Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset

Summary

Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (MONDO:0014940) is a disease caused by SQSTM1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: SQSTM1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
Mondo ID	MONDO:0014940
OMIM	617145
DOID	DOID:0081364
UMLS	C4310693
MedGen	934660
GARD	0027264
Is cancer (heuristic)	no

Also known as: NADGP · neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset · neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset; NADGP

Data availability: 27 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

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 with ataxia, dystonia, and gaze palsy, childhood-onset

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

27 retrieved; paginated sample, class counts are floors:

11 pathogenic, 7 uncertain significance, 3 benign, 2 conflicting classifications of pathogenicity, 2 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
984628	NM_003900.5(SQSTM1):c.175dup (p.Arg59fs)	LOC129995449	Pathogenic	no assertion criteria provided
1323651	NM_003900.5(SQSTM1):c.415del (p.Arg139fs)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1334783	NM_003900.5(SQSTM1):c.301+2T>A	SQSTM1	Pathogenic	no assertion criteria provided
1334784	NM_003900.5(SQSTM1):c.934_936delinsTGA (p.Arg312Ter)	SQSTM1	Pathogenic	no assertion criteria provided
1334785	NM_003900.5(SQSTM1):c.875_876insT (p.Ser294fs)	SQSTM1	Pathogenic	no assertion criteria provided
1691078	NM_003900.5(SQSTM1):c.784_820del (p.Gly262fs)	SQSTM1	Pathogenic	no assertion criteria provided
1704477	NM_003900.5(SQSTM1):c.1135_1138del (p.Glu379fs)	SQSTM1	Pathogenic	criteria provided, single submitter
265780	NM_003900.5(SQSTM1):c.2T>A (p.Met1Lys)	SQSTM1	Pathogenic	no assertion criteria provided
265781	NM_003900.5(SQSTM1):c.311_312del (p.Glu104fs)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
265782	NM_003900.5(SQSTM1):c.286C>T (p.Arg96Ter)	SQSTM1	Pathogenic	criteria provided, multiple submitters, no conflicts
4292363	NM_003900.5(SQSTM1):c.106G>T (p.Glu36Ter)	SQSTM1	Pathogenic	criteria provided, single submitter
2585020	NM_003900.5(SQSTM1):c.969+1G>C	SQSTM1	Likely pathogenic	criteria provided, single submitter
4845868	NM_003900.5(SQSTM1):c.247_248insA (p.Leu83fs)	SQSTM1	Likely pathogenic	criteria provided, single submitter
1019776	NM_003900.5(SQSTM1):c.1A>G (p.Met1Val)	SQSTM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8108	NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu)	SQSTM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931366	NM_016175.4(MRNIP):c.937G>T (p.Glu313Ter)	MRNIP	Uncertain significance	criteria provided, single submitter
4277620	NM_003831.5(RIOK3):c.1445dup (p.Leu482fs)	RIOK3	Uncertain significance	criteria provided, single submitter
3068681	NM_003900.5(SQSTM1):c.1279G>A (p.Ala427Thr)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3780664	NM_003900.5(SQSTM1):c.98C>A (p.Ala33Glu)	SQSTM1	Uncertain significance	criteria provided, single submitter
3892555	NM_003900.5(SQSTM1):c.223G>A (p.Val75Ile)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
571746	NM_003900.5(SQSTM1):c.457G>A (p.Val153Ile)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
976109	NM_003900.5(SQSTM1):c.1060_1061del (p.Gln354fs)	SQSTM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1248589	NM_003900.5(SQSTM1):c.755-23G>A	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
259189	NM_003900.5(SQSTM1):c.876C>T (p.Asp292=)	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
259191	NM_003900.5(SQSTM1):c.936G>A (p.Arg312=)	SQSTM1	Benign	criteria provided, multiple submitters, no conflicts
475410	NM_003900.5(SQSTM1):c.984G>A (p.Ser328=)	SQSTM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
542164	NM_003900.5(SQSTM1):c.1176G>A (p.Pro392=)	SQSTM1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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
SQSTM1	Definitive	Autosomal recessive	neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	gencc,clinvar
RIOK3	HGNC:11451	ENSG00000101782	O14730	Serine/threonine-protein kinase RIO3	clinvar
MRNIP	HGNC:30817	ENSG00000161010	Q6NTE8	MRN complex-interacting protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.
RIOK3	Serine/threonine-protein kinase RIO3	Serine/threonine-protein kinase involved in a ribosome quality control that takes place when ribosomes have stalled, leading to 18S non-functional rRNA decay and degradation of the 40S ribosomal subunit.
MRNIP	MRN complex-interacting protein	Plays a role in the cellular response to DNA damage and the maintenance of genome stability through its association with the MRN damage-sensing complex.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf
RIOK3	Kinase	yes		RIO_kinase, Kinase-like_dom_sf, Ser/Thr_kinase_Rio3
MRNIP	Other/Unknown	no		MRNIP, MRNIP_N

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
jejunal mucosa	1
mucosa of sigmoid colon	1
sperm	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
RIOK3	295	ubiquitous	marker	jejunal mucosa, sperm, mucosa of sigmoid colon
MRNIP	155	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SQSTM1	7,269
MRNIP	3,672
RIOK3	1,868

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SQSTM1	Q13501	26
RIOK3	O14730	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MRNIP	Q6NTE8	56.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. 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
p75NTR signals via NF-kB	1	951.7×	0.015	SQSTM1
Mitophagy	1	519.1×	0.015	SQSTM1
Pexophagy	1	475.8×	0.015	SQSTM1
p75NTR recruits signalling complexes	1	439.2×	0.015	SQSTM1
NF-kB is activated and signals survival	1	439.2×	0.015	SQSTM1
NRIF signals cell death from the nucleus	1	356.9×	0.015	SQSTM1
PINK1-PRKN Mediated Mitophagy	1	178.4×	0.021	SQSTM1
Nuclear events mediated by NFE2L2	1	167.9×	0.021	SQSTM1
Selective autophagy	1	139.3×	0.021	SQSTM1
Interleukin-1 family signaling	1	135.9×	0.021	SQSTM1
Signaling by ALK in cancer	1	135.9×	0.021	SQSTM1
Cell death signalling via NRAGE, NRIF and NADE	1	109.8×	0.024	SQSTM1
p75 NTR receptor-mediated signalling	1	93.6×	0.026	SQSTM1
Signaling by ALK fusions and activated point mutants	1	75.1×	0.027	SQSTM1
Autophagy	1	74.2×	0.027	SQSTM1
Cellular response to chemical stress	1	71.4×	0.027	SQSTM1
Death Receptor Signaling	1	69.6×	0.027	SQSTM1
Interleukin-1 signaling	1	62.1×	0.028	SQSTM1
KEAP1-NFE2L2 pathway	1	60.1×	0.028	SQSTM1
Macroautophagy	1	57.7×	0.028	SQSTM1
Signaling by Interleukins	1	32.1×	0.047	SQSTM1
Major pathway of rRNA processing in the nucleolus and cytosol	1	30.9×	0.047	RIOK3
Diseases of signal transduction by growth factor receptors and second messengers	1	28.4×	0.049	SQSTM1
Neddylation	1	23.7×	0.056	SQSTM1
Cytokine Signaling in Immune system	1	20.4×	0.062	SQSTM1
Cellular responses to stress	1	18.4×	0.066	SQSTM1
Cellular responses to stimuli	1	15.7×	0.074	SQSTM1
Post-translational protein modification	1	9.6×	0.116	SQSTM1
Disease	1	6.5×	0.158	SQSTM1
Immune System	1	6.5×	0.158	SQSTM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to dsDNA	1	2808.7×	0.009	RIOK3
brown fat cell proliferation	1	1872.4×	0.009	SQSTM1
protein targeting to vacuole involved in autophagy	1	1872.4×	0.009	SQSTM1
negative regulation of MDA-5 signaling pathway	1	1404.3×	0.009	RIOK3
cellular response to dsRNA	1	1123.5×	0.009	RIOK3
regulation of double-strand break repair via nonhomologous end joining	1	1123.5×	0.009	MRNIP
response to mitochondrial depolarisation	1	936.2×	0.009	SQSTM1
regulation of Ras protein signal transduction	1	624.1×	0.012	SQSTM1
aggrephagy	1	561.7×	0.012	SQSTM1
protein localization to perinuclear region of cytoplasm	1	468.1×	0.012	SQSTM1
negative regulation of toll-like receptor 4 signaling pathway	1	374.5×	0.012	SQSTM1
membraneless organelle assembly	1	374.5×	0.012	SQSTM1
pexophagy	1	351.1×	0.012	SQSTM1
regulation of protein complex stability	1	351.1×	0.012	SQSTM1
regulation of mitochondrion organization	1	280.9×	0.012	SQSTM1
cellular response to stress	1	280.9×	0.012	SQSTM1
negative regulation of ferroptosis	1	267.5×	0.012	SQSTM1
maturation of SSU-rRNA	1	255.3×	0.012	RIOK3
autophagy of mitochondrion	1	244.2×	0.012	SQSTM1
positive regulation of protein kinase activity	1	224.7×	0.012	MRNIP
positive regulation of long-term synaptic potentiation	1	224.7×	0.012	SQSTM1
temperature homeostasis	1	216.1×	0.012	SQSTM1
protein localization to chromatin	1	193.7×	0.013	MRNIP
positive regulation of innate immune response	1	175.5×	0.014	RIOK3
regulation of canonical NF-kappaB signal transduction	1	160.5×	0.015	SQSTM1
negative regulation of protein-containing complex assembly	1	151.8×	0.015	RIOK3
mitotic G2 DNA damage checkpoint signaling	1	147.8×	0.015	MRNIP
response to ionizing radiation	1	137.0×	0.015	MRNIP
immune system process	1	130.6×	0.015	SQSTM1
positive regulation of interferon-beta production	1	130.6×	0.015	RIOK3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RIOK3	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RIOK3	17	4
SQSTM1	0	0
MRNIP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	RIOK3
AXITINIB	4	RIOK3
RUXOLITINIB	4	RIOK3
BOSUTINIB	4	RIOK3
NINTEDANIB	4	RIOK3
SUNITINIB	4	RIOK3
CRIZOTINIB	4	RIOK3
MIDOSTAURIN	4	RIOK3
DOVITINIB	3	RIOK3
LESTAURTINIB	3	RIOK3
RUBOXISTAURIN	3	RIOK3
SU-014813	2	RIOK3
R-406	2	RIOK3
BI-2536	2	RIOK3
TOZASERTIB	2	RIOK3
GSK-461364	1	RIOK3
KW-2449	1	RIOK3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RIOK3	84	Binding:84
SQSTM1	20	Binding:20

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

17 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.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	RIOK3
AXITINIB	4	RIOK3
RUXOLITINIB	4	RIOK3
BOSUTINIB	4	RIOK3
NINTEDANIB	4	RIOK3
SUNITINIB	4	RIOK3
CRIZOTINIB	4	RIOK3
MIDOSTAURIN	4	RIOK3
DOVITINIB	3	RIOK3
LESTAURTINIB	3	RIOK3
RUBOXISTAURIN	3	RIOK3
SU-014813	2	RIOK3
R-406	2	RIOK3
BI-2536	2	RIOK3
TOZASERTIB	2	RIOK3
GSK-461364	1	RIOK3
KW-2449	1	RIOK3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RIOK3
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	2	SQSTM1, MRNIP

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)
SQSTM1	20	—
MRNIP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.