Hypomyelinating leukodystrophy 6

Summary

Hypomyelinating leukodystrophy 6 (MONDO:0012905) is a disease caused by TUBB4A (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TUBB4A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 270

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		216	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelinating leukodystrophy 6
Mondo ID	MONDO:0012905
MeSH	C567314
OMIM	612438
Orphanet	139441
DOID	DOID:0060798
UMLS	C2676244
MedGen	436642
GARD	0010917
Is cancer (heuristic)	no

Also known as: H-ABC · HABC · HLD6 · hypomyelinating leukodystrophy type 6 · hypomyelination with atrophy of basal ganglia and cerebellum · leukodystrophy, hypomyelinating, 6 · leukodystrophy, hypomyelinating, type 6

Data availability: 270 ClinVar variants · 6 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › hypomyelinating leukodystrophy 6

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, leukodystrophy, hypomyelinating, 17, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

270 retrieved; paginated sample, class counts are floors:

101 likely benign, 76 uncertain significance, 22 benign, 19 likely pathogenic, 13 pathogenic/likely pathogenic, 11 conflicting classifications of pathogenicity, 11 benign/likely benign, 9 not provided, 8 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
139452	NM_006087.4(TUBB4A):c.5G>A (p.Arg2Gln)	LOC130063295	Pathogenic	criteria provided, multiple submitters, no conflicts
50984	NM_006087.4(TUBB4A):c.4C>G (p.Arg2Gly)	LOC130063295	Pathogenic	no assertion criteria provided
135658	NM_006087.4(TUBB4A):c.1228G>A (p.Glu410Lys)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
135659	NM_006087.4(TUBB4A):c.467G>T (p.Arg156Leu)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
192383	NM_006087.4(TUBB4A):c.568C>T (p.His190Tyr)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209201	NM_006087.4(TUBB4A):c.1164G>C (p.Met388Ile)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2124806	NM_006087.4(TUBB4A):c.737T>C (p.Leu246Pro)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217025	NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265314	NM_006087.4(TUBB4A):c.785G>A (p.Arg262His)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267772	NM_006087.4(TUBB4A):c.730G>A (p.Gly244Ser)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267773	NM_006087.4(TUBB4A):c.4C>T (p.Arg2Trp)	TUBB4A	Pathogenic	criteria provided, single submitter
267774	NM_006087.4(TUBB4A):c.533C>T (p.Thr178Met)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267777	NM_006087.4(TUBB4A):c.731G>T (p.Gly244Val)	TUBB4A	Pathogenic	no assertion criteria provided
267781	NM_006087.3:c.900C>A	TUBB4A	Pathogenic	no assertion criteria provided
267783	NM_006087.4(TUBB4A):c.941C>T (p.Ala314Val)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267792	NM_006087.4(TUBB4A):c.1164G>A (p.Met388Ile)	TUBB4A	Pathogenic	criteria provided, multiple submitters, no conflicts
267793	NM_006087.4(TUBB4A):c.1172G>A (p.Arg391His)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2843042	NM_006087.4(TUBB4A):c.755A>G (p.Lys252Arg)	TUBB4A	Pathogenic	criteria provided, single submitter
429952	NM_006087.4(TUBB4A):c.286G>A (p.Gly96Arg)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50985	NM_006087.4(TUBB4A):c.745G>A (p.Asp249Asn)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803516	NM_006087.4(TUBB4A):c.730G>C (p.Gly244Arg)	TUBB4A	Pathogenic	criteria provided, single submitter
1256060	NM_006087.4(TUBB4A):c.796T>A (p.Phe266Ile)	TUBB4A	Likely pathogenic	criteria provided, multiple submitters, no conflicts
139453	NM_006087.4(TUBB4A):c.533C>G (p.Thr178Arg)	TUBB4A	Likely pathogenic	criteria provided, single submitter
1450009	NM_006087.4(TUBB4A):c.736C>A (p.Leu246Met)	TUBB4A	Likely pathogenic	criteria provided, single submitter
1694453	NM_006087.4(TUBB4A):c.544C>T (p.Pro182Ser)	TUBB4A	Likely pathogenic	criteria provided, single submitter
1805115	NM_006087.4(TUBB4A):c.493A>G (p.Asn165Asp)	TUBB4A	Likely pathogenic	criteria provided, single submitter
2442020	NM_006087.4(TUBB4A):c.211G>A (p.Gly71Ser)	TUBB4A	Likely pathogenic	criteria provided, single submitter
267780	NM_006087.4(TUBB4A):c.874C>A (p.Gln292Lys)	TUBB4A	Likely pathogenic	criteria provided, single submitter
267789	NM_006087.4(TUBB4A):c.1099T>C (p.Phe367Leu)	TUBB4A	Likely pathogenic	criteria provided, single submitter
267790	NM_006087.4(TUBB4A):c.1162A>G (p.Met388Val)	TUBB4A	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TUBB4A	Definitive	Autosomal dominant	hypomyelinating leukodystrophy 6	10
UFM1	Definitive	Autosomal recessive	leukodystrophy, hypomyelinating, 14	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TUBB4A	Orphanet:139441	Hypomyelination with atrophy of basal ganglia and cerebellum
TUBB4A	Orphanet:98805	Primary dystonia, DYT4 type
UFM1	Orphanet:139441	Hypomyelination with atrophy of basal ganglia and cerebellum

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TUBB4A	HGNC:20774	ENSG00000104833	P04350	Tubulin beta-4A chain	gencc,clinvar
UFM1	HGNC:20597	ENSG00000120686	P61960	Ubiquitin-fold modifier 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TUBB4A	Tubulin beta-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
UFM1	Ubiquitin-fold modifier 1	Ubiquitin-like modifier which can be covalently attached via an isopeptide bond to lysine residues of substrate proteins as a monomer or a lysine-linked polymer.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TUBB4A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
UFM1	Other/Unknown	no		UFM1, Ubiquitin-like_domsf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
caput epididymis	1
choroid plexus epithelium	1
corpus epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TUBB4A	201	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
UFM1	295	ubiquitous	marker	corpus epididymis, choroid plexus epithelium, caput epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TUBB4A	5,138
UFM1	1,729

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UFM1	P61960	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBB4A	P04350	92.25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 93. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	543.8×	0.016	TUBB4A
Transport of connexons to the plasma membrane	1	543.8×	0.016	TUBB4A
Gap junction trafficking and regulation	1	475.8×	0.016	TUBB4A
Gap junction trafficking	1	475.8×	0.016	TUBB4A
Post-chaperonin tubulin folding pathway	1	475.8×	0.016	TUBB4A
Formation of tubulin folding intermediates by CCT/TriC	1	423.0×	0.016	TUBB4A
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	407.9×	0.016	TUBB4A
Prefoldin mediated transfer of substrate to CCT/TriC	1	393.8×	0.016	TUBB4A
Activation of AMPK downstream of NMDARs	1	380.7×	0.016	TUBB4A
RHO GTPases activate IQGAPs	1	346.1×	0.016	TUBB4A
Sealing of the nuclear envelope (NE) by ESCRT-III	1	346.1×	0.016	TUBB4A
HCMV Infection	1	326.3×	0.016	TUBB4A
Chaperonin-mediated protein folding	1	300.5×	0.016	TUBB4A
Gap junction assembly	1	292.8×	0.016	TUBB4A
Nuclear Envelope (NE) Reassembly	1	292.8×	0.016	TUBB4A
Selective autophagy	1	278.5×	0.016	TUBB4A
Protein folding	1	259.6×	0.016	TUBB4A
Centrosome maturation	1	253.8×	0.016	TUBB4A
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.016	TUBB4A
Cargo trafficking to the periciliary membrane	1	248.3×	0.016	TUBB4A
Aggrephagy	1	248.3×	0.016	TUBB4A
Carboxyterminal post-translational modifications of tubulin	1	237.9×	0.016	TUBB4A
Recycling pathway of L1	1	223.9×	0.016	TUBB4A
COPI-independent Golgi-to-ER retrograde traffic	1	207.6×	0.016	TUBB4A
Post NMDA receptor activation events	1	203.9×	0.016	TUBB4A
Intraflagellar transport	1	200.3×	0.016	TUBB4A
Antimicrobial mechanism of IFN-stimulated genes	1	196.9×	0.016	TUBB4A
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	193.6×	0.016	TUBB4A
Activation of NMDA receptors and postsynaptic events	1	184.2×	0.016	TUBB4A
Signaling by Hedgehog	1	184.2×	0.016	TUBB4A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein K69-linked ufmylation	1	1685.2×	0.004	UFM1
protein ufmylation	1	1203.7×	0.004	UFM1
regulation of intracellular estrogen receptor signaling pathway	1	936.2×	0.004	UFM1
negative regulation of microtubule polymerization	1	648.1×	0.004	TUBB4A
negative regulation of protein import into nucleus	1	468.1×	0.005	UFM1
reticulophagy	1	351.1×	0.005	UFM1
response to endoplasmic reticulum stress	1	83.4×	0.019	UFM1
mitotic cell cycle	1	66.9×	0.020	TUBB4A
microtubule cytoskeleton organization	1	60.6×	0.020	TUBB4A
brain development	1	39.8×	0.028	UFM1
negative regulation of apoptotic process	1	17.4×	0.057	UFM1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TUBB4A	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBB4A	21	4
UFM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
PATUPILONE	3	TUBB4A
ABT-751	2	TUBB4A
MAYTANSINE	2	TUBB4A
DOLASTATIN-10	2	TUBB4A
INDIBULIN	2	TUBB4A
PARBENDAZOLE	2	TUBB4A
NOCODAZOLE	2	TUBB4A
COMBRETASTATIN	1	TUBB4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TUBB4A	1,758	Binding:1718, Functional:34, ADMET:6
UFM1	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TUBB4A	1,758

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

21 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
COLCHICINE	4	TUBB4A
VINBLASTINE	4	TUBB4A
LEVOFLOXACIN ANHYDROUS	4	TUBB4A
DOCETAXEL	4	TUBB4A
NOSCAPINE	4	TUBB4A
VINBLASTINE SULFATE	4	TUBB4A
PACLITAXEL	4	TUBB4A
LEVOFLOXACIN	4	TUBB4A
VINORELBINE	4	TUBB4A
TIRBANIBULIN	4	TUBB4A
PODOFILOX	4	TUBB4A
VINCRISTINE	4	TUBB4A
DOCETAXEL ANHYDROUS	4	TUBB4A
PATUPILONE	3	TUBB4A
ABT-751	2	TUBB4A
MAYTANSINE	2	TUBB4A
DOLASTATIN-10	2	TUBB4A
INDIBULIN	2	TUBB4A
PARBENDAZOLE	2	TUBB4A
NOCODAZOLE	2	TUBB4A
COMBRETASTATIN	1	TUBB4A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TUBB4A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	UFM1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
UFM1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.