DEE39
MCID: DVL036
MIFTS: 39

Developmental and Epileptic Encephalopathy 39 (DEE39)

Categories: Cancer diseases, Ear diseases, Eye diseases, Fetal diseases, Genetic diseases, Liver diseases, Mental diseases, Metabolic diseases, Neuronal diseases, Rare diseases, Respiratory diseases

Aliases & Classifications for Developmental and Epileptic Encephalopathy 39

MalaCards integrated aliases for Developmental and Epileptic Encephalopathy 39:

Name: Developmental and Epileptic Encephalopathy 39 57 12
Hypomyelination, Global Cerebral 57 73 29 13 6 39
Agc1 Deficiency 57 12 58 73
Epileptic Encephalopathy with Global Cerebral Demyelination 12 58
Epileptic Encephalopathy, Early Infantile, 39 57 73
Early Infantile Epileptic Encephalopathy 39 12 15
Aspartate-Glutamate Carrier 1 Deficiency 57 73
Global Cerebral Hypomyelination 73 36
Eiee39 57 73
Hereditary Central Nervous System Demyelinating Diseases 44
Mitochondrial Aspartate-Glutamate Carrier 1 Deficiency 58
Epileptic Encephalopathy, Early Infantile, 39; Eiee39 57
Dee39 57

Characteristics:

OMIM®:

57 (Updated 05-Mar-2021)
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy
two unrelated families have been reported (last curated july 2016)


HPO:

31
developmental and epileptic encephalopathy 39:
Inheritance autosomal recessive inheritance
Onset and clinical course infantile onset


Classifications:

Orphanet: 58  
Rare neurological diseases
Inborn errors of metabolism


External Ids:

Disease Ontology 12 DOID:0080349
OMIM® 57 612949
OMIM Phenotypic Series 57 PS308350
KEGG 36 H01305
ICD10 via Orphanet 33 E88.8
Orphanet 58 ORPHA353217
MedGen 41 C2751855

Summaries for Developmental and Epileptic Encephalopathy 39

OMIM® : 57 Developmental and epileptic encephalopathy-39 (DEE39) is an autosomal recessive neurologic syndrome characterized clinically by global developmental delay apparent in early infancy, early-onset seizures, hypotonia with poor motor function, and hypomyelination on brain imaging. Other features include absent speech and inability to walk; spasticity and hyperreflexia has also been reported. Although there is significant hypomyelination on brain imaging, the disorder is not classified as a primary leukodystrophy. The myelination defect most likely stems from primary neuronal dysfunction due to impaired mitochondrial transport activity (summary by Wibom et al., 2009 and Falk et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. (612949) (Updated 05-Mar-2021)

MalaCards based summary : Developmental and Epileptic Encephalopathy 39, also known as hypomyelination, global cerebral, is related to hypotonia and epilepsy, and has symptoms including seizures and muscle spasticity. An important gene associated with Developmental and Epileptic Encephalopathy 39 is SLC25A12 (Solute Carrier Family 25 Member 12), and among its related pathways/superpathways is Mitochondrial protein import. Affiliated tissues include eye and brain, and related phenotypes are spasticity and hyperreflexia

Disease Ontology : 12 A developmental and epileptic encephalopathy characterized by global developmental delay apparent in early infancy, early-onset seizures, hypotonia, poor motor function, and hypomyelination in the brain that has material basis in mutation in the SLC25A12 gene on chromosome 2q31.

KEGG : 36 Global cerebral hypomyelination is a syndrome characterized by arrested psychomotor development, hypotonia, and seizures. A missense mutation in the SLC25A12, which encodes the AGC1 protein, causes this syndrome. AGC1 is thought to be important in providing energy for neurons in the central nervous system.

UniProtKB/Swiss-Prot : 73 Epileptic encephalopathy, early infantile, 39: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected. Inheritance is autosomal recessive.

Related Diseases for Developmental and Epileptic Encephalopathy 39

Diseases in the Developmental and Epileptic Encephalopathy family:

Developmental and Epileptic Encephalopathy 9 Developmental and Epileptic Encephalopathy 8
Developmental and Epileptic Encephalopathy 2 Developmental and Epileptic Encephalopathy 36
Developmental and Epileptic Encephalopathy 90 Developmental and Epileptic Encephalopathy 1
Developmental and Epileptic Encephalopathy 3 Developmental and Epileptic Encephalopathy 4
Developmental and Epileptic Encephalopathy 39 Developmental and Epileptic Encephalopathy 5
Developmental and Epileptic Encephalopathy 7 Developmental and Epileptic Encephalopathy 11
Developmental and Epileptic Encephalopathy 12 Developmental and Epileptic Encephalopathy 13
Developmental and Epileptic Encephalopathy 14 Developmental and Epileptic Encephalopathy 15
Developmental and Epileptic Encephalopathy 16 Developmental and Epileptic Encephalopathy 17
Developmental and Epileptic Encephalopathy 18 Developmental and Epileptic Encephalopathy 19
Developmental and Epileptic Encephalopathy 21 Developmental and Epileptic Encephalopathy 23
Developmental and Epileptic Encephalopathy 24 Developmental and Epileptic Encephalopathy 26
Developmental and Epileptic Encephalopathy 27 Developmental and Epileptic Encephalopathy 28
Developmental and Epileptic Encephalopathy 29 Developmental and Epileptic Encephalopathy 30
Developmental and Epileptic Encephalopathy 31 Developmental and Epileptic Encephalopathy 32
Developmental and Epileptic Encephalopathy 33 Developmental and Epileptic Encephalopathy 50
Developmental and Epileptic Encephalopathy 34 Developmental and Epileptic Encephalopathy 35
Developmental and Epileptic Encephalopathy 37 Developmental and Epileptic Encephalopathy 38
Developmental and Epileptic Encephalopathy 40 Developmental and Epileptic Encephalopathy 41
Developmental and Epileptic Encephalopathy 42 Developmental and Epileptic Encephalopathy 43
Developmental and Epileptic Encephalopathy 44 Developmental and Epileptic Encephalopathy 45
Developmental and Epileptic Encephalopathy 46 Developmental and Epileptic Encephalopathy 47
Developmental and Epileptic Encephalopathy 48 Developmental and Epileptic Encephalopathy 49
Developmental and Epileptic Encephalopathy 51 Developmental and Epileptic Encephalopathy 52
Developmental and Epileptic Encephalopathy 53 Developmental and Epileptic Encephalopathy 54
Developmental and Epileptic Encephalopathy 55 Developmental and Epileptic Encephalopathy 56
Developmental and Epileptic Encephalopathy 57 Developmental and Epileptic Encephalopathy 58
Developmental and Epileptic Encephalopathy 59 Developmental and Epileptic Encephalopathy 60
Developmental and Epileptic Encephalopathy 61 Developmental and Epileptic Encephalopathy 62
Developmental and Epileptic Encephalopathy 63 Developmental and Epileptic Encephalopathy 64
Developmental and Epileptic Encephalopathy 65 Developmental and Epileptic Encephalopathy 66
Developmental and Epileptic Encephalopathy 67 Developmental and Epileptic Encephalopathy 68
Developmental and Epileptic Encephalopathy 69 Developmental and Epileptic Encephalopathy 70
Developmental and Epileptic Encephalopathy 71 Developmental and Epileptic Encephalopathy 72
Developmental and Epileptic Encephalopathy 73 Developmental and Epileptic Encephalopathy 74
Developmental and Epileptic Encephalopathy 75 Developmental and Epileptic Encephalopathy 76
Developmental and Epileptic Encephalopathy 78 Developmental and Epileptic Encephalopathy 79
Developmental and Epileptic Encephalopathy 80 Developmental and Epileptic Encephalopathy 81
Developmental and Epileptic Encephalopathy 82 Developmental and Epileptic Encephalopathy 83
Developmental and Epileptic Encephalopathy 84 Developmental and Epileptic Encephalopathy 86
Developmental and Epileptic Encephalopathy 87 Developmental and Epileptic Encephalopathy 88
Developmental and Epileptic Encephalopathy 89

Diseases related to Developmental and Epileptic Encephalopathy 39 via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 hypotonia 10.3
2 epilepsy 10.1
3 cerebral atrophy 10.1
4 infantile epilepsy syndrome 10.1
5 seizure disorder 10.0
6 urea cycle disorder 9.9 SLC25A13 SLC25A12
7 citrullinemia, classic 9.9 SLC25A13 SLC25A12
8 asperger syndrome 9.8 SLC25A13 SLC25A12
9 citrullinemia, type ii, adult-onset 9.6 SLC25A22 SLC25A13 SLC25A12
10 hyperornithinemia-hyperammonemia-homocitrullinuria syndrome 9.3 SLC25A48 SLC25A47 SLC25A22 SLC25A13

Graphical network of the top 20 diseases related to Developmental and Epileptic Encephalopathy 39:



Diseases related to Developmental and Epileptic Encephalopathy 39

Symptoms & Phenotypes for Developmental and Epileptic Encephalopathy 39

Human phenotypes related to Developmental and Epileptic Encephalopathy 39:

31 (show all 9)
# Description HPO Frequency HPO Source Accession
1 spasticity 31 HP:0001257
2 hyperreflexia 31 HP:0001347
3 global developmental delay 31 HP:0001263
4 absent speech 31 HP:0001344
5 severe muscular hypotonia 31 HP:0006829
6 poor eye contact 31 HP:0000817
7 epileptic encephalopathy 31 HP:0200134
8 cerebral hypomyelination 31 HP:0006808
9 seizure 31 HP:0001250

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Mar-2021)
Neurologic Central Nervous System:
seizures
spasticity
hyperreflexia
epileptic encephalopathy
delayed psychomotor development, profound
more
Respiratory:
apneic spells

Head And Neck Eyes:
poor eye contact

Laboratory Abnormalities:
increased plasma lactate

Clinical features from OMIM®:

612949 (Updated 05-Mar-2021)

UMLS symptoms related to Developmental and Epileptic Encephalopathy 39:


seizures, muscle spasticity

Drugs & Therapeutics for Developmental and Epileptic Encephalopathy 39

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Natural History Study of Children With Metachromatic Leukodystrophy Terminated NCT01963650

Search NIH Clinical Center for Developmental and Epileptic Encephalopathy 39

Cochrane evidence based reviews: hereditary central nervous system demyelinating diseases

Genetic Tests for Developmental and Epileptic Encephalopathy 39

Genetic tests related to Developmental and Epileptic Encephalopathy 39:

# Genetic test Affiliating Genes
1 Hypomyelination, Global Cerebral 29 SLC25A12

Anatomical Context for Developmental and Epileptic Encephalopathy 39

MalaCards organs/tissues related to Developmental and Epileptic Encephalopathy 39:

40
Eye, Brain

Publications for Developmental and Epileptic Encephalopathy 39

Articles related to Developmental and Epileptic Encephalopathy 39:

(show all 13)
# Title Authors PMID Year
1
AGC1 deficiency associated with global cerebral hypomyelination. 6 57 61
19641205 2009
2
Erratum to: AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate. 61 6
24973975 2014
3
AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate. 61 57
24515575 2014
4
AGC1 deficiency and cerebral hypomyelination. 57 61
19907050 2009
5
Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier. 57
15987682 2005
6
╬▓OHB Protective Pathways in Aralar-KO Neurons and Brain: An Alternative to Ketogenic Diet. 61
33087477 2020
7
Expanding Phenotypic Spectrum of Cerebral Aspartate-Glutamate Carrier Isoform 1 (AGC1) Deficiency. 61
31766059 2020
8
Deficiency of Mitochondrial Aspartate-Glutamate Carrier 1 Leads to Oligodendrocyte Precursor Cell Proliferation Defects Both In Vitro and In Vivo. 61
31514314 2019
9
ARALAR/AGC1 deficiency, a neurodevelopmental disorder with severe impairment of neuronal mitochondrial respiration, does not produce a primary increase in brain lactate. 61
28429368 2017
10
Down-regulation of the mitochondrial aspartate-glutamate carrier isoform 1 AGC1 inhibits proliferation and N-acetylaspartate synthesis in Neuro2A cells. 61
28235644 2017
11
Uncoupling Protein 2 (UCP2) Function in the Brain as Revealed by the Cerebral Metabolism of (1-13C)-Glucose. 61
27401256 2017
12
The ketogenic diet compensates for AGC1 deficiency and improves myelination. 61
26401995 2015
13
Deficiency of the mitochondrial transporter of aspartate/glutamate aralar/AGC1 causes hypomyelination and neuronal defects unrelated to myelin deficits in mouse brain. 61
21608011 2011

Variations for Developmental and Epileptic Encephalopathy 39

ClinVar genetic disease variations for Developmental and Epileptic Encephalopathy 39:

6 (show all 14)
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 SLC25A12 NM_003705.5(SLC25A12):c.1769A>G (p.Gln590Arg) SNV Pathogenic 6148 rs121434396 2:172644147-172644147 2:171787637-171787637
2 SLC25A12 NM_003705.5(SLC25A12):c.1058G>A (p.Arg353Gln) SNV Pathogenic 253136 rs886037851 2:172669962-172669962 2:171813452-171813452
3 SLC25A12 GRCh37/hg19 2q31.1(chr2:172644081-172644457) copy number loss Pathogenic 813326 2:172644081-172644457
4 SLC25A12 NM_003705.5(SLC25A12):c.326-2A>C SNV Likely pathogenic 804390 rs1573977142 2:172701020-172701020 2:171844510-171844510
5 SLC25A12 NM_003705.5(SLC25A12):c.225del (p.Glu76fs) Deletion Likely pathogenic 982872 2:172712444-172712444 2:171855934-171855934
6 SLC25A12 NM_003705.5(SLC25A12):c.1618G>A (p.Asp540Asn) SNV Likely pathogenic 488597 rs1553469156 2:172644425-172644425 2:171787915-171787915
7 SLC25A12 NM_003705.5(SLC25A12):c.1654G>A (p.Ala552Thr) SNV Uncertain significance 546880 rs142912356 2:172644389-172644389 2:171787879-171787879
8 SLC25A12 NM_003705.5(SLC25A12):c.67-6T>A SNV Uncertain significance 626170 rs1302626614 2:172725339-172725339 2:171868829-171868829
9 SLC25A12 NM_003705.5(SLC25A12):c.*994C>T SNV Uncertain significance 332325 rs189758490 2:172640790-172640790 2:171784280-171784280
10 SLC25A12 NM_003705.4(SLC25A12):c.-57_-56dupGC Microsatellite Uncertain significance 332350 rs759200327 2:172750779-172750780 2:171894269-171894270
11 SLC25A12 NM_003705.5(SLC25A12):c.13G>A (p.Val5Met) SNV Uncertain significance 332347 rs201557997 2:172749768-172749768 2:171893258-171893258
12 SLC25A12 NM_003705.5(SLC25A12):c.325G>A (p.Glu109Lys) SNV Uncertain significance 917534 2:172712344-172712344 2:171855834-171855834
13 SLC25A12 NM_003705.5(SLC25A12):c.1171+17C>G SNV Benign 930679 2:172669832-172669832 2:171813322-171813322
14 SLC25A12 NM_003705.5(SLC25A12):c.125G>A (p.Arg42His) SNV not provided 585055 rs143779282 2:172725275-172725275 2:171868765-171868765

UniProtKB/Swiss-Prot genetic disease variations for Developmental and Epileptic Encephalopathy 39:

73
# Symbol AA change Variation ID SNP ID
1 SLC25A12 p.Gln590Arg VAR_063253 rs121434396
2 SLC25A12 p.Arg353Gln VAR_071976 rs886037851

Expression for Developmental and Epileptic Encephalopathy 39

Search GEO for disease gene expression data for Developmental and Epileptic Encephalopathy 39.

Pathways for Developmental and Epileptic Encephalopathy 39

Pathways related to Developmental and Epileptic Encephalopathy 39 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 10.42 SLC25A13 SLC25A12

GO Terms for Developmental and Epileptic Encephalopathy 39

Cellular components related to Developmental and Epileptic Encephalopathy 39 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 membrane GO:0016020 9.86 SLC25A48 SLC25A47 SLC25A45 SLC25A39 SLC25A22 SLC25A13
2 integral component of membrane GO:0016021 9.76 SLC25A48 SLC25A47 SLC25A45 SLC25A39 SLC25A22 SLC25A13
3 mitochondrion GO:0005739 9.56 SLC25A48 SLC25A47 SLC25A45 SLC25A39 SLC25A22 SLC25A13
4 mitochondrial inner membrane GO:0005743 9.23 SLC25A48 SLC25A47 SLC25A45 SLC25A39 SLC25A22 SLC25A13

Biological processes related to Developmental and Epileptic Encephalopathy 39 according to GeneCards Suite gene sharing:

(show all 11)
# Name GO ID Score Top Affiliating Genes
1 amino acid transport GO:0006865 9.63 SLC25A48 SLC25A47 SLC25A45
2 transport GO:0006810 9.61 SLC25A22 SLC25A13 SLC25A12
3 L-glutamate transmembrane transport GO:0015813 9.58 SLC25A22 SLC25A13 SLC25A12
4 aspartate transmembrane transport GO:0015810 9.54 SLC25A22 SLC25A13 SLC25A12
5 L-aspartate transmembrane transport GO:0070778 9.5 SLC25A22 SLC25A13 SLC25A12
6 response to calcium ion GO:0051592 9.49 SLC25A13 SLC25A12
7 gluconeogenesis GO:0006094 9.48 SLC25A13 SLC25A12
8 acyl carnitine transmembrane transport GO:1902616 9.43 SLC25A48 SLC25A47 SLC25A45
9 malate-aspartate shuttle GO:0043490 9.33 SLC25A22 SLC25A13 SLC25A12
10 transmembrane transport GO:0055085 9.17 SLC25A48 SLC25A47 SLC25A45 SLC25A39 SLC25A22 SLC25A13
11 acyl carnitine transport GO:0006844 9.13 SLC25A48 SLC25A47 SLC25A45

Molecular functions related to Developmental and Epileptic Encephalopathy 39 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 transmembrane transporter activity GO:0022857 9.5 SLC25A22 SLC25A13 SLC25A12
2 L-glutamate transmembrane transporter activity GO:0005313 9.43 SLC25A22 SLC25A13 SLC25A12
3 L-aspartate transmembrane transporter activity GO:0015183 9.33 SLC25A22 SLC25A13 SLC25A12
4 ATP transmembrane transporter activity GO:0005347 9.17 SLC25A48 SLC25A47 SLC25A45 SLC25A39 SLC25A22 SLC25A13
5 acyl carnitine transmembrane transporter activity GO:0015227 9.13 SLC25A48 SLC25A47 SLC25A45

Sources for Developmental and Epileptic Encephalopathy 39

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Mar-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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