MCID: LKD019
MIFTS: 41

Leukodystrophy, Hypomyelinating, 6

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

Aliases & Classifications for Leukodystrophy, Hypomyelinating, 6

MalaCards integrated aliases for Leukodystrophy, Hypomyelinating, 6:

Name: Leukodystrophy, Hypomyelinating, 6 57 53 75 29 6 73
Habc 57 12 53 75
Hypomyelination with Atrophy of Basal Ganglia and Cerebellum 12 53 59
H-Abc 12 53 59
Hld6 57 12 53
Leukodystrophy, Hypomyelinating, with Atrophy of the Basal Ganglia and Cerebellum 57 53
Hypomyelinating Leukodystrophy with Atrophy of the Basal Ganglia and Cerebellum 12 75
Hypomyelinating Leukodystrophy 6 12 15
Leukodystrophy, Hypomyelinating, with Atrophy of the Basal Ganglia and Cerebellum; Habc 57
Leukodystrophy, Hypomyelinating, Type 6 40
Hld 75

Characteristics:

Orphanet epidemiological data:

59
hypomyelination with atrophy of basal ganglia and cerebellum
Inheritance: Autosomal dominant; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal;

OMIM:

57
Inheritance:
autosomal dominant

Miscellaneous:
variable severity
progressive disorder
most cases result from de novo mutation
initial development may appear normal
onset in infancy up to 3 years


HPO:

32
leukodystrophy, hypomyelinating, 6:
Onset and clinical course variable expressivity progressive
Inheritance autosomal recessive inheritance autosomal dominant inheritance sporadic


Classifications:

Orphanet: 59  
Rare neurological diseases


Summaries for Leukodystrophy, Hypomyelinating, 6

OMIM : 57 Hypomyelinating leukodystrophy-6, also known as hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum, is a neurologic disorder characterized by onset in infancy or early childhood of delayed motor development and gait instability, followed by extrapyramidal movement disorders, such as dystonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises, progressive spastic tetraplegia, ataxia, and, more rarely, seizures. Most patients have cognitive decline and speech delay, but some can function normally. Brain MRI shows a combination of hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen. The disorder usually shows sporadic occurrence, but sibs may be affected if a parent is somatic mosaic for the mutation (summary by Simons et al., 2013). Hypomyelinating leukodystrophies (HLD) comprise a genetically heterogeneous entity in which there is a substantial permanent deficit in myelin deposition within the brain, resulting in neurologic deficits (van der Knaap et al., 2002). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080. (612438)

MalaCards based summary : Leukodystrophy, Hypomyelinating, 6, also known as habc, is related to hypomyelinating leukodystrophy and aging, and has symptoms including ataxia, muscle rigidity and muscle spasticity. An important gene associated with Leukodystrophy, Hypomyelinating, 6 is TUBB4A (Tubulin Beta 4A Class IVa), and among its related pathways/superpathways are Development Slit-Robo signaling and Chaperonin-mediated protein folding. Affiliated tissues include cerebellum, brain and eye, and related phenotypes are nystagmus and intellectual disability

UniProtKB/Swiss-Prot : 75 Leukodystrophy, hypomyelinating, 6: A neurologic disorder characterized by onset in infancy or early childhood of delayed motor development and gait instability, followed by extrapyramidal movement disorders, such as dystonia, choreoathetosis, rigidity, opisthotonus, and oculogyric crises, progressive spastic tetraplegia, ataxia, and, more rarely, seizures. Most patients have cognitive decline and speech delay, but some can function normally. Brain MRI shows a combination of hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen.

NIH Rare Diseases : 53 Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC) is a disease that affects certain parts of the brain. Symptoms usually begin in infancy or early childhood and worsen over time. Severity of symptoms and rate of progression can vary. Symptoms may include delayed motor development, learning difficulties, upper-motor neuron dysfunction (spasticity, exaggerated reflexes, and Babinski signs), dystonia, rigidity, involuntary movements, and speech and swallowing problems. H-ABC is caused by a mutation in the TUBB4A gene. Inheritance is autosomal dominant, but most cases are due to a new mutation occurring for the first time in a person with the condition. Treatment may involve taking medications to ease symptoms, physical therapy, and surgery when dystonia does not improve with medication.

Disease Ontology : 12 A hypomyelinating leukodystrophy characterized by infant or early childhood onset of delayed motor development and gait instability, followed by extrapyramidal movement disorders, progressive spastic tetraplegia, ataxia, hypomyelination, cerebellar atrophy, and atrophy or disappearance of the putamen that has material basis in heterozygous mutation in the TUBB4A gene on chromosome 19p13.

Related Diseases for Leukodystrophy, Hypomyelinating, 6

Graphical network of the top 20 diseases related to Leukodystrophy, Hypomyelinating, 6:



Diseases related to Leukodystrophy, Hypomyelinating, 6

Symptoms & Phenotypes for Leukodystrophy, Hypomyelinating, 6

Symptoms via clinical synopsis from OMIM:

57
Neurologic Central Nervous System:
seizures
ataxia
spasticity
dysarthria
tremor
more
Head And Neck Eyes:
optic atrophy
poor vision
oculogyric eye movements
nystagmus (uncommon)

Head And Neck Ears:
hearing loss (uncommon)

Head And Neck Head:
microcephaly

Growth Height:
short stature


Clinical features from OMIM:

612438

Human phenotypes related to Leukodystrophy, Hypomyelinating, 6:

32 (show all 23)
# Description HPO Frequency HPO Source Accession
1 nystagmus 32 occasional (7.5%) HP:0000639
2 intellectual disability 32 HP:0001249
3 seizures 32 HP:0001250
4 ataxia 32 HP:0001251
5 spasticity 32 HP:0001257
6 dysarthria 32 HP:0001260
7 tremor 32 HP:0001337
8 hearing impairment 32 occasional (7.5%) HP:0000365
9 delayed speech and language development 32 HP:0000750
10 microcephaly 32 HP:0000252
11 visual impairment 32 HP:0000505
12 optic atrophy 32 HP:0000648
13 short stature 32 HP:0004322
14 specific learning disability 32 HP:0001328
15 dystonia 32 HP:0001332
16 rigidity 32 HP:0002063
17 choreoathetosis 32 HP:0001266
18 cerebellar atrophy 32 HP:0001272
19 motor delay 32 HP:0001270
20 leukodystrophy 32 HP:0002415
21 poor speech 32 HP:0002465
22 muscular hypotonia of the trunk 32 HP:0008936
23 cerebral hypomyelination 32 HP:0006808

UMLS symptoms related to Leukodystrophy, Hypomyelinating, 6:


ataxia, muscle rigidity, muscle spasticity, seizures, tremor

Drugs & Therapeutics for Leukodystrophy, Hypomyelinating, 6

Search Clinical Trials , NIH Clinical Center for Leukodystrophy, Hypomyelinating, 6

Genetic Tests for Leukodystrophy, Hypomyelinating, 6

Genetic tests related to Leukodystrophy, Hypomyelinating, 6:

# Genetic test Affiliating Genes
1 Leukodystrophy, Hypomyelinating, 6 29 TUBB4A

Anatomical Context for Leukodystrophy, Hypomyelinating, 6

MalaCards organs/tissues related to Leukodystrophy, Hypomyelinating, 6:

41
Cerebellum, Brain, Eye

Publications for Leukodystrophy, Hypomyelinating, 6

Articles related to Leukodystrophy, Hypomyelinating, 6:

# Title Authors Year
1
Data on the effect of hypomyelinating leukodystrophy 6 (HLD6)-associated mutations on the TUBB4A properties. ( 28275661 )
2017

Variations for Leukodystrophy, Hypomyelinating, 6

UniProtKB/Swiss-Prot genetic disease variations for Leukodystrophy, Hypomyelinating, 6:

75
# Symbol AA change Variation ID SNP ID
1 TUBB4A p.Asp249Asn VAR_069799 rs483352809

ClinVar genetic disease variations for Leukodystrophy, Hypomyelinating, 6:

6
(show top 50) (show all 123)
# Gene Variation Type Significance SNP ID Assembly Location
1 TUBB4A NM_006087.3(TUBB4A): c.4C> G (p.Arg2Gly) single nucleotide variant Pathogenic rs587776983 GRCh37 Chromosome 19, 6502220: 6502220
2 TUBB4A NM_006087.3(TUBB4A): c.4C> G (p.Arg2Gly) single nucleotide variant Pathogenic rs587776983 GRCh38 Chromosome 19, 6502209: 6502209
3 TUBB4A NM_006087.3(TUBB4A): c.745G> A (p.Asp249Asn) single nucleotide variant Pathogenic rs483352809 GRCh37 Chromosome 19, 6495765: 6495765
4 TUBB4A NM_006087.3(TUBB4A): c.745G> A (p.Asp249Asn) single nucleotide variant Pathogenic rs483352809 GRCh38 Chromosome 19, 6495754: 6495754
5 TUBB4A NM_006087.3(TUBB4A): c.1228G> A (p.Glu410Lys) single nucleotide variant Pathogenic rs587777428 GRCh38 Chromosome 19, 6495271: 6495271
6 TUBB4A NM_006087.3(TUBB4A): c.1228G> A (p.Glu410Lys) single nucleotide variant Pathogenic rs587777428 GRCh37 Chromosome 19, 6495282: 6495282
7 TUBB4A NM_006087.3(TUBB4A): c.467G> T (p.Arg156Leu) single nucleotide variant Pathogenic rs587777429 GRCh38 Chromosome 19, 6496032: 6496032
8 TUBB4A NM_006087.3(TUBB4A): c.467G> T (p.Arg156Leu) single nucleotide variant Pathogenic rs587777429 GRCh37 Chromosome 19, 6496043: 6496043
9 TUBB4A NM_006087.3(TUBB4A): c.5G> A (p.Arg2Gln) single nucleotide variant Pathogenic rs587777467 GRCh38 Chromosome 19, 6502208: 6502208
10 TUBB4A NM_006087.3(TUBB4A): c.5G> A (p.Arg2Gln) single nucleotide variant Pathogenic rs587777467 GRCh37 Chromosome 19, 6502219: 6502219
11 TUBB4A NM_006087.3(TUBB4A): c.533C> G (p.Thr178Arg) single nucleotide variant Pathogenic rs587777468 GRCh38 Chromosome 19, 6495966: 6495966
12 TUBB4A NM_006087.3(TUBB4A): c.533C> G (p.Thr178Arg) single nucleotide variant Pathogenic rs587777468 GRCh37 Chromosome 19, 6495977: 6495977
13 TUBB4A NM_006087.3(TUBB4A): c.568C> T (p.His190Tyr) single nucleotide variant Pathogenic rs761635539 GRCh38 Chromosome 19, 6495931: 6495931
14 TUBB4A NM_006087.3(TUBB4A): c.568C> T (p.His190Tyr) single nucleotide variant Pathogenic rs761635539 GRCh37 Chromosome 19, 6495942: 6495942
15 TUBB4A NM_006087.3(TUBB4A): c.1164G> C (p.Met388Ile) single nucleotide variant Likely pathogenic rs797045074 GRCh37 Chromosome 19, 6495346: 6495346
16 TUBB4A NM_006087.3(TUBB4A): c.1164G> C (p.Met388Ile) single nucleotide variant Likely pathogenic rs797045074 GRCh38 Chromosome 19, 6495335: 6495335
17 TUBB4A NM_006087.3(TUBB4A): c.915G> A (p.Pro305=) single nucleotide variant Conflicting interpretations of pathogenicity rs149903666 GRCh38 Chromosome 19, 6495584: 6495584
18 TUBB4A NM_006087.3(TUBB4A): c.915G> A (p.Pro305=) single nucleotide variant Conflicting interpretations of pathogenicity rs149903666 GRCh37 Chromosome 19, 6495595: 6495595
19 TUBB4A NM_006087.3(TUBB4A): c.763G> A (p.Val255Ile) single nucleotide variant Pathogenic/Likely pathogenic rs767399782 GRCh38 Chromosome 19, 6495736: 6495736
20 TUBB4A NM_006087.3(TUBB4A): c.763G> A (p.Val255Ile) single nucleotide variant Pathogenic/Likely pathogenic rs767399782 GRCh37 Chromosome 19, 6495747: 6495747
21 TUBB4A NM_006087.3(TUBB4A): c.921C> T (p.His307=) single nucleotide variant Benign/Likely benign rs118102196 GRCh37 Chromosome 19, 6495589: 6495589
22 TUBB4A NM_006087.3(TUBB4A): c.921C> T (p.His307=) single nucleotide variant Benign/Likely benign rs118102196 GRCh38 Chromosome 19, 6495578: 6495578
23 TUBB4A NM_006087.3(TUBB4A): c.785G> A (p.Arg262His) single nucleotide variant Pathogenic rs886039470 GRCh37 Chromosome 19, 6495725: 6495725
24 TUBB4A NM_006087.3(TUBB4A): c.785G> A (p.Arg262His) single nucleotide variant Pathogenic rs886039470 GRCh38 Chromosome 19, 6495714: 6495714
25 TUBB4A NM_006087.3(TUBB4A): c.1054G> A (p.Ala352Thr) single nucleotide variant Pathogenic rs886041015 GRCh37 Chromosome 19, 6495456: 6495456
26 TUBB4A NM_006087.3(TUBB4A): c.1181T> G (p.Phe394Cys) single nucleotide variant Pathogenic rs886041022 GRCh37 Chromosome 19, 6495329: 6495329
27 TUBB4A NM_006087.3(TUBB4A): c.1181T> G (p.Phe394Cys) single nucleotide variant Pathogenic rs886041022 GRCh38 Chromosome 19, 6495318: 6495318
28 TUBB4A NM_006087.3(TUBB4A): c.1172G> A (p.Arg391His) single nucleotide variant Pathogenic rs886041021 GRCh37 Chromosome 19, 6495338: 6495338
29 TUBB4A NM_006087.3(TUBB4A): c.1172G> A (p.Arg391His) single nucleotide variant Pathogenic rs886041021 GRCh38 Chromosome 19, 6495327: 6495327
30 TUBB4A NM_006087.3(TUBB4A): c.1164G> A (p.Met388Ile) single nucleotide variant Pathogenic rs797045074 GRCh37 Chromosome 19, 6495346: 6495346
31 TUBB4A NM_006087.3(TUBB4A): c.1164G> A (p.Met388Ile) single nucleotide variant Pathogenic rs797045074 GRCh38 Chromosome 19, 6495335: 6495335
32 TUBB4A NM_006087.3(TUBB4A): c.1163T> C (p.Met388Thr) single nucleotide variant Pathogenic rs886041020 GRCh38 Chromosome 19, 6495336: 6495336
33 TUBB4A NM_006087.3(TUBB4A): c.1163T> C (p.Met388Thr) single nucleotide variant Pathogenic rs886041020 GRCh37 Chromosome 19, 6495347: 6495347
34 TUBB4A NM_006087.3(TUBB4A): c.1162A> G (p.Met388Val) single nucleotide variant Likely pathogenic rs886041019 GRCh38 Chromosome 19, 6495337: 6495337
35 TUBB4A NM_006087.3(TUBB4A): c.1162A> G (p.Met388Val) single nucleotide variant Likely pathogenic rs886041019 GRCh37 Chromosome 19, 6495348: 6495348
36 TUBB4A NM_006087.3(TUBB4A): c.1099T> C (p.Phe367Leu) single nucleotide variant Pathogenic rs886041018 GRCh37 Chromosome 19, 6495411: 6495411
37 TUBB4A NM_006087.3(TUBB4A): c.1099T> C (p.Phe367Leu) single nucleotide variant Pathogenic rs886041018 GRCh38 Chromosome 19, 6495400: 6495400
38 TUBB4A NM_006087.3(TUBB4A): c.1099T> A (p.Phe367Ile) single nucleotide variant Pathogenic rs886041018 GRCh37 Chromosome 19, 6495411: 6495411
39 TUBB4A NM_006087.3(TUBB4A): c.1099T> A (p.Phe367Ile) single nucleotide variant Pathogenic rs886041018 GRCh38 Chromosome 19, 6495400: 6495400
40 TUBB4A NM_006087.3(TUBB4A): c.1091C> A (p.Ala364Asp) single nucleotide variant Pathogenic rs886041017 GRCh37 Chromosome 19, 6495419: 6495419
41 TUBB4A NM_006087.3(TUBB4A): c.1091C> A (p.Ala364Asp) single nucleotide variant Pathogenic rs886041017 GRCh38 Chromosome 19, 6495408: 6495408
42 TUBB4A NM_006087.3(TUBB4A): c.1061G> A (p.Cys354Tyr) single nucleotide variant Pathogenic rs886041016 GRCh37 Chromosome 19, 6495449: 6495449
43 TUBB4A NM_006087.3(TUBB4A): c.1061G> A (p.Cys354Tyr) single nucleotide variant Pathogenic rs886041016 GRCh38 Chromosome 19, 6495438: 6495438
44 TUBB4A NM_006087.3(TUBB4A): c.1054G> A (p.Ala352Thr) single nucleotide variant Pathogenic rs886041015 GRCh38 Chromosome 19, 6495445: 6495445
45 TUBB4A NM_006087.3(TUBB4A): c.968T> G (p.Met323Arg) single nucleotide variant Pathogenic rs886041014 GRCh38 Chromosome 19, 6495531: 6495531
46 TUBB4A NM_006087.3(TUBB4A): c.968T> G (p.Met323Arg) single nucleotide variant Pathogenic rs886041014 GRCh37 Chromosome 19, 6495542: 6495542
47 TUBB4A NM_006087.3(TUBB4A): c.941C> T (p.Ala314Val) single nucleotide variant Likely pathogenic rs886041013 GRCh38 Chromosome 19, 6495558: 6495558
48 TUBB4A NM_006087.3(TUBB4A): c.941C> T (p.Ala314Val) single nucleotide variant Likely pathogenic rs886041013 GRCh37 Chromosome 19, 6495569: 6495569
49 TUBB4A NM_006087.3(TUBB4A): c.900G> T (p.Met300Ile) single nucleotide variant Pathogenic rs886041012 GRCh38 Chromosome 19, 6495599: 6495599
50 TUBB4A NM_006087.3(TUBB4A): c.900G> T (p.Met300Ile) single nucleotide variant Pathogenic rs886041012 GRCh37 Chromosome 19, 6495610: 6495610

Expression for Leukodystrophy, Hypomyelinating, 6

Search GEO for disease gene expression data for Leukodystrophy, Hypomyelinating, 6.

Pathways for Leukodystrophy, Hypomyelinating, 6

Pathways related to Leukodystrophy, Hypomyelinating, 6 according to GeneCards Suite gene sharing:

(show all 11)
# Super pathways Score Top Affiliating Genes
1
Show member pathways
12.16 TUBA8 TUBB3 TUBB4A
2
Show member pathways
12.04 TUBA8 TUBB3 TUBB4A
3
Show member pathways
12.01 TUBA8 TUBB3 TUBB4A
4
Show member pathways
11.77 TUBA8 TUBB3 TUBB4A
5
Show member pathways
11.68 STXBP1 TUBA8 TUBB3 TUBB4A
6
Show member pathways
11.67 TUBA8 TUBB3 TUBB4A
7 11.52 TUBA8 TUBB3 TUBB4A
8 11.44 STX7 TUBA8 TUBB3 TUBB4A
9 11.38 TUBA8 TUBB3 TUBB4A
10
Show member pathways
10.96 STXBP1 TUBA8 TUBB3 TUBB4A
11 10.28 STXBP1 UNC13B

GO Terms for Leukodystrophy, Hypomyelinating, 6

Cellular components related to Leukodystrophy, Hypomyelinating, 6 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 microtubule GO:0005874 9.5 TUBA8 TUBB3 TUBB4A
2 axon GO:0030424 9.43 STXBP1 TUBB3 VPS16
3 terminal bouton GO:0043195 9.37 STXBP1 UNC13B
4 early endosome GO:0005769 9.33 STX7 UHRF1BP1L VPS16
5 recycling endosome GO:0055037 9.13 STX7 VPS16 VPS53
6 GARP complex GO:0000938 8.62 UHRF1BP1L VPS53

Biological processes related to Leukodystrophy, Hypomyelinating, 6 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 cytoskeleton organization GO:0007010 9.58 TUBA8 TUBB3 TUBB4A
2 mitotic cell cycle GO:0000278 9.54 TUBA8 TUBB3 TUBB4A
3 microtubule cytoskeleton organization GO:0000226 9.5 TUBA8 TUBB3 TUBB4A
4 neurotransmitter secretion GO:0007269 9.46 STXBP1 UNC13B
5 glutamate secretion GO:0014047 9.43 STXBP1 UNC13B
6 synaptic vesicle maturation GO:0016188 9.26 STXBP1 UNC13B
7 regulation of SNARE complex assembly GO:0035542 9.16 STXBP1 VPS16
8 presynaptic dense core vesicle exocytosis GO:0099525 8.96 STXBP1 UNC13B
9 microtubule-based process GO:0007017 8.8 TUBA8 TUBB3 TUBB4A

Molecular functions related to Leukodystrophy, Hypomyelinating, 6 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 GTPase activity GO:0003924 9.43 TUBA8 TUBB3 TUBB4A
2 SNARE binding GO:0000149 9.16 STX7 STXBP1
3 syntaxin-1 binding GO:0017075 8.96 STXBP1 UNC13B
4 structural constituent of cytoskeleton GO:0005200 8.8 TUBA8 TUBB3 TUBB4A

Sources for Leukodystrophy, Hypomyelinating, 6

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
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