3); 6-18 | 1.8 (2); 1.7-1.9 |
D-2-HGA type II | 2486 (19); 448-11305 | 366 (9); 99-757 | 79 (4); 30-172 | 15.1 (5); 1.9-28.5 |
Pathophysiology of D-2-HGA
Therapeutic perspectives
l-2-hydroxyglutaric aciduria (MIM# 236792)
Clinical manifestations of L-2-HGA
Barbot et al 1997
| Topcu et al 2005
| |||
---|---|---|---|---|
Number of patients- clinical description | 12 | 6 | 29 | 106 |
Age onset | After infancy | ½-2 yr (100%) | 1-10 yr (67%) | 0-7 yr (97%) |
11-18 yr (24%) | ||||
19-30 yr (7%) | ||||
Insidious onset | + | + | + | |
Signs at diagnosis | ||||
developmental delay | + (33%) | + (83%) | + | + (52%) |
epilepsy | + (1 pt.) | + (1 pt.) | + (42%) | |
cerebellar ataxia | + (1 pt.) | + | + (20%) | |
Signs during disease course | ||||
developmental delay | + (100%) | + (100%) | + (79%) | + (93%) |
cerebellar ataxia | + (92%) | + (100%) | + (66%) | + (82%) |
epilepsy | + (50%) | + (67%) | + (41%) | + (72%) |
macrocephaly | + (52%) | + (48%) | ||
extrapyramidal symptoms | + (33%) | + (38%) | ||
Progression | Chronic, slowly | Slowly | Static | Slowly |
Number of patients - brain MRI performed | 10 | 6 | 24 | 56 |
Highly characteristic MRI abnormalities* | + | + | + | + |
L2HGDH mutations: the molecular basis of L-2-HGA
Metabolism in L-2-HGA
L-2-HGA patients (n) | Urinary L-2-HG (mmol/mol creat.) | References |
---|---|---|
Controls (18)
|
1.3- 19
| Gibson et al 1993a
|
L-2-HGA (9) | 332-2742 | Gibson et al 1993a
|
L-2-HGA (12) | 226-4299 | Barth et al 1993
|
L-2-HGA (7) | 630-1420 | Barbot et al 1997
|
L-2-HGA (29) | 1000-5520 | Topcu et al 2005
|
L-2-HGA (15) | 671-3392 | Kranendijk et al 2009
|
L-2-HGA (106) | 350-3357 | Steenweg et al 2010
|
L-2-HGA (mutations L2HGDH) | Steenweg et al 2010
| |
c.905C>T (6) | 1090 p = 0.012
#
| |
c.530_533delinsATT (9) | 2147 | |
L-2-HGA (mutations L2HGDH) | Steenweg et al 2010
| |
missense mutations (28) | 1431 p = 0.012
#
| |
presumed null mutations (28) | 1916 |
Mean (n); range | Urine (mmol/mol creatinine) | Plasma (μmol/L) | CSF (μmol/L) | |||
---|---|---|---|---|---|---|
Controls | L-2-HGA | Controls | L-2-HGA | Controls | L-2-HGA | |
L-2-HG | ||||||
Gibson et al 1993b
| 6 (18); 1.3-19 | 1283 (9); 332-2742 | 0.6 (10); 0.5-1.0 | 47 ( 8); 27-62 | 0.7 (10); 0.3-2.3 | 62 (6); 34-100 |
Barth et al 1993
| <52 | 1810 (12); 226-4299 | n.d. | 31 (10); 7-84 | n.d. | 122 (6); 23-474 |
Barbot et al 1997
| <15 | 1000 (6); 650-1420 |
-
| # |
-
| # |
mean (n); range | 1364 (27); 226-4299 | 39 (18); 7-84 | 92 (12); 23-474 | |||
Lysine | ||||||
Gibson et al 1993b
|
-
| - |
-
| - |
-
| - |
Barth et al 1993
|
7-45
| 27 (4); 11-42 | 120-230 | 279 (8); 70-380 | 10-25 | 79 (6); 66-89 |
Barbot et al 1997
|
7-58
| 89 (6); 36-168 | 40-163 | 285 (6); 185-396 | 14-25 | 77 (2); 60, 95 |
Pathophysiology of L-2-HGA
Therapeutic approaches
Combined d,l-2-hydroxyglutaric aciduria
Patient | Urine (mmol/mol creatinine) | Plasma (μmol/L) | CSF (μmol/L) | |||
---|---|---|---|---|---|---|
D-2-HG | L-2-HG | D-2-HG | L-2-HG | D-2-HG | L-2-HG | |
Controls
|
2.8-17
|
1.3-19
|
0.3-0.9
|
0.5-1.0
|
0.07-0.3
|
0.3-2.3
|
A | 315-1185 | 162-332 | 2.5 | 2.3-3.7 | 2.5 | 1.2 |
B | 520 | 142 | 2.22 | 1.07 | 0.49 | normal |
C* | 228 | 145 | -- | -- | -- | -- |
D* | 17.9-1072 | 25.2-430 | 2.48 | 2.22 | 0.42 | normal |
E | 632, 685, 786 | 32, 76, 83 | -- | -- | -- | -- |
F | 162, 306 | 127, 152 | 1.8, 4.6 | 1.91, 1.7 | -- | -- |
mean (n); range | 496 (6); 228-750 | 161 (6); 64-247 | 2.6 (4); 2.2-3.2 | 2.0 (4); 1.1-3.0 | 1.1 (3); 0.42-2.5 | normal (3) |
Patient A | Patient B | Patient C* | Patient D* | Patient E | Patient F | |
---|---|---|---|---|---|---|
Gender | Female | Female | Male | Female | Male | Female |
Age at death | 8 months | <11 months | 3.5 years | 2.5 months | 10 months | 1 month |
Consanguinity | - | - | + | + | - | - |
Epileptic encephalopathy | + | + | + | + | + | + |
Developmental delay | Severe | Severe | Severe | Severe | Severe | Severe |
Respiratory insufficiency | + | + | + | + | ||
Other signs | Facial dysmorphism | Hypotonia, cardiomyopathy | ||||
Brain MRI abnormalities | + | + | + | Not performed | Suggestive of mitochondrial disease#
| + |
Enlarged ventricles | + | + | + | + | ||
Subependymal pseudocysts | + | + | + | + | ||
Delayed gyration and myelination | + | + | + | + | ||
References | Wagner et al 1998
| Amiel et al 1999
| Muntau et al 2000
| Muntau et al 2000
| Wajner et al 2002
| Read et al 2005
|
Muntau et al 2000
|
Other disorders with accumulation of 2-HG
Neoplastic disorders with IDH mutations
D-2-HGA in skeletal dysplasia (MIM# 271550)
Multiple Acyl-CoA dehydrogenase deficiency (MADD, MIM# 231680, glutaric aciduria type II)
Succinic semialdehyde dehydrogenase deficiency (SSADH, MIM# 271980)
Miscellaneous disorders related with 2-HG
Final remarks
D-2-HGA type I (MIM# 600721) | D-2-HGA type II (MIM# 613657) | L-2-HGA (MIM# 236792) | D,L-2-HGA | |
---|---|---|---|---|
Metabolites mean (n); range (controls)
| Increased D-2-HG | Increased D-2-HG | Increased L-2-HG | Increased D-2-HG and L-2-HG |
Urine (mmol/mol creat.) | ||||
D-2-HG (6 (18); 2.8-17)
| 969 (20); 103-2414 | 2486 (19); 448-11305 | normal | 496 (6); 228-750 |
L-2-HG (6 (18); 1.3-19)
| normal | normal | 1364 (27); 226-4299 | 161 (6); 64-247 |
Plasma (μmol/L) | ||||
D-2-HG (0.7 (10); 0.3-0.9)
| 68 (7); 26-123 | 366 (9); 99-757 | normal | 2.6 (4); 2.2-3.2 |
L-2-HG (0.6 (10); 0.5-1.0)
| normal | normal | 39 (18); 7-84 | 2.0 (4); 1.1-3.0 |
CSF (μmol/L) | ||||
D-2-HG (0.1 (10); 0.07-0.3)
| 13 (3); 6-18 | 79 (4); 30-172 | normal | 1.1 (3); 0.42-2.5 |
L-2-HG (0.7 (10); 0.3-2.3)
| normal | normal | 92 (12); 23-474 | normal |
Other metabolites | -- | -- | Lysine increased in plasma and CSF, mostly normal in urine | Inconsistently increased urinary 2-KG, succinate, fumarate and lactate |
Enzyme |
d-2-hydroxyglutarate dehydrogenase | Isocitrate dehydrogenase 2 |
l-2-hydroxyglutarate dehydrogenase | -- |
D-2-HGDH | IDH2 | L-2-HGDH | ||
EC 1.1.99.- | EC 1.1.1.42 | EC 1.1.99.2 | ||
Defect mechanism | Impaired activity | Gain-of-function | Impaired activity | |
Gene |
D2HGDH
|
IDH2
|
L2HGDH
| -- |
GeneBank 728294 | GeneBank 3418 | GeneBank 79944 | ||
NM_152783 | NM_002168 | NM_024884 | ||
MIM# 609186 | MIM# 147650 | MIM# 609584 | ||
Type of mutations | Heterogeneous | c.419G>A, R140Q | Heterogeneous | |
c.418C>G, R140G | ||||
Trait | Autosomal recessive | Autosomal dominant | Autosomal recessive | |
Clinical signs | Developmental delay | Developmental delay | Developmental delay | Severe neonatal epileptic encephalopathy |
Hypotonia | Hypotonia | Epilepsy | ||
Seizures | Seizures | Cerebellar ataxia | ||
Cardiomyopathy | ||||
Onset at 0-6 years | Onset at 0-2 years | Insidious onset in childhood | Onset in infancy | |
Lifespan unknown | Shortened lifespan | Highly distinct brain MRI abnormalities | Shortened lifespan | |
Brain MRI abnormalities | Brain MRI abnormalities | Brain MRI abnormalities | ||
Therapeutic strategies | -- | -- | Riboflavin may improve symptoms | -- |
Cancer | -- | Not reported, but | Increased incidence of brain tumors | -- |
IDH2 mutations in neoplastic disorders | ||||
Key references | Achouri et al 2004
| Kranendijk et al 2010b
| Rzem et al 2004
| Muntau et al 2000
|
Kranendijk et al 2011
| Aghili et al 2009
| Read et al 2005
| ||
Kranendijk et al 2010a
| ||||