Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

Summary

Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (MONDO:0012622) is a disease caused by DARS2 (GenCC Definitive), with 2 cohort genes and 5 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DARS2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 181
• Phenotypes (HPO): 50
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		127	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0011397	Abnormality of the dorsal column of the spinal cord	Very frequent (80-99%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002191	Progressive spasticity	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002493	Upper motor neuron dysfunction	Frequent (30-79%)
HP:0002497	Spastic ataxia	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0006978	Dysmyelinating leukodystrophy	Frequent (30-79%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0002151	Increased circulating lactate concentration	Occasional (5-29%)
HP:0002166	Impaired vibration sensation in the lower limbs	Occasional (5-29%)
HP:0002490	Increased CSF lactate	Occasional (5-29%)
HP:0003477	Peripheral axonal neuropathy	Occasional (5-29%)
HP:0006858	Impaired distal proprioception	Occasional (5-29%)
HP:0007010	Poor fine motor coordination	Occasional (5-29%)
HP:0008969	Leg muscle stiffness	Occasional (5-29%)
HP:0010794	Impaired visuospatial constructive cognition	Occasional (5-29%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0000508	Ptosis	Very rare (<1-4%)
HP:0000514	Slow saccadic eye movements	Very rare (<1-4%)
HP:0000639	Nystagmus	Very rare (<1-4%)
HP:0000648	Optic atrophy	Very rare (<1-4%)
HP:0000651	Diplopia	Very rare (<1-4%)
HP:0001249	Intellectual disability	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001252	Hypotonia	Very rare (<1-4%)
HP:0001271	Polyneuropathy	Very rare (<1-4%)
HP:0001272	Cerebellar atrophy	Very rare (<1-4%)
HP:0001276	Hypertonia	Very rare (<1-4%)
HP:0001344	Absent speech	Very rare (<1-4%)
HP:0001350	Slurred speech	Very rare (<1-4%)
HP:0001371	Flexion contracture	Very rare (<1-4%)
HP:0002059	Cerebral atrophy	Very rare (<1-4%)
HP:0002078	Truncal ataxia	Very rare (<1-4%)
HP:0002079	Hypoplasia of the corpus callosum	Very rare (<1-4%)
HP:0005340	Spastic/hyperactive bladder	Very rare (<1-4%)
HP:0007668	Impaired pursuit initiation and maintenance	Very rare (<1-4%)
HP:0009055	Generalized limb muscle atrophy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome
Mondo ID	MONDO:0012622
MeSH	C567009
OMIM	611105
Orphanet	137898
SNOMED CT	703537008
UMLS	C1970180
MedGen	370845
GARD	0012652
NORD	1941
Is cancer (heuristic)	no

Also known as: LBSL · leukoencephalopathy with brain stem and spinal cord involvement - high lactate · leukoencephalopathy with brain stem and spinal cord involvement - lactate elevation · Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation · leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation · leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome · leukoencephalopathy with brain stem and spinal cord involvement-lactate elevation syndrome · leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

Data availability: 181 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

181 retrieved; paginated sample, class counts are floors:

72 uncertain significance, 31 conflicting classifications of pathogenicity, 24 likely pathogenic, 17 pathogenic/likely pathogenic, 15 pathogenic, 10 benign, 6 benign/likely benign, 6 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1802158	NM_018122.5(DARS2):c.[228-10C>A];[492+2T>C]		Pathogenic	criteria provided, single submitter
1057	NM_018122.5(DARS2):c.228-21_228-20delinsC	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1059	NM_018122.5(DARS2):c.787C>T (p.Arg263Ter)	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1060	NM_018122.5(DARS2):c.788G>A (p.Arg263Gln)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1061	NM_018122.5(DARS2):c.455G>T (p.Cys152Phe)	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1062	NM_018122.5(DARS2):c.492+2T>C	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1063	NM_018122.5(DARS2):c.133A>G (p.Ser45Gly)	DARS2	Pathogenic	no assertion criteria provided
1064	NM_018122.5(DARS2):c.536G>A (p.Arg179His)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1182591	NM_018122.5(DARS2):c.228-16C>A	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1188833	NM_018122.5(DARS2):c.742C>T (p.Gln248Ter)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1199571	NM_018122.5(DARS2):c.228-15C>A	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1256059	NM_018122.5(DARS2):c.562C>T (p.Arg188Ter)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324208	NM_018122.5(DARS2):c.1173_1179del (p.Ala392fs)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1372500	NM_018122.5(DARS2):c.559del (p.Leu187fs)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455328	NM_018122.5(DARS2):c.1395_1396del (p.Gly467fs)	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1722987	NM_018122.5(DARS2):c.397-2A>G	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1916206	NM_018122.5(DARS2):c.294G>T (p.Glu98Asp)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2087105	NM_018122.5(DARS2):c.1083_1086del (p.Lys362fs)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2202881	NM_018122.5(DARS2):c.796C>T (p.Arg266Ter)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2578589	NM_018122.5(DARS2):c.823C>T (p.Gln275Ter)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691462	NM_018122.5(DARS2):c.161dup (p.Cys54fs)	DARS2	Pathogenic	criteria provided, single submitter
2888230	NM_018122.5(DARS2):c.1552G>T (p.Glu518Ter)	DARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
3024559	NM_018122.5(DARS2):c.1675-1256_*115delinsGCAACATTTCGGCAACATTCCAACC	DARS2	Pathogenic	criteria provided, single submitter
3063594	NM_018122.5(DARS2):c.109del (p.Ser37fs)	DARS2	Pathogenic	criteria provided, single submitter
3251557	NM_018122.5(DARS2):c.119_120dup (p.Ile41fs)	DARS2	Pathogenic	criteria provided, single submitter
426745	NM_018122.5(DARS2):c.948del (p.Pro317fs)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
427120	NM_018122.5(DARS2):c.1762C>G (p.Leu588Val)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4847009	NM_018122.5(DARS2):c.566dup (p.Arg190fs)	DARS2	Pathogenic	criteria provided, single submitter
501895	NM_018122.5(DARS2):c.159_160del (p.Cys54fs)	DARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522973	NM_018122.5(DARS2):c.20T>A (p.Leu7Ter)	DARS2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
DARS2	Definitive	Autosomal dominant	leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DARS2	Orphanet:137898	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

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
DARS2	HGNC:25538	ENSG00000117593	Q6PI48	Aspartate–tRNA ligase, mitochondrial	gencc,clinvar
CENPL	HGNC:17879	ENSG00000120334	Q8N0S6	Centromere protein L	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DARS2	Aspartate–tRNA ligase, mitochondrial	Catalyzes the attachment of aspartate to tRNA(Asp) in a two-step reaction: aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp).
CENPL	Centromere protein L	Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DARS2	Enzyme (other)	yes	6.1.1.12	Asp/Asn-tRNA-synth_IIb, GAD-like_sf, Aa-tRNA-synt_II
CENPL	Other/Unknown	no		CENP-L

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
adrenal tissue	1
primordial germ cell in gonad	1
rectum	1
oocyte	1
secondary oocyte	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DARS2	180	ubiquitous	marker	primordial germ cell in gonad, rectum, adrenal tissue
CENPL	211	ubiquitous	marker	oocyte, ventricular zone, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DARS2	3,288
CENPL	1,106

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CENPL	Q8N0S6	12
DARS2	Q6PI48	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial tRNA aminoacylation	1	259.6×	0.043	DARS2
Nucleosome assembly	1	237.9×	0.043	CENPL
tRNA Aminoacylation	1	142.8×	0.043	DARS2
Chromosome Maintenance	1	105.7×	0.043	CENPL
Amplification of signal from the kinetochores	1	98.5×	0.043	CENPL
Deposition of new CENPA-containing nucleosomes at the centromere	1	79.3×	0.043	CENPL
Mitotic Spindle Checkpoint	1	79.3×	0.043	CENPL
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.043	CENPL
Mitotic Metaphase and Anaphase	1	48.4×	0.043	CENPL
Mitotic Anaphase	1	48.4×	0.043	CENPL
EML4 and NUDC in mitotic spindle formation	1	46.4×	0.043	CENPL
Cell Cycle Checkpoints	1	44.3×	0.043	CENPL
Resolution of Sister Chromatid Cohesion	1	43.3×	0.043	CENPL
RHO GTPases Activate Formins	1	38.8×	0.043	CENPL
Mitotic Prometaphase	1	34.6×	0.043	CENPL
RHO GTPase Effectors	1	34.0×	0.043	CENPL
M Phase	1	33.0×	0.043	CENPL
Translation	1	31.0×	0.043	DARS2
Separation of Sister Chromatids	1	30.4×	0.043	CENPL
Cell Cycle, Mitotic	1	24.1×	0.051	CENPL
Cell Cycle	1	18.0×	0.064	CENPL
Signaling by Rho GTPases	1	17.1×	0.064	CENPL
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.064	CENPL
Metabolism of proteins	1	6.2×	0.162	DARS2
Signal Transduction	1	5.1×	0.187	CENPL

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
mitochondrial asparaginyl-tRNA aminoacylation	1	8426.0×	3e-04	DARS2
aspartyl-tRNA aminoacylation	1	4213.0×	3e-04	DARS2
tRNA aminoacylation	1	4213.0×	3e-04	DARS2
chromosome segregation	1	86.9×	0.011	CENPL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DARS2	0	0
CENPL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DARS2	6.1.1.12	aspartate-tRNA ligase

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

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	DARS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CENPL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DARS2	0	—
CENPL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03624374	Not specified	RECRUITING	Natural History Study of Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL)
NCT05443906	Not specified	RECRUITING	Home Exercise for Individuals with Neurodegenerative Disease
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT05750979	Not specified	UNKNOWN	Quantifying Disease Progression in LBSL