HLD4
MCID: LKD008
MIFTS: 39

Leukodystrophy, Hypomyelinating, 4 (HLD4)

Categories: Ear diseases, Eye diseases, Fetal diseases, Genetic diseases, Mental diseases, Muscle diseases, Neuronal diseases, Rare diseases
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Aliases & Classifications for Leukodystrophy, Hypomyelinating, 4

MalaCards integrated aliases for Leukodystrophy, Hypomyelinating, 4:

Name: Leukodystrophy, Hypomyelinating, 4 57 73 12 71
Mitochondrial Hsp60 Chaperonopathy 57 11 58 73
Hypomyelinating Leukodystrophy 4 11 28 5 14
Mitchap60 Disease 57 11 73
Hld4 57 11 73
Pelizaeus-Merzbacher-Like Disease Due to Hspd1 Mutation 11 58
Leukodystrophy, Hypomyelinating, Type 4 38
Mitchap-60 Disease 73

Characteristics:


Inheritance:

Leukodystrophy, Hypomyelinating, 4: Autosomal recessive 57
Pelizaeus-Merzbacher-Like Disease Due to Hspd1 Mutation: Autosomal recessive 58

Age Of Onset:

Pelizaeus-Merzbacher-Like Disease Due to Hspd1 Mutation: Infancy,Neonatal 58

OMIM®:

57 (Updated 08-Dec-2022)
Miscellaneous:
onset between birth and 3 months of age
usually fatal in first 2 decades
exacerbation during febrile episodes
allelic disorder to autosomal dominant spg13


Classifications:

Orphanet: 58  
Rare neurological diseases


Summaries for Leukodystrophy, Hypomyelinating, 4

UniProtKB/Swiss-Prot: 73 A severe autosomal recessive hypomyelinating leukodystrophy. Clinically characterized by infantile-onset rotary nystagmus, progressive spastic paraplegia, neurologic regression, motor impairment, profound intellectual disability. Death usually occurs within the first two decades of life.

MalaCards based summary: Leukodystrophy, Hypomyelinating, 4, also known as mitochondrial hsp60 chaperonopathy, is related to pelizaeus-merzbacher-like disease and leukodystrophy, hypomyelinating, 2, and has symptoms including apnea, seizures and shallow breathing. An important gene associated with Leukodystrophy, Hypomyelinating, 4 is HSPD1 (Heat Shock Protein Family D (Hsp60) Member 1). Affiliated tissues include brain and peripheral nerve, and related phenotypes are seizure and hyperreflexia

Disease Ontology: 11 A hypomyelinating leukodystrophy characterized by autosomal recessive inheritance of hypotonia, nystagmus, psychomotor developmental delay, and severe hypomyelinating leukoencephalopathy that has material basis in homozygous mutation in the HSPD1 gene on chromosome 2q33.

More information from OMIM: 612233 PS312080

Related Diseases for Leukodystrophy, Hypomyelinating, 4

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, 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 43)
# Related Disease Score Top Affiliating Genes
1 pelizaeus-merzbacher-like disease 30.5 PLP1 GJC2
2 leukodystrophy, hypomyelinating, 2 30.3 PLP1 GJC2
3 spastic paraplegia 13, autosomal dominant 30.2 HSPE1 HSPD1 GJC2 CRYAA
4 paraplegia 30.1 PLP1 HSPD1 GJC2 CCT5
5 pelizaeus-merzbacher disease 29.3 TUBB4A POLR3A PLP1 HYCC1 HIKESHI GJC2
6 leukodystrophy 28.3 TUBB4A TMEM63A PYCR2 POLR3A PLP1 HYCC1
7 sennetsu fever 10.2 HSPE1 HSPD1
8 carrion's disease 10.2 HSPE1 HSPD1
9 contractures, pterygia, and spondylocarpotarsal fusion syndrome 1a 10.2
10 47 xxx syndrome 10.2
11 hallermann-streiff syndrome 10.2 GJC2 CRYAA
12 spastic paraplegia 25, autosomal recessive 10.2 TMEM63A POLR3A
13 tularemia 10.2 HSPE1 HSPD1
14 primary systemic mycosis 10.1 HYCC1 HSPD1
15 pathologic nystagmus 10.1 TMEM63A CRYAA
16 spastic paraplegia 75, autosomal recessive 10.1 PLP1 GJC2
17 spastic paraplegia 44, autosomal recessive 10.1 PLP1 GJC2
18 leukodystrophy, hypomyelinating, 11 10.0 TMEM63A POLR3A HIKESHI
19 alexander disease 10.0 PLP1 GJC2 CRYAA
20 congenital nystagmus 10.0 TMEM63A CRYAA
21 leukoencephalopathy with vanishing white matter 10.0 POLR3A PLP1 GJC2
22 allan-herndon-dudley syndrome 10.0 PLP1 HIKESHI
23 megalencephalic leukoencephalopathy with subcortical cysts 10.0 TMEM63A PLP1 GJC2
24 complement component 7 deficiency 10.0 HSPD1 HSPA9
25 peripheral demyelinating neuropathy, central dysmyelination, waardenburg syndrome, and hirschsprung disease 10.0 PLP1 HIKESHI GJC2
26 leukodystrophy, hypomyelinating, 9 9.9 POLR3A HYCC1 HIKESHI GJC2
27 spastic ataxia 8 9.9 PYCR2 HYCC1 HIKESHI
28 leukodystrophy, hypomyelinating, 13 9.9 PYCR2 HYCC1 HIKESHI
29 spastic ataxia 9.9 POLR3A PLP1 GJC2 CRYAA
30 leukodystrophy, hypomyelinating, 3 9.9 POLR3A PLP1 HYCC1 GJC2
31 cerebral degeneration 9.9 POLR3A PLP1 GJC2 CRYAA
32 codas syndrome 9.9 LONP1 HSPA9
33 leukodystrophy, hypomyelinating, 10 9.8 PYCR2 POLR3A HYCC1 HIKESHI
34 spastic paraplegia 2, x-linked 9.8 PLP1 GJC2
35 leukodystrophy, hypomyelinating, 12 9.8 PYCR2 HYCC1 HIKESHI GJC2
36 hypomyelinating leukoencephalopathy 9.8 POLR3A PLP1 HYCC1 HIKESHI GJC2
37 leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism 9.6 TMEM63A POLR3A PLP1 HYCC1 HIKESHI GJC2
38 charcot-marie-tooth disease 9.6 PLP1 HIP1 GJC2 CRYAA
39 megalencephalic leukoencephalopathy with subcortical cysts 2a 9.6 TUBB4A PLP1 HSPD1 HIP1
40 leukodystrophy, hypomyelinating, 5 9.5 TUBB4A POLR3A PLP1 HYCC1 GJC2
41 leukodystrophy, hypomyelinating, 6 9.4 TUBB4A PYCR2 POLR3A PLP1 GJC2
42 hypomyelinating leukodystrophy 8.6 TUBB4A TMEM63A PYCR2 POLR3A PLP1 HYCC1
43 hereditary spastic paraplegia 8.6 TUBB4A POLR3A PLP1 LONP1 HSPE1 HSPD1

Graphical network of the top 20 diseases related to Leukodystrophy, Hypomyelinating, 4:



Diseases related to Leukodystrophy, Hypomyelinating, 4

Symptoms & Phenotypes for Leukodystrophy, Hypomyelinating, 4

Human phenotypes related to Leukodystrophy, Hypomyelinating, 4:

30 (show all 16)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 seizure 30 HP:0001250
2 hyperreflexia 30 HP:0001347
3 nystagmus 30 HP:0000639
4 hypotonia 30 HP:0001252
5 global developmental delay 30 HP:0001263
6 flexion contracture 30 HP:0001371
7 feeding difficulties in infancy 30 HP:0008872
8 strabismus 30 HP:0000486
9 apnea 30 HP:0002104
10 progressive spasticity 30 HP:0002191
11 babinski sign 30 HP:0003487
12 leukodystrophy 30 HP:0002415
13 choreoathetosis 30 HP:0001266
14 intellectual disability, profound 30 HP:0002187
15 generalized hypotonia 30 HP:0001290
16 secondary microcephaly 30 HP:0005484

Symptoms via clinical synopsis from OMIM®:

57 (Updated 08-Dec-2022)
Neurologic Central Nervous System:
hyperreflexia
hypotonia
choreoathetosis
seizures
extensor plantar responses
more
Abdomen Gastrointestinal:
feeding difficulties

Skeletal:
joint contractures

Laboratory Abnormalities:
intermittent increase of urinary ethylmalonic acid
serum lactate may be increased during encephalopathic exacerbations

Head And Neck Eyes:
nystagmus
strabismus

Respiratory:
shallow breathing
apneic episodes

Head And Neck Head:
microcephaly, acquired

Clinical features from OMIM®:

612233 (Updated 08-Dec-2022)

UMLS symptoms related to Leukodystrophy, Hypomyelinating, 4:


apnea; seizures; shallow breathing

MGI Mouse Phenotypes related to Leukodystrophy, Hypomyelinating, 4:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 9.65 CCT5 GJC2 HIP1 HSPD1 HYCC1 PLP1
2 mortality/aging MP:0010768 9.36 CCT5 GJC2 HIKESHI HIP1 HSPA9 HSPD1

Drugs & Therapeutics for Leukodystrophy, Hypomyelinating, 4

Search Clinical Trials, NIH Clinical Center for Leukodystrophy, Hypomyelinating, 4

Genetic Tests for Leukodystrophy, Hypomyelinating, 4

Genetic tests related to Leukodystrophy, Hypomyelinating, 4:

# Genetic test Affiliating Genes
1 Hypomyelinating Leukodystrophy 4 28 HSPD1

Anatomical Context for Leukodystrophy, Hypomyelinating, 4

Organs/tissues related to Leukodystrophy, Hypomyelinating, 4:

MalaCards : Brain
ODiseA: Peripheral Nerve, Brain

Publications for Leukodystrophy, Hypomyelinating, 4

Articles related to Leukodystrophy, Hypomyelinating, 4:

# Title Authors PMID Year
1
Hypomyelinating Leukodystrophy due to HSPD1 Mutations: A New Patient. 62 57 5
27405012 2016
2
Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. 62 57 5
18571143 2008
3
A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy. 62
33076433 2020
4
A recurrent de novo HSPD1 variant is associated with hypomyelinating leukodystrophy. 62
32532876 2020
5
Data on the effect of hypomyelinating leukodystrophy 6 (HLD6)-associated mutations on the TUBB4A properties. 62
28275661 2017
6
Hypomyelinating leukodystrophy-associated missense mutation in HSPD1 blunts mitochondrial dynamics. 62
25957474 2015
7
Late onset motoneuron disorder caused by mitochondrial Hsp60 chaperone deficiency in mice. 62
23466696 2013
8
A cell model to study different degrees of Hsp60 deficiency in HEK293 cells. 62
21717087 2011
9
The MitCHAP-60 disease is due to entropic destabilization of the human mitochondrial Hsp60 oligomer. 62
19706612 2009

Variations for Leukodystrophy, Hypomyelinating, 4

ClinVar genetic disease variations for Leukodystrophy, Hypomyelinating, 4:

5
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 HSPD1 NM_002156.5(HSPD1):c.86A>G (p.Asp29Gly) SNV Pathogenic
17558 rs72466451 GRCh37: 2:198363487-198363487
GRCh38: 2:197498763-197498763
2 POLR3A NM_007055.4(POLR3A):c.2471A>C (p.His824Pro) SNV Likely Pathogenic
590969 rs1564617866 GRCh37: 10:79760741-79760741
GRCh38: 10:78000983-78000983
3 HSPD1 NM_002156.5(HSPD1):c.139T>G (p.Leu47Val) SNV Likely Pathogenic
816623 rs2086193735 GRCh37: 2:198363434-198363434
GRCh38: 2:197498710-197498710
4 HSPD1 NM_002156.5(HSPD1):c.947T>C (p.Met316Thr) SNV Uncertain Significance
1029563 rs528363238 GRCh37: 2:198354943-198354943
GRCh38: 2:197490219-197490219
5 HSPD1 NM_002156.5(HSPD1):c.1394_1406del (p.Ile465fs) DEL Uncertain Significance
976190 rs2086047405 GRCh37: 2:198352745-198352757
GRCh38: 2:197488021-197488033
6 HSPD1 NM_002156.5(HSPD1):c.1712G>T (p.Gly571Val) SNV Uncertain Significance
410975 rs374322039 GRCh37: 2:198351780-198351780
GRCh38: 2:197487056-197487056
7 HSPD1 NM_002156.5(HSPD1):c.871C>G (p.Leu291Val) SNV Uncertain Significance
410974 rs139649754 GRCh37: 2:198355019-198355019
GRCh38: 2:197490295-197490295
8 HSPD1 NM_002156.5(HSPD1):c.1257C>A (p.Asp419Glu) SNV Uncertain Significance
1705500 GRCh37: 2:198353174-198353174
GRCh38: 2:197488450-197488450
9 HSPD1 NM_002156.5(HSPD1):c.1681A>G (p.Met561Val) SNV Likely Benign
800207 rs371969794 GRCh37: 2:198351811-198351811
GRCh38: 2:197487087-197487087
10 HSPD1 NM_002156.5(HSPD1):c.273A>G (p.Lys91=) SNV Benign
129241 rs8539 GRCh37: 2:198362018-198362018
GRCh38: 2:197497294-197497294

UniProtKB/Swiss-Prot genetic disease variations for Leukodystrophy, Hypomyelinating, 4:

73
# Symbol AA change Variation ID SNP ID
1 HSPD1 p.Asp29Gly VAR_054785 rs72466451

Expression for Leukodystrophy, Hypomyelinating, 4

Search GEO for disease gene expression data for Leukodystrophy, Hypomyelinating, 4.

Pathways for Leukodystrophy, Hypomyelinating, 4

GO Terms for Leukodystrophy, Hypomyelinating, 4

Cellular components related to Leukodystrophy, Hypomyelinating, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrial matrix GO:0005759 9.65 PYCR2 LONP1 HSPE1 HSPD1 HSPA9
2 myelin sheath GO:0043209 9.1 TUBB4A PLP1 GJC2

Biological processes related to Leukodystrophy, Hypomyelinating, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 protein stabilization GO:0050821 9.86 HSPD1 HIP1 CRYAA CCT5
2 activation of cysteine-type endopeptidase activity involved in apoptotic process GO:0006919 9.8 HSPE1 HSPD1 HIP1
3 protein folding GO:0006457 9.7 HSPE1 HSPD1 HSPA9 CCT5
4 chaperone-mediated protein complex assembly GO:0051131 9.67 HSPD1 LONP1
5 protein refolding GO:0042026 9.43 CRYAA HSPA9 HSPD1
6 positive regulation of calcium ion transmembrane transport GO:1904427 8.92 PLP1 GJC2

Molecular functions related to Leukodystrophy, Hypomyelinating, 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 unfolded protein binding GO:0051082 9.65 HSPE1 HSPD1 HSPA9 CRYAA CCT5
2 ATP-dependent protein folding chaperone GO:0140662 9.23 HSPE1 HSPD1 HSPA9 CCT5

Sources for Leukodystrophy, Hypomyelinating, 4

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 08-Dec-2022)
61 PubChem
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 Tocris
71 UMLS
72 UMLS via Orphanet
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