Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities

Summary

Encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities (MONDO:0060562) is a disease caused by LIPT2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: Not yet documented (Worldwide) [Orphanet-validated]
• Causal gene: LIPT2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 17

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	Not yet documented		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities
Mondo ID	MONDO:0060562
OMIM	617668
Orphanet	447795
UMLS	C4540052
MedGen	1624694
GARD	0027988
Is cancer (heuristic)	no

Also known as: encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities · NELABA

Data availability: 17 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Mendelian encephalopathy › encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities

Related subtypes (18): encephalopathy, recurrent, of childhood, encephalopathy, axonal, with necrotizing myopathy, cardiomyopathy, and cataracts, Bonnemann-Meinecke-Reich syndrome, severe neonatal-onset encephalopathy with microcephaly, ethylmalonic encephalopathy, familial encephalopathy with neuroserpin inclusion bodies, spongiform encephalopathy with neuropsychiatric features, familial acute necrotizing encephalopathy, encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1, severe neurodegenerative syndrome with lipodystrophy, encephalopathy due to defective mitochondrial and peroxisomal fission 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, encephalopathy, progressive, with amyotrophy and optic atrophy, encephalitis/encephalopathy, mild, with reversible myelin vacuolization, encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome, encephalopathy, porphyria-related

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

17 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 conflicting classifications of pathogenicity, 3 benign, 2 benign/likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
438641	NM_001144869.3(LIPT2):c.314T>G (p.Leu105Arg)	LIPT2-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502311	NM_001144869.3(LIPT2):c.1A>T (p.Met1Leu)	LIPT2	Likely pathogenic	criteria provided, single submitter
126426	NM_005472.5(KCNE3):c.10A>G (p.Thr4Ala)	KCNE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
5541	NM_005472.5(KCNE3):c.248G>A (p.Arg83His)	KCNE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
438639	NM_001144869.3(LIPT2):c.377T>G (p.Leu126Arg)	LIPT2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
438640	NM_001144869.3(LIPT2):c.89T>C (p.Leu30Pro)	LIPT2-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1031159	NM_001144869.3(LIPT2):c.167T>C (p.Val56Ala)	LIPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1031160	NM_001144869.3(LIPT2):c.284G>A (p.Gly95Asp)	LIPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1033330	NM_001144869.3(LIPT2):c.162G>A (p.Gly54=)	LIPT2	Uncertain significance	criteria provided, single submitter
1059955	NM_001144869.3(LIPT2):c.107T>C (p.Ile36Thr)	LIPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1339189	NM_001144869.3(LIPT2):c.326G>A (p.Gly109Asp)	LIPT2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433463	NM_001144869.3(LIPT2):c.288G>C (p.Gln96His)	LIPT2	Uncertain significance	criteria provided, single submitter
1165286	NM_001144869.3(LIPT2):c.22T>C (p.Leu8=)	LIPT2	Benign	criteria provided, multiple submitters, no conflicts
1169390	NM_001144869.3(LIPT2):c.568A>T (p.Thr190Ser)	LIPT2	Benign	criteria provided, multiple submitters, no conflicts
1601557	NM_001144869.3(LIPT2):c.273C>T (p.Phe91=)	LIPT2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
378087	NM_001144869.3(LIPT2):c.466+14A>C	LIPT2	Benign	criteria provided, multiple submitters, no conflicts
771448	NM_001144869.3(LIPT2):c.690C>T (p.Pro230=)	LIPT2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
LIPT2	Strong	Autosomal recessive	encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNE3	Orphanet:130	Brugada syndrome
KCNE3	Orphanet:681	Hypokalemic periodic paralysis

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LIPT2	HGNC:37216	ENSG00000175536	A6NK58	Octanoyl-[acyl-carrier-protein]:protein N-octanoyltransferase LIPT2, mitochondrial	gencc,clinvar
LIPT2-AS1	HGNC:56172	ENSG00000254837		LIPT2 antisense RNA 1	clinvar
KCNE3	HGNC:6243	ENSG00000175538	Q9Y6H6	Potassium voltage-gated channel subfamily E member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LIPT2	Octanoyl-[acyl-carrier-protein]:protein N-octanoyltransferase LIPT2, mitochondrial	Catalyzes the transfer of endogenously produced octanoic acid from octanoyl-acyl-carrier-protein (octanoyl-ACP) onto the lipoyl domains of lipoate-dependent enzymes such as the protein H of the glycine cleavage system (GCSH).
KCNE3	Potassium voltage-gated channel subfamily E member 3	Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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
Ion channel	1	37.2×	0.080
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LIPT2	Enzyme (other)	yes	2.3.1.181	Octanoyltransferase, BPL_LPL_catalytic, aa-tRNA-synth_II/BPL/LPL
LIPT2-AS1	Other/Unknown	no
KCNE3	Ion channel	yes		K_chnl_KCNE, K_chnl_volt-dep_bsu_KCNE3

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
left testis	1
bronchial epithelial cell	1
leukocyte	1
monocyte	1
nasal cavity epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LIPT2	134	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, left testis
LIPT2-AS1	215		yes	primordial germ cell in gonad, bronchial epithelial cell, male germ line stem cell (sensu Vertebrata) in testis
KCNE3	227	broad	marker	nasal cavity epithelium, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNE3	1,467
LIPT2	617
LIPT2-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNE3	Q9Y6H6	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LIPT2	A6NK58	93.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
Phase 3 - rapid repolarisation	1	571.0×	0.006	KCNE3
Protein lipoylation	1	519.1×	0.006	LIPT2
Phase 2 - plateau phase	1	380.7×	0.006	KCNE3
Cardiac conduction	1	54.4×	0.032	KCNE3
Muscle contraction	1	38.6×	0.036	KCNE3
Post-translational protein modification	1	9.6×	0.118	LIPT2
Metabolism of proteins	1	6.2×	0.155	LIPT2

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
negative regulation of membrane repolarization during ventricular cardiac muscle cell action potential	1	8426.0×	0.002	KCNE3
obsolete positive regulation of oxygen metabolic process	1	4213.0×	0.002	LIPT2
negative regulation of delayed rectifier potassium channel activity	1	1404.3×	0.002	KCNE3
protein lipoylation	1	1203.7×	0.002	LIPT2
negative regulation of potassium ion export across plasma membrane	1	1203.7×	0.002	KCNE3
intracellular chloride ion homeostasis	1	842.6×	0.002	KCNE3
membrane repolarization during action potential	1	842.6×	0.002	KCNE3
membrane repolarization during ventricular cardiac muscle cell action potential	1	842.6×	0.002	KCNE3
potassium ion export across plasma membrane	1	526.6×	0.003	KCNE3
ventricular cardiac muscle cell action potential	1	495.6×	0.003	KCNE3
regulation of ventricular cardiac muscle cell membrane repolarization	1	421.3×	0.003	KCNE3
regulation of heart rate by cardiac conduction	1	187.2×	0.006	KCNE3
sodium ion transport	1	135.9×	0.007	KCNE3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
LIPT2	0	0
LIPT2-AS1	0	0
KCNE3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LIPT2	2.3.1.181	lipoyl(octanoyl) transferase

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	KCNE3
D	Druggable family + AlphaFold only, no drug	1	LIPT2
E	Difficult family or no structure, no drug	1	LIPT2-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LIPT2	0	—
LIPT2-AS1	0	—
KCNE3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.