HLD9
MCID: LKD016
MIFTS: 41

Leukodystrophy, Hypomyelinating, 9 (HLD9)

Categories: Ear diseases, Eye diseases, Fetal diseases, Genetic diseases, Mental diseases, Muscle diseases, Neuronal diseases, Rare diseases
Data Licensing
For inquiries, contact:

Aliases & Classifications for Leukodystrophy, Hypomyelinating, 9

MalaCards integrated aliases for Leukodystrophy, Hypomyelinating, 9:

Name: Leukodystrophy, Hypomyelinating, 9 57 73 71
Hypomyelinating Leukodystrophy 9 11 28 5 14
Hld9 57 11 73
Rars-Related Autosomal Recessive Hypomyelinating Leukodystrophy 11 58
Leukodystrophy, Hypomyelinating, Type 9 38

Characteristics:


Inheritance:

Leukodystrophy, Hypomyelinating, 9: Autosomal recessive 57
Rars-Related Autosomal Recessive Hypomyelinating Leukodystrophy: Autosomal recessive 58

Prevelance:

Rars-Related Autosomal Recessive Hypomyelinating Leukodystrophy: <1/1000000 (Worldwide) 58

Age Of Onset:

Rars-Related Autosomal Recessive Hypomyelinating Leukodystrophy: Infancy,Neonatal 58

OMIM®:

57 (Updated 24-Oct-2022)
Miscellaneous:
variable severity
onset in the first year of life
six patients from 5 families have been reported (last curated november 2018)


Classifications:

Orphanet: 58  
Rare neurological diseases


Summaries for Leukodystrophy, Hypomyelinating, 9

OMIM®: 57 Hypomyelinating leukodystrophy-9 is an autosomal recessive neurologic disorder characterized by onset of delayed psychomotor development, spasticity, and nystagmus in the first year of life. Additional neurologic features such as ataxia and abnormal movements may also occur. Brain imaging shows diffuse hypomyelination affecting all regions of the brain (summary by Wolf et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080. (616140) (Updated 24-Oct-2022)

MalaCards based summary: Leukodystrophy, Hypomyelinating, 9, also known as hypomyelinating leukodystrophy 9, is related to polr3-related leukodystrophy and cerebellofaciodental syndrome, and has symptoms including ataxia and action tremor. An important gene associated with Leukodystrophy, Hypomyelinating, 9 is RARS1 (Arginyl-TRNA Synthetase 1), and among its related pathways/superpathways is tRNA Aminoacylation. Affiliated tissues include brain, eye and peripheral nerve, and related phenotypes are hyperreflexia and nystagmus

Orphanet: 58 A rare, genetic leukodystrophy characterized by developmental delay, increased muscle tone leading later to spasticity, mild ataxia, nystagmus, dysarthria, intentional tremor, and mild intellectual disability. Brain imaging reveals supratentorial and infratentorial hypomyelination.

Disease Ontology: 11 A hypomyelinating leukodystrophy characterized by delayed psychomotor development, spasticity, and nystagmus starting in the first year of life that has material basis in compound heterozygous mutation in the RARS gene on chromosome 5q34.

UniProtKB/Swiss-Prot: 73 An autosomal recessive neurodegenerative disorder characterized by delayed psychomotor development, severe spasticity, nystagmus, and ataxia associated with diffuse hypomyelination apparent on brain MRI.

Related Diseases for Leukodystrophy, Hypomyelinating, 9

Diseases in the Hypomyelinating Leukodystrophy family:

Leukodystrophy, Hypomyelinating, 3 Leukodystrophy, Hypomyelinating, 2
Leukodystrophy, Hypomyelinating, 5 Leukodystrophy, Hypomyelinating, 4
Leukodystrophy, Hypomyelinating, 6 Leukodystrophy, Hypomyelinating, 9
Leukodystrophy, Hypomyelinating, 10 Leukodystrophy, Hypomyelinating, 11
Leukodystrophy, Hypomyelinating, 12 Leukodystrophy, Hypomyelinating, 13
Leukodystrophy, Hypomyelinating, 14 Leukodystrophy, Hypomyelinating, 15
Leukodystrophy, Hypomyelinating, 16 Leukodystrophy, Hypomyelinating, 17
Leukodystrophy, Hypomyelinating, 18 Leukodystrophy, Hypomyelinating, 19, Transient Infantile
Leukodystrophy, Hypomyelinating, 20 Leukodystrophy, Hypomyelinating, 21
Leukodystrophy, Hypomyelinating, 22 Leukodystrophy, Hypomyelinating, 24

Diseases related to Leukodystrophy, Hypomyelinating, 9 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 32)
# Related Disease Score Top Affiliating Genes
1 polr3-related leukodystrophy 10.1 POLR3B POLR3A
2 cerebellofaciodental syndrome 10.0 POLR3B POLR3A
3 boucher-neuhauser syndrome 10.0 POLR3B POLR3A
4 leukodystrophy, hypomyelinating, 5 10.0 POLR3A HYCC1 GJC2
5 gordon holmes syndrome 9.9 POLR3B POLR3A
6 leukodystrophy, hypomyelinating, 6 9.9 POLR3B POLR3A GJC2
7 cerebrooculofacioskeletal syndrome 2 9.9 POLR3B POLR3A ERCC6
8 dystonia 11, myoclonic 9.9 POLR3B POLR3A
9 childhood ataxia with central nervous system hypomyelination / vanishing white matter 9.9 EIF2B4 EIF2B3
10 hemangioma of intra-abdominal structure 9.9 EIF2B4 EIF2B3
11 glycogen storage disease xv 9.8 EIF2B4 EIF2B3
12 combined saposin deficiency 9.8 EIF2B4 EIF2B3
13 mehmo syndrome 9.8 EIF2B4 EIF2B3
14 leukoencephalopathy, hereditary diffuse, with spheroids 1 9.8 EIF2B4 EIF2B3
15 leukodystrophy, hypomyelinating, 4 9.8 POLR3A HYCC1 HIKESHI GJC2
16 tooth agenesis 9.7 POLR3B POLR3A GJC2 ERCC6
17 mitochondrial dna depletion syndrome 4a 9.7 RARS2 ERCC6
18 spastic ataxia 9.7 RARS2 POLR3B POLR3A GJC2
19 leukodystrophy, hypomyelinating, 3 9.6 POLR3A HYCC1 GJC2 AIMP1
20 hypomyelinating leukoencephalopathy 9.6 POLR3B POLR3A HYCC1 HIKESHI GJC2
21 leukodystrophy, hypomyelinating, 11 9.6 POLR3B POLR3A HIKESHI EIF2B3
22 leukodystrophy, hypomyelinating, 12 9.4 HYCC1 HIKESHI GJC2 EIF2B4 EIF2B3
23 leukoencephalopathy with vanishing white matter 9.4 POLR3B POLR3A GJC2 EIF2B4 EIF2B3
24 spastic ataxia 8 9.3 POLR3B HYCC1 HIKESHI EIF2B4 EIF2B3
25 peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease 9.3 POLR3B HIKESHI GJC2 EIF2B4 EIF2B3
26 leukodystrophy, hypomyelinating, 13 9.3 POLR3B HYCC1 HIKESHI EIF2B4 EIF2B3
27 cerebral degeneration 9.2 POLR3B POLR3A GJC2 ERCC6 EIF2B4 EIF2B3
28 leukodystrophy, hypomyelinating, 10 9.2 POLR3B POLR3A HYCC1 HIKESHI EIF2B4 EIF2B3
29 pelizaeus-merzbacher disease 8.8 RARS1 POLR3B POLR3A HYCC1 HIKESHI GJC2
30 leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism 8.6 POLR3B POLR3A HYCC1 HIKESHI GJC2 EIF2B4
31 hypomyelinating leukodystrophy 8.6 RARS2 RARS1 POLR3B POLR3A HYCC1 HIKESHI
32 leukodystrophy 8.2 RARS1 POLR3B POLR3A HYCC1 HIKESHI GJC2

Graphical network of the top 20 diseases related to Leukodystrophy, Hypomyelinating, 9:



Diseases related to Leukodystrophy, Hypomyelinating, 9

Symptoms & Phenotypes for Leukodystrophy, Hypomyelinating, 9

Human phenotypes related to Leukodystrophy, Hypomyelinating, 9:

58 30 (show all 31)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hyperreflexia 58 30 Frequent (33%) Frequent (79-30%)
HP:0001347
2 nystagmus 58 30 Frequent (33%) Frequent (79-30%)
HP:0000639
3 global developmental delay 58 30 Frequent (33%) Frequent (79-30%)
HP:0001263
4 intellectual disability, mild 58 30 Frequent (33%) Frequent (79-30%)
HP:0001256
5 developmental stagnation 58 30 Frequent (33%) Frequent (79-30%)
HP:0007281
6 dysmetria 58 30 Frequent (33%) Frequent (79-30%)
HP:0001310
7 dystonia 58 30 Frequent (33%) Frequent (79-30%)
HP:0001332
8 poor eye contact 58 30 Frequent (33%) Frequent (79-30%)
HP:0000817
9 poor head control 58 30 Frequent (33%) Frequent (79-30%)
HP:0002421
10 difficulty walking 58 30 Frequent (33%) Frequent (79-30%)
HP:0002355
11 hypoplasia of the corpus callosum 58 30 Frequent (33%) Frequent (79-30%)
HP:0002079
12 intention tremor 58 30 Frequent (33%) Frequent (79-30%)
HP:0002080
13 lower limb spasticity 58 30 Frequent (33%) Frequent (79-30%)
HP:0002061
14 cerebral hypomyelination 58 30 Frequent (33%) Frequent (79-30%)
HP:0006808
15 lower limb hypertonia 58 30 Frequent (33%) Frequent (79-30%)
HP:0006895
16 progressive extrapyramidal movement disorder 58 30 Frequent (33%) Frequent (79-30%)
HP:0007153
17 infantile axial hypotonia 58 30 Frequent (33%) Frequent (79-30%)
HP:0009062
18 hyperintensity of cerebral white matter on mri 58 30 Frequent (33%) Frequent (79-30%)
HP:0030890
19 microcephaly 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0000252
20 vomiting 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0002013
21 increased serum lactate 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0002151
22 focal-onset seizure 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0007359
23 pseudobulbar paralysis 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0007024
24 diffuse cerebral atrophy 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0002506
25 absent smooth pursuit 58 30 Occasional (7.5%) Occasional (29-5%)
HP:0007179
26 dysarthria 58 30 Frequent (79-30%)
HP:0001260
27 intellectual disability 30 HP:0001249
28 spasticity 30 HP:0001257
29 ataxia 58 Frequent (79-30%)
30 abnormality of extrapyramidal motor function 30 HP:0002071
31 leukodystrophy 30 HP:0002415

Symptoms via clinical synopsis from OMIM®:

57 (Updated 24-Oct-2022)
Neurologic Central Nervous System:
hyperreflexia
ataxia
dysarthria
dysmetria
intention tremor
more
Head And Neck Head:
microcephaly (1 patient)

Head And Neck Eyes:
nystagmus
poor smooth pursuit
poor visual fixation (1 patient)

Muscle Soft Tissue:
hypertonicity of the lower limbs

Clinical features from OMIM®:

616140 (Updated 24-Oct-2022)

UMLS symptoms related to Leukodystrophy, Hypomyelinating, 9:


ataxia; action tremor

MGI Mouse Phenotypes related to Leukodystrophy, Hypomyelinating, 9:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 9.56 AIMP1 EIF2B4 ERCC6 GJC2 HYCC1 POLR3A
2 mortality/aging MP:0010768 9.28 AIMP1 EIF2B3 EIF2B4 ERCC6 GJC2 HIKESHI

Drugs & Therapeutics for Leukodystrophy, Hypomyelinating, 9

Search Clinical Trials, NIH Clinical Center for Leukodystrophy, Hypomyelinating, 9

Genetic Tests for Leukodystrophy, Hypomyelinating, 9

Genetic tests related to Leukodystrophy, Hypomyelinating, 9:

# Genetic test Affiliating Genes
1 Hypomyelinating Leukodystrophy 9 28 RARS1

Anatomical Context for Leukodystrophy, Hypomyelinating, 9

Organs/tissues related to Leukodystrophy, Hypomyelinating, 9:

MalaCards : Brain, Eye
ODiseA: Peripheral Nerve, Brain

Publications for Leukodystrophy, Hypomyelinating, 9

Articles related to Leukodystrophy, Hypomyelinating, 9:

# Title Authors PMID Year
1
Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease. 57 5
28905880 2017
2
Mutations in RARS cause hypomyelination. 57 5
24777941 2014
3
Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation. 62 5
31737794 2019
4
Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease. 5
33515434 2021
5
RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum. 5
31814314 2020

Variations for Leukodystrophy, Hypomyelinating, 9

ClinVar genetic disease variations for Leukodystrophy, Hypomyelinating, 9:

5 (show all 26)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 RARS1 NM_002887.4(RARS1):c.45+1G>T SNV Pathogenic
162081 rs672601373 GRCh37: 5:167913549-167913549
GRCh38: 5:168486544-168486544
2 RARS1 NM_002887.4(RARS1):c.96_97del (p.Cys32fs) MICROSAT Pathogenic
162082 rs672601374 GRCh37: 5:167915655-167915656
GRCh38: 5:168488650-168488651
3 RARS1 NM_002887.4(RARS1):c.1846_1847del (p.Tyr616fs) DEL Pathogenic
424864 rs1064792894 GRCh37: 5:167945040-167945041
GRCh38: 5:168518035-168518036
4 RARS1 NM_002887.4(RARS1):c.2T>C (p.Met1Thr) SNV Pathogenic
391980 rs769713780 GRCh37: 5:167913505-167913505
GRCh38: 5:168486500-168486500
5 RARS1 NM_002887.4(RARS1):c.5A>G (p.Asp2Gly) SNV Pathogenic
162080 rs672601372 GRCh37: 5:167913508-167913508
GRCh38: 5:168486503-168486503
6 RARS1 NM_002887.4(RARS1):c.1A>G (p.Met1Val) SNV Pathogenic
162083 rs672601375 GRCh37: 5:167913504-167913504
GRCh38: 5:168486499-168486499
7 RARS1 NM_002887.4(RARS1):c.1367C>T (p.Ser456Leu) SNV Pathogenic/Likely Pathogenic
265854 rs139644798 GRCh37: 5:167937606-167937606
GRCh38: 5:168510601-168510601
8 RARS1 NM_002887.4(RARS1):c.1535G>A (p.Arg512Gln) SNV Likely Pathogenic
162084 rs369398935 GRCh37: 5:167943865-167943865
GRCh38: 5:168516860-168516860
9 RARS1 NM_002887.4(RARS1):c.1316C>A (p.Ala439Asp) SNV Likely Pathogenic
977922 rs779915495 GRCh37: 5:167933806-167933806
GRCh38: 5:168506801-168506801
10 RARS1 NM_002887.4(RARS1):c.614_615del (p.Lys205fs) DEL Likely Pathogenic
1324988 GRCh37: 5:167922353-167922354
GRCh38: 5:168495348-168495349
11 RARS1 NM_002887.4(RARS1):c.1805_1806dup (p.Glu603fs) MICROSAT Likely Pathogenic
1324989 GRCh37: 5:167944991-167944992
GRCh38: 5:168517986-168517987
12 RARS1 NM_002887.4(RARS1):c.204del (p.Lys68fs) DEL Likely Pathogenic
1324990 GRCh37: 5:167919685-167919685
GRCh38: 5:168492680-168492680
13 RARS1 NM_002887.4(RARS1):c.1863_1866del (p.Gln623fs) DEL Likely Pathogenic
1324991 GRCh37: 5:167945054-167945057
GRCh38: 5:168518049-168518052
14 RARS1 NM_002887.4(RARS1):c.104T>G (p.Leu35Ter) SNV Likely Pathogenic
1324992 GRCh37: 5:167915665-167915665
GRCh38: 5:168488660-168488660
15 RARS1 NM_002887.4(RARS1):c.11T>A (p.Leu4Gln) SNV Uncertain Significance
1029653 rs374019310 GRCh37: 5:167913514-167913514
GRCh38: 5:168486509-168486509
16 RARS1 NM_002887.4(RARS1):c.161G>A (p.Arg54Gln) SNV Uncertain Significance
1029654 rs199706413 GRCh37: 5:167915722-167915722
GRCh38: 5:168488717-168488717
17 RARS1 NM_002887.4(RARS1):c.1816A>T (p.Thr606Ser) SNV Uncertain Significance
1030600 rs773197957 GRCh37: 5:167945010-167945010
GRCh38: 5:168518005-168518005
18 RARS1 NM_002887.4(RARS1):c.793C>T (p.Pro265Ser) SNV Uncertain Significance
1030601 rs144891956 GRCh37: 5:167924324-167924324
GRCh38: 5:168497319-168497319
19 RARS1 NM_002887.4(RARS1):c.860A>G (p.Lys287Arg) SNV Uncertain Significance
1030602 rs556591376 GRCh37: 5:167927633-167927633
GRCh38: 5:168500628-168500628
20 RARS1 NM_002887.4(RARS1):c.36G>C (p.Leu12=) SNV Uncertain Significance
1033549 rs1272430190 GRCh37: 5:167913539-167913539
GRCh38: 5:168486534-168486534
21 RARS1 NM_002887.4(RARS1):c.1127T>A (p.Val376Glu) SNV Likely Benign
382395 rs146939849 GRCh37: 5:167933095-167933095
GRCh38: 5:168506090-168506090
22 RARS1 NM_002887.4(RARS1):c.1237-43dup DUP Benign
1177984 GRCh37: 5:167933673-167933674
GRCh38: 5:168506668-168506669
23 RARS1 NM_002887.4(RARS1):c.181-41T>A SNV Benign
1234982 GRCh37: 5:167919623-167919623
GRCh38: 5:168492618-168492618
24 RARS1 NM_002887.4(RARS1):c.478+40C>G SNV Benign
1244618 GRCh37: 5:167921047-167921047
GRCh38: 5:168494042-168494042
25 RARS1 NM_002887.4(RARS1):c.7G>A (p.Val3Ile) SNV Benign
380030 rs244903 GRCh37: 5:167913510-167913510
GRCh38: 5:168486505-168486505
26 RARS1 NM_002887.4(RARS1):c.1497G>A (p.Ala499=) SNV Benign
380005 rs653568 GRCh37: 5:167943827-167943827
GRCh38: 5:168516822-168516822

UniProtKB/Swiss-Prot genetic disease variations for Leukodystrophy, Hypomyelinating, 9:

73
# Symbol AA change Variation ID SNP ID
1 RARS1 p.Asp2Gly VAR_072666 rs672601372
2 RARS1 p.Arg512Gln VAR_072667 rs369398935

Expression for Leukodystrophy, Hypomyelinating, 9

Search GEO for disease gene expression data for Leukodystrophy, Hypomyelinating, 9.

Pathways for Leukodystrophy, Hypomyelinating, 9

Pathways related to Leukodystrophy, Hypomyelinating, 9 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
10.74 RARS2 RARS1 AIMP1

GO Terms for Leukodystrophy, Hypomyelinating, 9

Cellular components related to Leukodystrophy, Hypomyelinating, 9 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 RNA polymerase III complex GO:0005666 9.46 POLR3B POLR3A
2 DNA-directed RNA polymerase complex GO:0000428 9.26 POLR3B POLR3A
3 aminoacyl-tRNA synthetase multienzyme complex GO:0017101 9.26 RARS1 AIMP1
4 eukaryotic translation initiation factor 2B complex GO:0005851 8.92 EIF2B4 EIF2B3

Biological processes related to Leukodystrophy, Hypomyelinating, 9 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 tRNA aminoacylation for protein translation GO:0006418 9.62 RARS2 RARS1
2 oligodendrocyte development GO:0014003 9.56 EIF2B4 EIF2B3
3 arginyl-tRNA aminoacylation GO:0006420 9.26 RARS2 RARS1
4 tRNA metabolic process GO:0006399 9.16 RARS2 RARS1
5 translation GO:0006412 9.1 RARS2 RARS1 EIF2B4 EIF2B3 AIMP1

Molecular functions related to Leukodystrophy, Hypomyelinating, 9 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 DNA-directed 5'-3' RNA polymerase activity GO:0003899 9.56 POLR3B POLR3A
2 nucleotidyltransferase activity GO:0016779 9.26 POLR3B POLR3A EIF2B3
3 aminoacyl-tRNA ligase activity GO:0004812 9.16 RARS2 RARS1
4 arginine-tRNA ligase activity GO:0004814 8.92 RARS2 RARS1

Sources for Leukodystrophy, Hypomyelinating, 9

2 CDC
6 CNVD
8 Cosmic
9 dbSNP
10 DGIdb
16 EFO
17 ExPASy
18 FMA
19 GARD
27 GO
28 GTR
29 HMDB
30 HPO
31 ICD10
32 ICD10 via Orphanet
33 ICD11
34 ICD9CM
35 IUPHAR
36 LifeMap
38 LOVD
40 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
52 NINDS
53 Novoseek
55 ODiseA
56 OMIM via Orphanet
57 OMIM® (Updated 24-Oct-2022)
61 PubChem
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 Tocris
71 UMLS
72 UMLS via Orphanet
Content
Loading form....