HLD9
MCID: LKD016
MIFTS: 35

Leukodystrophy, Hypomyelinating, 9 (HLD9)

Categories: Eye diseases, Fetal diseases, Genetic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Leukodystrophy, Hypomyelinating, 9

MalaCards integrated aliases for Leukodystrophy, Hypomyelinating, 9:

Name: Leukodystrophy, Hypomyelinating, 9 56 73 29 6 71
Hld9 56 12 73
Rars-Related Autosomal Recessive Hypomyelinating Leukodystrophy 12 58
Hypomyelinating Leukodystrophy 9 12 15
Leukodystrophy, Hypomyelinating, Type 9 39

Characteristics:

Orphanet epidemiological data:

58
rars-related autosomal recessive hypomyelinating leukodystrophy
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal;

OMIM:

56
Inheritance:
autosomal recessive

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


HPO:

31
leukodystrophy, hypomyelinating, 9:
Inheritance autosomal recessive inheritance
Onset and clinical course variable expressivity


Classifications:

Orphanet: 58  
Rare neurological diseases


Summaries for Leukodystrophy, Hypomyelinating, 9

OMIM : 56 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)

MalaCards based summary : Leukodystrophy, Hypomyelinating, 9, also known as hld9, is related to robinow syndrome, autosomal recessive 1 and leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism, and has symptoms including ataxia and action tremor. An important gene associated with Leukodystrophy, Hypomyelinating, 9 is RARS1 (Arginyl-TRNA Synthetase 1). Affiliated tissues include brain and eye, and related phenotypes are global developmental delay and intellectual disability, mild

Disease Ontology : 12 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 Leukodystrophy, hypomyelinating, 9: 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

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

(show all 17)
# Related Disease Score Top Affiliating Genes
1 robinow syndrome, autosomal recessive 1 9.9 RARS1 ERCC6
2 leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism 9.6 POLR3A GJC2
3 pelizaeus-merzbacher disease 9.6 RARS1 GJC2 ERCC6
4 hallermann-streiff syndrome 9.6 POLR3A GJC2
5 spastic ataxia 9.6 POLR3A GJC2
6 spastic ataxia 8 9.6 POLR3A GJC2
7 leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism 9.6 POLR3A GJC2
8 treacher collins syndrome 1 9.5 TXNL4A POLR3A
9 leukoencephalopathy with vanishing white matter 9.5 POLR3A GJC2
10 specific developmental disorder 9.4 POLR3A ERCC6
11 cerebral degeneration 9.3 POLR3A GJC2 ERCC6
12 tooth agenesis 9.3 POLR3A ERCC6
13 hypomyelinating leukoencephalopathy 9.2 POLR3A GJC2 FAM126A
14 leukodystrophy, hypomyelinating, 4 9.2 POLR3A GJC2 FAM126A
15 leukodystrophy, hypomyelinating, 5 9.1 TXNL4A GJC2 FAM126A ERCC6
16 hypomyelinating leukodystrophy 8.9 POLR3A GJC2 FAM126A ERCC6
17 leukodystrophy 8.6 RARS1 POLR3A GJC2 FAM126A ERCC6

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

Symptoms via clinical synopsis from OMIM:

56
Neurologic Central Nervous System:
ataxia
hyperreflexia
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

UMLS symptoms related to Leukodystrophy, Hypomyelinating, 9:


ataxia, action tremor

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

26 (show all 13)
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Decreased shRNA abundance (Z-score < -2) GR00366-A-107 9.44 ERCC6
2 Decreased shRNA abundance (Z-score < -2) GR00366-A-11 9.44 TXNL4A
3 Decreased shRNA abundance (Z-score < -2) GR00366-A-134 9.44 ERCC6
4 Decreased shRNA abundance (Z-score < -2) GR00366-A-136 9.44 ERCC6
5 Decreased shRNA abundance (Z-score < -2) GR00366-A-151 9.44 ERCC6
6 Decreased shRNA abundance (Z-score < -2) GR00366-A-173 9.44 TXNL4A
7 Decreased shRNA abundance (Z-score < -2) GR00366-A-188 9.44 ERCC6
8 Decreased shRNA abundance (Z-score < -2) GR00366-A-20 9.44 ERCC6
9 Decreased shRNA abundance (Z-score < -2) GR00366-A-200 9.44 ERCC6
10 Decreased shRNA abundance (Z-score < -2) GR00366-A-23 9.44 ERCC6
11 Decreased shRNA abundance (Z-score < -2) GR00366-A-42 9.44 TXNL4A
12 Decreased shRNA abundance (Z-score < -2) GR00366-A-44 9.44 ERCC6
13 Decreased shRNA abundance (Z-score < -2) GR00366-A-91 9.44 ERCC6

MGI Mouse Phenotypes related to Leukodystrophy, Hypomyelinating, 9:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 9.02 ERCC6 FAM126A GJC2 POLR3A RARS1

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 Leukodystrophy, Hypomyelinating, 9 29 RARS1

Anatomical Context for Leukodystrophy, Hypomyelinating, 9

MalaCards organs/tissues related to Leukodystrophy, Hypomyelinating, 9:

40
Brain, Eye

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. 6 56
28905880 2017
2
Mutations in RARS cause hypomyelination. 6 56
24777941 2014
3
Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation. 61
31737794 2019

Variations for Leukodystrophy, Hypomyelinating, 9

ClinVar genetic disease variations for Leukodystrophy, Hypomyelinating, 9:

6 ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 RARS1 NM_002887.4(RARS1):c.5A>G (p.Asp2Gly)SNV Pathogenic 162080 rs672601372 5:167913508-167913508 5:168486503-168486503
2 RARS1 NM_002887.4(RARS1):c.45+1G>TSNV Pathogenic 162081 rs672601373 5:167913549-167913549 5:168486544-168486544
3 RARS1 NM_002887.4(RARS1):c.94_95TG[1] (p.Cys32fs)short repeat Pathogenic 162082 rs672601374 5:167915655-167915656 5:168488650-168488651
4 RARS1 NM_002887.4(RARS1):c.1A>G (p.Met1Val)SNV Pathogenic 162083 rs672601375 5:167913504-167913504 5:168486499-168486499
5 RARS1 NM_002887.4(RARS1):c.1367C>T (p.Ser456Leu)SNV Pathogenic 265854 rs139644798 5:167937606-167937606 5:168510601-168510601
6 RARS1 NM_002887.4(RARS1):c.1846_1847del (p.Tyr616fs)deletion Pathogenic 424864 rs1064792894 5:167945040-167945041 5:168518035-168518036
7 RARS1 NM_002887.4(RARS1):c.2T>C (p.Met1Thr)SNV Pathogenic 391980 rs769713780 5:167913505-167913505 5:168486500-168486500
8 RARS1 NM_002887.4(RARS1):c.1535G>A (p.Arg512Gln)SNV Likely pathogenic 162084 rs369398935 5:167943865-167943865 5:168516860-168516860
9 RARS1 NM_002887.4(RARS1):c.7G>A (p.Val3Ile)SNV Benign 380030 rs244903 5:167913510-167913510 5:168486505-168486505

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

GO Terms for Leukodystrophy, Hypomyelinating, 9

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

# Name GO ID Score Top Affiliating Genes
1 response to toxic substance GO:0009636 8.62 GJC2 ERCC6

Sources for Leukodystrophy, Hypomyelinating, 9

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
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
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
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50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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