Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Summary

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome (MONDO:0013971) is a disease caused by EARS2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EARS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 129

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome
Mondo ID	MONDO:0013971
OMIM	614924
Orphanet	314051
DOID	DOID:0111493
SNOMED CT	763366000
UMLS	C4706421
MedGen	1645614
GARD	0013381
Is cancer (heuristic)	no

Also known as: combined oxidative phosphorylation defect type 12 · combined oxidative phosphorylation deficiency 12 · combined oxidative phosphorylation deficiency caused by mutation in EARS2 · combined oxidative phosphorylation deficiency type 12 · COXPD12 · EARS2 combined oxidative phosphorylation deficiency · leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome · LTBL

Data availability: 129 ClinVar variants · 1 GenCC gene-disease record.

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 › combined oxidative phosphorylation deficiency › leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Related subtypes (57): severe X-linked mitochondrial encephalomyopathy, hepatoencephalopathy due to combined oxidative phosphorylation defect type 1, combined oxidative phosphorylation defect type 2, fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3, combined oxidative phosphorylation defect type 4, hypotonia with lactic acidemia and hyperammonemia, combined oxidative phosphorylation defect type 7, combined oxidative phosphorylation defect type 8, combined oxidative phosphorylation defect type 9, mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, combined oxidative phosphorylation defect type 11, combined oxidative phosphorylation defect type 13, combined oxidative phosphorylation defect type 14, combined oxidative phosphorylation defect type 15, infantile hypertrophic cardiomyopathy due to MRPL44 deficiency, combined oxidative phosphorylation defect type 17, growth and developmental delay-hypotonia-vision impairment-lactic acidosis syndrome, combined oxidative phosphorylation deficiency 19, combined oxidative phosphorylation defect type 20, combined oxidative phosphorylation defect type 21, mitochondrial proton-transporting ATP synthase complex deficiency, combined oxidative phosphorylation defect type 23, combined oxidative phosphorylation defect type 24, combined oxidative phosphorylation defect type 25, combined oxidative phosphorylation defect type 26, combined oxidative phosphorylation defect type 27, combined oxidative phosphorylation deficiency 28, combined oxidative phosphorylation deficiency 29, combined oxidative phosphorylation defect type 30, lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome, combined oxidative phosphorylation deficiency 40, combined oxidative phosphorylation deficiency 41, combined oxidative phosphorylation deficiency 42, combined oxidative phosphorylation deficiency 43, combined oxidative phosphorylation deficiency 44, combined oxidative phosphorylation deficiency 52, combined oxidative phosphorylation deficiency 53, combined oxidative phosphorylation deficiency 54, combined oxidative phosphorylation deficiency 37, combined oxidative phosphorylation deficiency 38, combined oxidative phosphorylation deficiency 39, combined oxidative phosphorylation deficiency 45, combined oxidative phosphorylation deficiency 46, combined oxidative phosphorylation deficiency 47, combined oxidative phosphorylation deficiency 48, combined oxidative phosphorylation deficiency 51, combined oxidative phosphorylation deficiency 32, combined oxidative phosphorylation deficiency 33, combined oxidative phosphorylation deficiency 34, combined oxidative phosphorylation deficiency 35, combined oxidative phosphorylation deficiency 36, combined oxidative phosphorylation deficiency 55, combined oxidative phosphorylation deficiency 56, combined oxidative phosphorylation deficiency 57, combined oxidative phosphorylation deficiency 58, combined oxidative phosphorylation deficiency 59, combined oxidative phosphorylation deficiency 60

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

129 retrieved; paginated sample, class counts are floors:

55 uncertain significance, 22 benign, 18 conflicting classifications of pathogenicity, 8 pathogenic, 7 pathogenic/likely pathogenic, 7 likely pathogenic, 7 likely benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
39788	NM_001083614.2(EARS2):c.[1279_1280insTCC;502A>G]		Pathogenic	no assertion criteria provided
1452135	NM_001083614.2(EARS2):c.417_418del (p.Cys140fs)	EARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705024	NM_001083614.2(EARS2):c.376C>T (p.Gln126Ter)	EARS2	Pathogenic	criteria provided, single submitter
3339818	NM_001083614.2(EARS2):c.428C>G (p.Ser143Ter)	EARS2	Pathogenic	criteria provided, multiple submitters, no conflicts
3375261	NM_001083614.2(EARS2):c.1A>G (p.Met1Val)	EARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3385233	NM_001083614.2:c.(?_-8)_65del	EARS2	Pathogenic	criteria provided, single submitter
39787	NM_001083614.2(EARS2):c.322C>T (p.Arg108Trp)	EARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39789	NM_001083614.2(EARS2):c.328G>A (p.Gly110Ser)	EARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39791	NM_001083614.2(EARS2):c.286G>A (p.Glu96Lys)	EARS2	Pathogenic	criteria provided, single submitter
39792	NM_001083614.2(EARS2):c.500G>A (p.Cys167Tyr)	EARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39793	NM_001083614.2(EARS2):c.193A>G (p.Lys65Glu)	EARS2	Pathogenic	criteria provided, single submitter
419276	NM_001083614.2(EARS2):c.212del (p.Phe71fs)	EARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449533	NM_001083614.2(EARS2):c.320G>A (p.Arg107His)	EARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803228	NM_001083614.2(EARS2):c.684C>A (p.Tyr228Ter)	EARS2	Pathogenic	criteria provided, single submitter
973189	NM_001083614.2(EARS2):c.1283del (p.Pro428fs)	EARS2	Pathogenic	no assertion criteria provided
2440017	NM_001083614.2(EARS2):c.451A>T (p.Lys151Ter)	EARS2	Likely pathogenic	criteria provided, single submitter
2627742	NM_001083614.2(EARS2):c.947C>G (p.Ser316Ter)	EARS2	Likely pathogenic	no assertion criteria provided
3731523	NM_001083614.2(EARS2):c.719del (p.Gly240fs)	EARS2	Likely pathogenic	criteria provided, single submitter
440959	NM_001083614.2(EARS2):c.334G>C (p.Ala112Pro)	EARS2	Likely pathogenic	criteria provided, single submitter
4531599	NM_001083614.2(EARS2):c.499T>C (p.Cys167Arg)	EARS2	Likely pathogenic	criteria provided, single submitter
4845824	NM_001083614.2(EARS2):c.485+1G>A	EARS2	Likely pathogenic	criteria provided, single submitter
973188	NM_001083614.2(EARS2):c.319C>T (p.Arg107Cys)	EARS2	Likely pathogenic	no assertion criteria provided
1254352	NM_001083614.2(EARS2):c.569G>A (p.Arg190His)	EARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1992179	NM_001083614.2(EARS2):c.1488+16G>A	EARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265109	NM_001083614.2(EARS2):c.1547G>A (p.Arg516Gln)	EARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290959	NM_001083614.2(EARS2):c.280A>G (p.Met94Val)	EARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318540	NM_001083614.2(EARS2):c.1489-14C>T	EARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318541	NM_001083614.2(EARS2):c.1488+15C>T	EARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318547	NM_001083614.2(EARS2):c.1071G>A (p.Leu357=)	EARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
318549	NM_001083614.2(EARS2):c.959-15C>T	EARS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · 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
EARS2	Strong	Autosomal recessive	leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EARS2	Orphanet:314051	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

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
EARS2	HGNC:29419	ENSG00000103356	Q5JPH6	Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EARS2	Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial	Non-discriminating glutamyl-tRNA synthetase that catalyzes aminoacylation of both mitochondrial tRNA(Glu) and tRNA(Gln) and participates in RNA aminoacylation for mitochondrial protein translation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EARS2	Other/Unknown	no		Glu/Gln-tRNA-synth, aa-tRNA-synth_I_CS, Glu-tRNA-ligase_bac/mito

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
adrenal tissue	1
primordial germ cell in gonad	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EARS2	229	ubiquitous	marker	adrenal tissue, right lobe of liver, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EARS2	3,667

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EARS2	Q5JPH6	89.84

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Mitochondrial tRNA aminoacylation	1	519.1×	0.007	EARS2
tRNA Aminoacylation	1	285.5×	0.007	EARS2
Translation	1	62.1×	0.021	EARS2
Metabolism of proteins	1	12.4×	0.081	EARS2

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
tRNA aminoacylation for mitochondrial protein translation	1	16852.0×	1e-04	EARS2
glutamyl-tRNA aminoacylation	1	8426.0×	1e-04	EARS2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
EARS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	EARS2

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)
EARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.