Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction

Summary

Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction (MONDO:0859304) is a disease caused by LETM1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: LETM1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction
Mondo ID	MONDO:0859304
OMIM	620089
UMLS	C5774240
MedGen	1824013
GARD	0027311
Is cancer (heuristic)	no

Data availability: 10 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 › neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction

Related subtypes (81): Huntington disease and related disorders, agenesis of the corpus callosum with peripheral neuropathy, striatonigral degeneration, angioid streaks of choroid, amyotrophic lateral sclerosis-parkinsonism-dementia complex, inherited Creutzfeldt-Jakob disease, mitochondrial DNA depletion syndrome 4a, cerebellar ataxia-hypogonadism syndrome, myoclonic cerebellar dyssynergia, cerebral sclerosis similar to Pelizaeus-Merzbacher disease, Chediak-Higashi syndrome, encephalopathy due to beta-mercaptolactate-cysteine disulfiduria, PEHO syndrome, deafness dystonia syndrome, Kennedy disease, fatal familial insomnia, Huntington disease-like 1, neuronal intranuclear inclusion disease, ataxia-telangiectasia-like disorder, radiation sensitivity/chromosome instability syndrome, autosomal dominant, Huntington disease-like 2, microphthalmia-brain atrophy syndrome, neurodegenerative syndrome due to cerebral folate transport deficiency, hereditary sensory neuropathy-deafness-dementia syndrome, infantile cerebellar-retinal degeneration, Alzheimer disease 17, hypotonia, infantile, with psychomotor retardation and characteristic facies, Alzheimer disease 18, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, severe neurodegenerative syndrome with lipodystrophy, developmental and epileptic encephalopathy, 35, combined oxidative phosphorylation deficiency 29, neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, neuronal ceroid lipofuscinosis, frontotemporal dementia with motor neuron disease, frontotemporal dementia, GM2 gangliosidosis, attenuated Chédiak-Higashi syndrome, autosomal recessive cerebral atrophy, neurodegeneration with brain iron accumulation, fatal post-viral neurodegenerative disorder, ferro-cerebro-cutaneous syndrome, PRKAR1B-related neurodegenerative dementia with intermediate filaments, ITM2B amyloidosis, corticobasal syndrome, infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome, recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, posterior cortical atrophy, progressive supranuclear palsy, leukodystrophy, hereditary spastic paraplegia, facial onset sensory and motor neuronopathy, X-linked neurodegenerative syndrome, Bertini type, X-linked neurodegenerative syndrome, Hamel type, boylan dew greco syndrome, hereditary motor neuron disease, neurodegeneration, childhood-onset, with ataxia, tremor, optic atrophy, and cognitive decline, frontotemporal dementia and/or amyotrophic lateral sclerosis, neurodegeneration, childhood-onset, with hypotonia, respiratory insufficiency, and brain imaging abnormalities, neurodegeneration with ataxia and late-onset optic atrophy, neurodegeneration, childhood-onset, with cerebellar atrophy, neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia, neurodegeneration, infantile-onset, biotin-responsive, hereditary optic atrophy, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, psychomotor regression-oculomotor apraxia-movement disorder-nephropathy syndrome, familial Alzheimer disease, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, hereditary cerebellar ataxia, DCTN1-related neurodegeneration, early-childhood-onset neurodegeneration with retinitis pigmentosa, sensorineural hearing loss, and demyelinating peripheral neuropathy, TUBB4A-related neurologic disorder, neurodegeneration, childhood-onset, with progressive microcephaly, neurodegeneration and seizures due to copper transport defect, neurodegeneration with developmental delay, early respiratory failure, myoclonic seizures, and brain abnormalities, neurodegeneration, childhood-onset, with cerebellar ataxia and cognitive decline, neurodegenerative disorder, X-linked, female-restricted, with parkinsonism and cognitive impairment, neurodegenerative disorder with cerebellar and caudate atrophy, APP-related brain and vascular amyloidosis

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

10 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1300216	NM_012318.3(LETM1):c.878T>A (p.Ile293Asn)	LETM1	Pathogenic	no assertion criteria provided
1300218	NM_012318.3(LETM1):c.2094del (p.Asp699fs)	LETM1	Pathogenic	no assertion criteria provided
1300221	NM_012318.3(LETM1):c.881G>A (p.Arg294Gln)	LETM1	Pathogenic	no assertion criteria provided
1300225	NM_012318.3(LETM1):c.2071-9C>G	LETM1	Pathogenic	no assertion criteria provided
3381225	NM_012318.3(LETM1):c.1791delinsAA (p.Tyr598fs)	LETM1	Likely pathogenic	criteria provided, single submitter
4849458	NM_012318.3(LETM1):c.1456del (p.Gln486fs)	LETM1	Likely pathogenic	criteria provided, single submitter
1370872	NM_012318.3(LETM1):c.888_889del (p.Arg299fs)	LETM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1300219	NM_012318.3(LETM1):c.2220G>C (p.Ter740Tyr)	LETM1	Uncertain significance	criteria provided, single submitter
1926071	NM_012318.3(LETM1):c.1430A>G (p.Gln477Arg)	LETM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3590460	NM_012318.3(LETM1):c.1538C>T (p.Pro513Leu)	LETM1	Uncertain significance	criteria provided, single submitter

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
LETM1	Strong	Autosomal recessive	neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LETM1	Orphanet:280	Wolf-Hirschhorn 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
LETM1	HGNC:6556	ENSG00000168924	O95202	Mitochondrial proton/calcium exchanger protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LETM1	Mitochondrial proton/calcium exchanger protein	Plays an important role in maintenance of mitochondrial morphology and in mediating either calcium or potassium/proton antiport.

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)
LETM1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS

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
buccal mucosa cell	1
mucosa of transverse colon	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LETM1	268	ubiquitous	marker	mucosa of transverse colon, sural nerve, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LETM1	2,029

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LETM1	O95202	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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 calcium ion transport	1	543.8×	0.013	LETM1
Complex III assembly	1	439.2×	0.013	LETM1
RHOG GTPase cycle	1	148.3×	0.025	LETM1
Respiratory electron transport	1	95.2×	0.025	LETM1
Aerobic respiration and respiratory electron transport	1	88.5×	0.025	LETM1
RHO GTPase cycle	1	60.1×	0.031	LETM1
Signaling by Rho GTPases	1	34.2×	0.041	LETM1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.041	LETM1
Transport of small molecules	1	25.1×	0.049	LETM1
Metabolism	1	11.6×	0.095	LETM1
Signal Transduction	1	10.2×	0.098	LETM1

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
calcium export from the mitochondrion	1	5617.3×	9e-04	LETM1
negative regulation of mitochondrial calcium ion concentration	1	4213.0×	9e-04	LETM1
mitochondrial potassium ion transmembrane transport	1	4213.0×	9e-04	LETM1
regulation of cellular hyperosmotic salinity response	1	3370.4×	9e-04	LETM1
protein hexamerization	1	1404.3×	0.002	LETM1
cristae formation	1	1053.2×	0.002	LETM1
mitochondrial calcium ion transmembrane transport	1	991.3×	0.002	LETM1
mitochondrial calcium ion homeostasis	1	991.3×	0.002	LETM1
inner mitochondrial membrane organization	1	842.6×	0.002	LETM1
calcium ion transport	1	181.2×	0.007	LETM1
mitochondrion organization	1	151.8×	0.007	LETM1
protein homooligomerization	1	122.1×	0.008	LETM1

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
LETM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LETM1	1	Binding:1

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	LETM1

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)
LETM1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.