Hypomyelination with brain stem and spinal cord involvement and leg spasticity

Summary

Hypomyelination with brain stem and spinal cord involvement and leg spasticity (MONDO:0014115) is a disease caused by DARS1 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DARS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 24
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelination with brain stem and spinal cord involvement and leg spasticity
Mondo ID	MONDO:0014115
OMIM	615281
Orphanet	363412
UMLS	C4755254
MedGen	1667792
GARD	0017554
Is cancer (heuristic)	no

Also known as: HBSL · hypomyelination with brainstem and spinal cord involvement and leg spasticity

Data availability: 24 ClinVar variants · 4 GenCC gene-disease records.

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 › hypomyelination with brain stem and spinal cord involvement and leg spasticity

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, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, 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

24 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 5 pathogenic, 5 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
143190	NM_001349.4(DARS1):c.839A>T (p.His280Leu)	DARS1	Pathogenic	no assertion criteria provided
50986	NM_001349.4(DARS1):c.1099G>T (p.Asp367Tyr)	DARS1	Pathogenic	no assertion criteria provided
50987	NM_001349.4(DARS1):c.821C>T (p.Ala274Val)	DARS1	Pathogenic	no assertion criteria provided
50988	NM_001349.4(DARS1):c.766A>C (p.Met256Leu)	DARS1	Pathogenic	no assertion criteria provided
50990	NM_001349.4(DARS1):c.1379G>A (p.Arg460His)	DARS1	Pathogenic	no assertion criteria provided
3765823	NM_001349.4(DARS1):c.735C>G (p.Tyr245Ter)	DARS1	Likely pathogenic	criteria provided, single submitter
50991	NM_001349.4(DARS1):c.1480C>G (p.Arg494Gly)	DARS1	Likely pathogenic	criteria provided, single submitter
522693	NM_001349.4(DARS1):c.1481G>A (p.Arg494His)	DARS1	Likely pathogenic	criteria provided, single submitter
1696555	NM_001349.4(DARS1):c.403G>A (p.Val135Ile)	DARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
488394	NM_001349.4(DARS1):c.1277T>C (p.Leu426Ser)	DARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
50989	NM_001349.4(DARS1):c.1459C>T (p.Arg487Cys)	DARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
512090	NM_001349.4(DARS1):c.125-18C>T	DARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
735228	NM_001349.4(DARS1):c.484C>T (p.Pro162Ser)	DARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030430	NM_001349.4(DARS1):c.644T>C (p.Phe215Ser)	DARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031971	NM_001349.4(DARS1):c.1493G>A (p.Arg498Gln)	DARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696554	NM_001349.4(DARS1):c.1231-455A>G	DARS1	Uncertain significance	criteria provided, single submitter
1702952	NM_001349.4(DARS1):c.1298A>G (p.His433Arg)	DARS1	Uncertain significance	criteria provided, single submitter
2440706	NM_001349.4(DARS1):c.1288C>T (p.Gln430Ter)	DARS1	Uncertain significance	criteria provided, single submitter
3068269	NM_001349.4(DARS1):c.564+2264G>A	DARS1	Uncertain significance	criteria provided, single submitter
4293598	NM_001349.4(DARS1):c.752A>C (p.Gln251Pro)	DARS1	Uncertain significance	criteria provided, single submitter
488395	NM_001349.4(DARS1):c.242G>A (p.Arg81His)	DARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
982592	NM_001349.4(DARS1):c.845A>C (p.His282Pro)	DARS1	Uncertain significance	criteria provided, single submitter
383416	NM_001349.4(DARS1):c.505-13T>C	DARS1	Benign	criteria provided, multiple submitters, no conflicts
516398	NM_001349.4(DARS1):c.505-3del	DARS1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
DARS1	Definitive	Autosomal recessive	hypomyelination with brain stem and spinal cord involvement and leg spasticity	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DARS1	Orphanet:363412	Hypomyelination with brain stem and spinal cord involvement and leg spasticity

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DARS1	HGNC:2678	ENSG00000115866	P14868	Aspartate–tRNA ligase, cytoplasmic	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DARS1	Aspartate–tRNA ligase, cytoplasmic	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DARS1	Enzyme (other)	yes	6.1.1.12	Asp/Asn-tRNA-synth_IIb, Aa-tRNA-synt_II, NA-bd_OB_tRNA

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
oocyte	1
pericardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DARS1	300	ubiquitous	marker	oocyte, pericardium, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DARS1	2,886

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DARS1	P14868	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 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
Cytosolic tRNA aminoacylation	1	439.2×	0.014	DARS1
tRNA Aminoacylation	1	285.5×	0.014	DARS1
Selenoamino acid metabolism	1	196.9×	0.014	DARS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.014	DARS1
MITF-M-regulated melanocyte development	1	114.2×	0.018	DARS1
Metabolism of amino acids and derivatives	1	67.6×	0.023	DARS1
Translation	1	62.1×	0.023	DARS1
Developmental Biology	1	14.5×	0.086	DARS1
Metabolism of proteins	1	12.4×	0.086	DARS1
Metabolism	1	11.6×	0.086	DARS1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
aspartyl-tRNA aminoacylation	1	8426.0×	4e-04	DARS1
protein-containing complex assembly	1	113.9×	0.010	DARS1
translation	1	102.8×	0.010	DARS1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DARS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DARS1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DARS1	6.1.1.12	aspartate-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	DARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
DARS1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies