SQSTM1-Related Childhood-Onset Neurodegeneration

Mendelian MONDO:0014940 Pathograph 27 Show in embeddings browser Autosomal recessive cerebellar ataxia Congenital disorder of autophagy

Childhood-onset neurodegeneration with ataxia, dystonia and gaze palsy (NADGP) is an ultra-rare autosomal recessive neurodegenerative disorder caused by biallelic loss-of-function variants in SQSTM1, the gene encoding the selective-autophagy cargo receptor p62/sequestosome-1. Early development is normal; affected children present in later childhood or adolescence with progressive gait ataxia and evolve a combined cerebellar, extrapyramidal and oculomotor syndrome — appendicular ataxia, dysarthria, dystonia, choreoathetosis, vertical supranuclear gaze palsy and mild cognitive decline. The zygosity split matters and is the reason this is a separate entry. SQSTM1 is far better known for two *dominant* diseases caused by heterozygous, usually missense, alleles: Paget disease of bone (recurrent UBA-domain p.Pro392Leu) and ALS/frontotemporal dementia. Those are allelic disorders of altered p62 function in adults. NADGP is instead a state of complete p62 absence, confirmed by immunoblot in patient fibroblasts, and every reported NADGP allele to date is predicted-null (nonsense, frameshift, splice, start-loss, or a synonymous change shown to disrupt splicing). No missense NADGP allele has been reported. The two disease groups therefore differ in zygosity, allele class, age of onset and affected organ system, and their evidence must not be merged. Mechanistically the disorder sits with the congenital disorders of autophagy. p62 polymerises through its PB1 domain, binds ubiquitinated cargo through its UBA domain and delivers that cargo to the forming autophagosome through its LC3-interacting region. Its absence leaves selective autophagy without a cargo adaptor: patient and knockout cells fail to build ubiquitin-positive aggregates in response to misfolded-protein stress, autophagic flux decelerates, and the early PINK1-dependent steps of mitochondrial quality control are disrupted even though bulk mitochondrial clearance is preserved. A caveat that constrains everything downstream: no human neuropathology has been published. The step from cellular proteostatic and mitochondrial failure to region-selective degeneration of cerebellum, brainstem gaze centres and basal ganglia is inferred from imaging, from zebrafish sqstm1 knockdown and from p62-null mice, not demonstrated in patient tissue. It is curated here as an explicit knowledge gap rather than asserted.

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1
Inheritance
7
Pathophys.
18
Phenotypes
1
Hypotheses
3
Gaps
27
Pathograph
1
Genes
4
Medical Actions
5
Differentials
6
Models
22
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic — homozygous or compound heterozygous — loss-of-function SQSTM1 variants segregating in multiple independent, frequently consanguineous families. Obligate heterozygous carriers are reported clinically unaffected for this phenotype. This is the axis that separates NADGP from the dominant SQSTM1 disorders.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:27545679 SUPPORT Human Clinical
"we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline"
The defining report establishes biallelic loss-of-function inheritance across four independent families.
PMID:29959261 SUPPORT Human Clinical
"This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and links this phenotype to defective selective autophagy."
Independent replication of biallelic inactivating inheritance in three consanguineous families.
PMID:39126919 SUPPORT In Vitro
"Pathogenic variants in SQSTM1 gene are known to cause Neurodegeneration with ataxia, dystonia, and gaze palsy in autosomal recessive inheritance fashion."
States the autosomal recessive mode of inheritance for this named phenotype.
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Mechanistic Hypotheses

1
Blunted KEAP1-NRF2 antioxidant signalling contributes to neuronal loss
nrf2_axis_failure EMERGING
Beyond its cargo-receptor role, p62 sequesters KEAP1 and thereby stabilises NRF2. The proposal is that complete p62 absence leaves NRF2 under-protected, blunts the antioxidant transcriptional programme and lowers the threshold at which stressed cerebellar and brainstem neurons decompensate. The supporting biochemistry is established, but only in the opposite direction — p62 overproduction stabilising NRF2 — and no NADGP patient or patient-derived cell has been assayed for NRF2 target-gene output. The hypothesis is curated separately because it is the one mechanistic branch here that would be directly therapeutically actionable if confirmed.
Pathograph links
Absence of p62/Sequestosome-1 Protein -> Blunted KEAP1-NRF2 Antioxidant Response INDIRECT KNOWN INTERMEDIATES p62 also competes with NRF2 for the same binding site on KEAP1. Its absence is inferred to reduce NRF2 stabilisation and therefore antioxidant gene transcription. This edge is hypothesis-scoped and has not been demonstrated in patients.
Blunted KEAP1-NRF2 Antioxidant Response -> Cerebellar and Brainstem Neuron Proteostatic Stress INDIRECT KNOWN INTERMEDIATES Reduced antioxidant capacity is proposed to lower the threshold at which affected neurons decompensate. Not demonstrated in this disorder.
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Discussions and Knowledge Gaps

3
Which neuronal populations actually degenerate in NADGP, and does the pathology match the cerebellar-brainstem-basal ganglia pattern inferred from the clinical syndrome?
KNOWLEDGE GAP nadgp_no_human_neuropathology
Attached to
pathophysiology#Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia
No autopsy neuropathology has been published for this disorder. The regional map curated on that node is read off the clinical syndrome, off MRI that is frequently normal, and off model systems — it is not a tissue observation. In particular, Purkinje cell loss is assumed rather than shown, which is why this entry conforms only to the trigger node of the cerebellar Purkinje degeneration module and not to its degeneration node. Any curator tempted to strengthen that edge should note that the evidence to do so does not yet exist.
Proposed experiments
Post-mortem neuropathological characterisation of NADGP
nadgp_postmortem_neuropathology
Systematic neuropathological examination of a NADGP brain — cerebellar cortex and deep nuclei, rostral midbrain vertical-gaze centres, striatum and pallidum — with quantification of Purkinje and granule cell density, ubiquitin and p62 immunostaining, and assessment of tau and iron deposition.
Would support
pathophysiology#Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia
Supporting outcome
  • Selective loss of Purkinje and granule neurons with midbrain and striatal involvement, matching the clinical syndrome.
Refuting outcome
  • Preserved cerebellar cortical neurons with the pathology localising elsewhere, which would require the regional model curated here to be rewritten.
Do the defining phenotypes of the p62-null mouse — tau hyperphosphorylation with neurofibrillary tangles, and mature-onset obesity with insulin resistance — occur in humans with complete p62 absence?
HUMAN MODEL MISMATCH nadgp_mouse_human_mismatch
Attached to
pathophysiology#Cerebellar and Brainstem Neuron Proteostatic Stress animal_models#Mouse
The p62-null mouse is the only constitutive mammalian model of this genotype, and it is a poor phenotypic match. It develops an Alzheimer-like tauopathy with hippocampal involvement, memory impairment and depression-like behaviour, and separately a mature-onset obesity and insulin-resistance syndrome. Human NADGP presents in childhood as a cerebellar, extrapyramidal and oculomotor disorder; no tau pathology has been looked for in patients because no tissue exists, and no metabolic phenotype has been reported in any published family. This is evidence that exists in a model whose translational validity is the open question, not absent evidence. It matters practically: the tau result has been used to argue that p62 is a general anti-tauopathy factor, and importing that framing into NADGP would assert a mechanism no patient observation supports.
Proposed experiments
Tau and metabolic phenotyping of NADGP patients
nadgp_tau_and_metabolic_phenotyping
Prospective assessment of plasma and CSF phosphorylated-tau species and, where feasible, tau PET in genetically confirmed NADGP patients, alongside structured metabolic phenotyping for obesity, glucose intolerance and insulin resistance.
Would refute
animal_models#Mouse
Supporting outcome
  • Elevated phosphorylated tau and a metabolic syndrome in patients, which would upgrade the mouse from a poor to a fair model.
Refuting outcome
  • Normal tau biomarkers and normal metabolic phenotype, confirming that the mouse phenotypes are species-specific and must not be curated as human mechanism.
Show evidence (2 references)
PMID:16517408 SUPPORT Model Organism
"We report here that p62(-/-) mice develop mature-onset obesity, leptin resistance, as well as impaired glucose and insulin intolerance."
Documents the mouse metabolic phenotype that has no counterpart in the human disorder.
PMID:35662390 SUPPORT Model Organism
"In PS19 mice deficient in p62 (PS19/p62-KO), increased accumulation of phosphorylated tau, acceleration of neuronal loss, and exacerbation of neuroinflammation were observed in the hippocampus as compared with PS19 mice."
Reinforces the mouse tau-centred framing of p62 loss, which is the framing this mismatch warns against importing into NADGP.
Are heterozygous carriers of a NADGP truncating allele at increased risk of Paget disease of bone or of ALS/frontotemporal dementia, the dominant SQSTM1 disorders?
KNOWLEDGE GAP nadgp_heterozygote_risk
Attached to
genetic#SQSTM1 inheritance#Autosomal recessive inheritance
The dominant SQSTM1 disorders are caused predominantly by missense alleles — the recurrent UBA-domain p.Pro392Leu in Paget disease, and missense variants in ALS cohorts — whereas every NADGP allele reported is a null. Whether a single null allele confers any risk of the dominant phenotypes is unknown: NADGP parents are reported unaffected, but they are young relative to the age of onset of Paget disease and ALS and no cohort has been followed. The answer determines whether carrier relatives identified during cascade testing need surveillance, and it also bears on whether the dominant diseases are haploinsufficiency or altered-function disorders.
Proposed experiments
Longitudinal surveillance of obligate NADGP carriers
nadgp_carrier_cohort_surveillance
Assembly of a multi-family cohort of obligate heterozygous carriers of NADGP null alleles with longitudinal bone turnover markers, skeletal imaging and neurological assessment, compared against age-matched non-carrier relatives.
Would support
genetic#SQSTM1
Show evidence (2 references)
PMID:11992264 SUPPORT Human Clinical
"Screening SQSTM1/p62 for mutations led to the identification of a recurrent nonconservative change (P392L) flanking the ubiquitin-associated domain (UBA) (position 394-440) of the protein that was not present in 291 control individuals."
Establishes that the dominant Paget allele is a specific UBA-domain missense change, not a null — the contrast that makes carrier risk an open rather than settled question.
PMID:22084127 SUPPORT Human Clinical
"We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS)."
Shows the ALS-associated allele spectrum is predominantly heterozygous missense, reinforcing the allele-class distinction from NADGP.
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Pathophysiology

7
Biallelic SQSTM1 Loss-of-Function
Two null SQSTM1 alleles — nonsense, frameshift, canonical-splice, start-loss, or a synonymous change that disrupts splicing — are inherited from carrier parents. The resulting transcripts are degraded or encode truncated, non-functional protein.
SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Absence of p62/Sequestosome-1 Protein Null alleles on both chromosomes leave no functional p62 to be translated.
Show evidence (1 reference)
PMID:27545679 SUPPORT Human Clinical
"we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline"
Establishes biallelic SQSTM1 loss of function as the initiating lesion.
Absence of p62/Sequestosome-1 Protein
p62 protein is undetectable in patient cells. This is a complete-absence state rather than an altered-function state, which is the molecular distinction from the dominant SQSTM1 disorders, where a missense p62 is present but behaves abnormally.
Blunted KEAP1-NRF2 antioxidant signalling contributes to neuronal loss
ubiquitin-binding autophagy cargo receptor activity of p62 GO:0043130 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves ubiquitin-binding autophagy cargo receptor activity of p62, annotated with ubiquitin binding (GO:0043130), qualified as loss of function. GO:0043130 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Experimental models
Patient dermal fibroblasts PRIMARY CELL CULTURE Direct patient material establishing the complete-absence state at protein level.
Patient urine-derived cells PRIMARY CELL CULTURE Establishes that both alleles fail to produce normally spliced SQSTM1 transcript, supporting a null state without requiring a skin biopsy.
Patient iPSC line IGIBi010-A IPSC DERIVED MODEL Carries a patient null genotype and is available for differentiation into disease-relevant neuronal lineages.
Downstream
Failure of Selective Autophagy Cargo Recognition p62 is the adaptor that couples ubiquitinated cargo to the autophagosome; without it the coupling step has no substrate-recognition module.
Blunted KEAP1-NRF2 Antioxidant Response p62 also competes with NRF2 for the same binding site on KEAP1. Its absence is inferred to reduce NRF2 stabilisation and therefore antioxidant gene transcription. This edge is hypothesis-scoped and has not been demonstrated in patients. Blunted KEAP1-NRF2 antioxidant signalling contributes to neuronal loss
Show evidence (2 references)
PMID:27545679 SUPPORT In Vitro
"We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation."
Directly demonstrates absent p62 protein in patient-derived cells, establishing this node as a measured rather than inferred state.
PMID:39587727 SUPPORT In Vitro
"An SQSTM1 protein expression assay using urine-derived cells (UDCs) demonstrated that both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of premessenger RNA."
Independent functional confirmation, in a second patient-derived cell type, that the alleles abolish normal p62 production.
Failure of Selective Autophagy Cargo Recognition
Without p62 the cell cannot polymerise ubiquitinated cargo into sequestration-competent bodies or hand them to LC3 on the phagophore. Patient and knockout cells fail to form ubiquitin-positive aggregates under misfolded-protein stress and autophagic flux slows. Note that this is a cargo-recognition lesion, not a defect of the core autophagy machinery: the autophagosome can still be built, but selectively loading it fails.
macroautophagy GO:0016236 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased macroautophagy (GO:0016236). GO:0016236 is a biological process from the Gene Ontology. ↓ DECREASED aggrephagy GO:0035973 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased aggrephagy (GO:0035973). GO:0035973 is a biological process from the Gene Ontology. ↓ DECREASED
LC3-interacting region binding of p62 to the phagophore GO:0030674 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves LC3-interacting region binding of p62 to the phagophore, annotated with protein-macromolecule adaptor activity (GO:0030674), qualified as loss of function. GO:0030674 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Impaired Mitochondrial Quality Control Damaged mitochondria are one of the cargo classes that p62 normally routes to the autophagosome.
Cerebellar and Brainstem Neuron Proteostatic Stress Undegraded ubiquitinated cargo accumulates in long-lived post-mitotic neurons, which have limited capacity to dilute it by division.
Show evidence (4 references)
PMID:29959261 SUPPORT In Vitro
"We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux."
Directly demonstrates the cargo-handling and flux defect that defines this node.
PMID:16286508 SUPPORT INDIRECT In Vitro
"The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation conditions."
Establishes the normal p62-LC3 coupling step whose loss this node describes. Indirect because it is p62 depletion in a non-patient experimental system, not NADGP material.
PMID:17580304 SUPPORT INDIRECT In Vitro
"Here we show for the first time a direct interaction between p62 and the autophagic effector proteins LC3A and -B"
Identifies the adaptor interaction the LIR motif mediates, which is what the molecular-function binding on this node describes: p62 bridges cargo to ATG8/LC3 rather than binding ubiquitin at this end of the protein. Indirect because it maps the normal interaction in HeLa cells rather than measuring it in NADGP material.
+ 1 more reference
Impaired Mitochondrial Quality Control
p62 loss disrupts the early, PINK1-dependent steps of mitophagy — PINK1 recruitment and ubiquitin phosphorylation on depolarised mitochondria — and alters mitochondrial gene expression and respiratory function. Importantly, bulk clearance of mitochondria is preserved, so the defect is best described as impaired mitochondrial function and early-response quality control rather than a mitophagy block.
autophagy of mitochondrion GO:0000422 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagy of mitochondrion (GO:0000422). GO:0000422 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
SQSTM1-knockout human iPSC-derived cortical neurons IPSC DERIVED MODEL Reproduces altered mitochondrial gene expression, respiratory function and autophagic flux, and localises the mitophagy lesion to the early PINK1-dependent steps.
Downstream
Cerebellar and Brainstem Neuron Proteostatic Stress Mitochondrial dysfunction compounds the proteostatic burden in neurons with high and sustained metabolic demand.
Show evidence (3 references)
PMID:33891871 SUPPORT In Vitro
"We show that SQSTM1 depletion causes altered mitochondrial gene expression and functionality, as well as autophagy flux, in iPSC-derived neurons."
Demonstrates the mitochondrial consequence in a human neuronal context.
PMID:33891871 SUPPORT In Vitro
"However, SQSTM1 is not essential for mitophagy despite having a significant impact on early PINK1-dependent mitophagy processes including PINK1 recruitment and phosphorylation of ubiquitin on depolarized mitochondria."
Delimits the claim: the lesion is in the early PINK1-dependent steps, not in mitochondrial clearance overall. Curated so this node is not overread as a mitophagy block.
PMID:27545679 SUPPORT In Vitro
"We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation."
The same early mitochondrial-depolarisation response defect, measured in patient fibroblasts rather than an engineered knockout.
Blunted KEAP1-NRF2 Antioxidant Response
p62's KEAP1-interacting region normally competes with NRF2 for the KEAP1 binding site, so p62 stabilises NRF2 and sustains antioxidant gene transcription. Complete p62 loss is therefore predicted to leave NRF2 less protected from KEAP1-directed degradation and the antioxidant response blunted. This node is an inference from the inverse experiment (p62 overproduction stabilises NRF2); it has not been measured in NADGP patients or patient cells, and is scoped to a hypothesis group for that reason.
Blunted KEAP1-NRF2 antioxidant signalling contributes to neuronal loss
cellular response to oxidative stress GO:0034599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cerebellar and Brainstem Neuron Proteostatic Stress Reduced antioxidant capacity is proposed to lower the threshold at which affected neurons decompensate. Not demonstrated in this disorder. Blunted KEAP1-NRF2 antioxidant signalling contributes to neuronal loss
Show evidence (2 references)
PMID:20173742 SUPPORT INDIRECT In Vitro
"p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2."
Establishes the molecular interaction on which this node depends.
PMID:20173742 SUPPORT INDIRECT In Vitro
"Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes."
Indirect and inverted: the demonstrated direction is that excess p62 stabilises NRF2, from which blunted NRF2 signalling under complete p62 absence is inferred rather than shown.
Cerebellar and Brainstem Neuron Proteostatic Stress
Long-lived cerebellar and brainstem neurons carry the combined burden of undegraded ubiquitinated cargo, dysfunctional mitochondria and — hypothetically — reduced antioxidant reserve. This is the disorder-specific substitution into the conserved cerebellar-degeneration trigger node, whose module description explicitly admits impaired protein quality control as one of its heterogeneous initiating lesions.
cerebellar Purkinje cell CL:0000121 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar Purkinje cell, annotated with Purkinje cell (CL:0000121). CL:0000121 is a cell type from the Cell Ontology. cerebellar granule cell CL:0001031 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar granule cell (CL:0001031). CL:0001031 is a cell type from the Cell Ontology.
cellular response to oxidative stress GO:0034599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Zebrafish sqstm1 knockdown Zebrafish recapitulates Loss of sqstm1 produces a reproducible cerebellar structural phenotype, tying the gene directly to the cerebellar axis of the human disorder.
p62/Sqstm1 knockout mouse Mouse partially recapitulates Establishes that constitutive p62 loss is sufficient to cause neurodegeneration in a mammal, which is the claim the human disorder needs from this model.
Downstream
Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia Inferred step. No human neuropathology has been published, so the transition from cellular stress to region-selective neuronal loss rests on imaging and model systems.
Show evidence (2 references)
PMID:29959261 SUPPORT INDIRECT Model Organism
"The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy."
Ties loss of sqstm1 specifically to cerebellar structural failure. Indirect because it is a zebrafish knockdown, not human tissue.
PMID:18346206 SUPPORT INDIRECT Model Organism
"we report age-dependent constitutive activation of glycogen synthase kinase 3beta, protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and neurodegeneration"
Shows that constitutive p62 loss is sufficient to cause neurodegeneration in a mammal. Indirect: the mouse lesion is tau-driven and its relevance to human NADGP is unproven.
Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia
Progressive, bilateral and symmetric degeneration selectively involving cerebellar circuitry, the rostral brainstem supranuclear vertical-gaze pathways, and the basal ganglia, with milder diffuse cortical involvement. The regional pattern is read off the clinical syndrome and imaging rather than from tissue: cerebellar atrophy is variable and often absent on MRI, and brainstem lesions have been reported only once.
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology. brainstem UBERON:0002298 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brainstem (UBERON:0002298). UBERON:0002298 is an anatomical location from the Uberon multi-species anatomy ontology. basal ganglia UBERON:0002420 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in basal ganglia, annotated with basal ganglion (UBERON:0002420). UBERON:0002420 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive Gait Ataxia Loss of cerebellar cortical output produces truncal and gait incoordination.
Progressive Appendicular Ataxia The same loss of cerebellar output produces limb dysmetria and upper-limb clumsiness.
Dysarthria Cerebellar involvement of speech motor control.
Vertical Supranuclear Gaze Palsy Involvement of rostral midbrain supranuclear vertical-gaze pathways.
Oculomotor Apraxia Saccade-initiation failure in all directions, reflecting wider involvement of the brainstem and cerebellar saccadic circuitry than the vertical-gaze pathways alone.
Nystagmus Gaze-holding failure from loss of cerebellar control of the neural integrator.
Tremor Intention tremor follows cerebellar outflow involvement; head tremor is reported with it in the same patient.
Bradykinesia with Limb Rigidity Basal ganglia involvement producing a hypokinetic-rigid pattern.
Dystonia Basal ganglia involvement.
Choreoathetosis Basal ganglia involvement producing hyperkinetic movement.
Cognitive Decline Diffuse cortical and subcortical involvement.
Cerebellar Atrophy Where cerebellar tissue loss is sufficient it becomes visible on MRI, though it frequently is not.
Show evidence (2 references)
PMID:29959261 SUPPORT Human Clinical
"To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families."
The combined cerebellar, oculomotor and extrapyramidal syndrome is the clinical signature of this regional distribution.
PMID:34147300 SUPPORT Human Clinical
"Our case had brainstem lesions on brain magnetic resonance imaging that have not been previously reported."
Direct radiological evidence of brainstem involvement, although reported in a single patient.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SQSTM1-Related Childhood-Onset Neurodegeneration Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Cardiovascular 1
Orthostatic Hypotension OCCASIONAL HP:0001278 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Orthostatic hypotension (HP:0001278). HP:0001278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30638816 SUPPORT Human Clinical
"Furthermore, we report dysautonomic features such as orthostatic hypotension and sudomotor dysfunction, along with other non-motor symptoms."
Reports orthostatic hypotension as a dysautonomic feature of the disorder.
Ear 1
Hearing Loss OCCASIONAL Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41307082 SUPPORT INDIRECT Human Clinical
"Additional symptoms previously described include dystonia, choreoathetoid movements, dyskinesia, hearing loss, and hypogonadotropic hypogonadism"
Lists hearing loss among features reported in the prior published cases. Indirect because the statement summarises earlier reports rather than a measurement made in the patients of this paper, in whom it was explicitly absent.
Eye 4
Vertical Supranuclear Gaze Palsy FREQUENT HP:0000511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertical supranuclear gaze palsy (HP:0000511). HP:0000511 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39587727 SUPPORT Human Clinical
"biallelic pathogenic variants of SQSTM1 can cause child-onset and multisystem neurodegeneration, including cerebellar ataxia, dystonia, and vertical gaze palsy (NADGP)"
Names vertical gaze palsy as one of the three phenotype-defining features.
PMID:41307082 SUPPORT Human Clinical
"During 2 years of follow-up, the second patient developed gaze palsy."
Documents that gaze palsy can emerge after the ataxia, so its absence at first assessment does not exclude the diagnosis.
Oculomotor Apraxia OCCASIONAL HP:0000657 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oculomotor apraxia (HP:0000657). HP:0000657 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41307082 SUPPORT Human Clinical
"Neurological examination revealed oculomotor apraxia, with difficulty moving his eyes in all directions (frozen eye)."
Names oculomotor apraxia on examination in a patient homozygous for a truncating SQSTM1 allele.
Nystagmus OCCASIONAL HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gaze-evoked nystagmus, annotated with Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39587727 SUPPORT Human Clinical
"mild intellectual disturbance, gaze palsy, gaze directional nystagmus, choric gait disturbance, and cerebellar ataxia were noted"
Records gaze-directional nystagmus in a patient with compound heterozygous null SQSTM1 alleles. The HP binding is the general nystagmus term; HPO's gaze-evoked qualifier is carried in preferred_term.
Iridoplegia OCCASIONAL Abnormal pupillary function HP:0007686 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Iridoplegia, annotated with Abnormal pupillary function (HP:0007686). HP:0007686 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30638816 SUPPORT Human Clinical
"In addition to the previously described syndrome characterized by cerebellar ataxia, dystonia, choreoathetosis, cognitive impairment and gaze palsy, two subjects presented with iridoplegia."
Reports iridoplegia in two patients. The HP binding is the parent term for abnormal pupillary function; HPO has no exact iridoplegia term, so the specificity is carried in preferred_term.
Metabolism 1
Sudomotor Dysfunction OCCASIONAL Abnormal sweat homeostasis HP:0040127 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudomotor dysfunction, annotated with Abnormal sweat homeostasis (HP:0040127). HP:0040127 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30638816 SUPPORT Human Clinical
"Furthermore, we report dysautonomic features such as orthostatic hypotension and sudomotor dysfunction, along with other non-motor symptoms."
Reports sudomotor dysfunction alongside orthostatic hypotension.
Nervous System 11
Progressive Gait Ataxia VERY_FREQUENT HP:0002066 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait ataxia (HP:0002066), qualified as course progressive. HP:0002066 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (3 references)
PMID:27545679 SUPPORT Human Clinical
"we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline"
Gait abnormality and ataxia head the list of defining features in the index cohort.
PMID:41307082 SUPPORT Human Clinical
"Physical examination revealed frozen eye movements, gait ataxia, and dysarthria."
Gait ataxia on examination in an independently reported patient.
PMID:31525130 SUPPORT INDIRECT Human Clinical
"We describe here a case of progressive childhood-onset cerebellar ataxia with vertical supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging (MRI) of brain."
Establishes progressive childhood-onset cerebellar ataxia as the presenting syndrome. Indirect for this node because the report names the cerebellar syndrome as a whole rather than the gait component specifically.
Progressive Appendicular Ataxia VERY_FREQUENT Limb ataxia HP:0002070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive appendicular (limb) ataxia, annotated with Limb ataxia (HP:0002070), qualified as course progressive. HP:0002070 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:39587727 SUPPORT Human Clinical
"Both limb and truncal ataxia were evident."
Records limb ataxia as a component separable from truncal involvement in a genetically confirmed patient.
PMID:41307082 SUPPORT Human Clinical
"Additional findings included dysmetria on the finger-to-nose test and an abnormal tandem gait."
Dysmetria on finger-to-nose testing is the appendicular sign this phenotype names.
Dysarthria VERY_FREQUENT HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260), qualified as course progressive. HP:0001260 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:27545679 SUPPORT Human Clinical
"we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline"
Dysarthria is named among the defining features of the index cohort.
Dystonia FREQUENT HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332), qualified as course progressive. HP:0001332 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:30638816 SUPPORT Human Clinical
"Homozygous sequestomosome-1 gene mutations have been recently linked to neurodegeneration with dystonia, ataxia and gaze palsy."
Dystonia is one of the three features by which the disorder is defined.
Choreoathetosis OCCASIONAL HP:0001266 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choreoathetosis (HP:0001266). HP:0001266 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30638816 SUPPORT Human Clinical
"In addition to the previously described syndrome characterized by cerebellar ataxia, dystonia, choreoathetosis, cognitive impairment and gaze palsy, two subjects presented with iridoplegia."
Names choreoathetosis as part of the established syndrome.
PMID:39587727 SUPPORT Human Clinical
"Our patients experienced chorea during adolescence."
Chorea in adolescence in an independently reported family.
Cognitive Decline FREQUENT Mental deterioration HP:0001268 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mental deterioration (HP:0001268), qualified as course progressive. HP:0001268 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:27545679 SUPPORT Human Clinical
"we identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families with a childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline"
Cognitive decline is named among the defining features of the index cohort.
Myoclonus OCCASIONAL HP:0001336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonus (HP:0001336). HP:0001336 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34147300 SUPPORT Human Clinical
"Here we describe a patient with progressive cerebellar ataxia and gaze palsy, as well as myoclonus, cognitive impairment and growth retardation with a homozygous SQSTM1 variant NM_003900.5:c.55G > T (p.Glu19*)."
Reports myoclonus in a genetically confirmed patient.
Tremor OCCASIONAL HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Head and intention tremor, annotated with Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41307082 SUPPORT Human Clinical
"he began experiencing involuntary movements, gait instability, head tremors, lip smacking, periodic limb movements during sleep, and intention tremors in his hands"
Documents head and intention tremor as presenting features in a genetically confirmed patient.
Bradykinesia with Limb Rigidity OCCASIONAL HP:0002067 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bradykinesia with mild upper-limb rigidity, annotated with Bradykinesia (HP:0002067). HP:0002067 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41307082 SUPPORT Human Clinical
"He exhibited slow movements, gait ataxia (clumsy gait), dysarthria, and mild rigidity in the upper limbs."
Records slowed movement and limb rigidity on examination in a genetically confirmed patient.
Cerebellar Atrophy VARIABLE HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:29112993 SUPPORT INDIRECT Other
"Predominant involvement of the long white matter tracts and the cerebellum are anatomic and imaging hallmarks, with common findings that include a thinning of the corpus callosum and cerebellar hypoplasia or atrophy."
Group-level imaging statement across the congenital disorders of autophagy, of which this disorder is one. Indirect because the claim is made for the class rather than measured in NADGP patients specifically.
PMID:39587727 REFUTE Human Clinical
"Cerebellar ataxia is a characteristic manifestation of this disorder; however, brain magnetic resonance imaging studies have not shown significant cerebellar atrophy."
Directly contradicts cerebellar atrophy as a constant feature; these genetically confirmed patients had ataxia without significant atrophy.
PMID:31525130 REFUTE Human Clinical
"We describe here a case of progressive childhood-onset cerebellar ataxia with vertical supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging (MRI) of brain."
A genetically confirmed patient with an entirely normal brain MRI, refuting any requirement for cerebellar atrophy.
Brainstem MRI Signal Abnormality VERY_RARE Abnormal brainstem MRI signal intensity HP:0012747 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal brainstem MRI signal intensity (HP:0012747). HP:0012747 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34147300 SUPPORT Human Clinical
"Our case had brainstem lesions on brain magnetic resonance imaging that have not been previously reported."
The single report of brainstem MRI lesions in this disorder.
🧬

Genetic Associations

1
SQSTM1 (CAUSATIVE)
Gene: SQSTM1 hgnc:11280 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SQSTM1 (hgnc:11280). hgnc:11280 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (4 references)
PMID:29959261 SUPPORT Human Clinical
"We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA)."
Documents the null allele classes — splice-site and truncating — that characterise this disorder.
PMID:41307082 SUPPORT Human Clinical
"In both cases, initial workup was unremarkable, but whole-exome sequencing revealed a novel homozygous pathogenic truncating mutation, SQSTM1 (c.838G>T, p. Glu280Ter)."
A further homozygous truncating allele, recurrent in two unrelated Iranian families.
PMID:35957775 SUPPORT Human Clinical
"A homozygous deletion variant that changes the frame shift in the SQSTM1 gene named c.790 Del A .T was detected in case childhood onset and progressive neurodegeneration with ataxia, and gaze palsy."
An independent homozygous frameshift allele in the same phenotype.
+ 1 more reference
💊

Medical Actions

4
Physical Therapy and Rehabilitation
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Physiotherapy for gait, balance and falls prevention, and maintenance of function as ambulation declines. No disease-specific rehabilitation protocol has been published; practice mirrors that for other childhood-onset ataxia-dystonia syndromes.
Speech and Language Therapy
Action: Speech Language TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. NCIT:C159273
Platform: Behavioral / lifestyle
Management of progressive cerebellar dysarthria and, in later disease, of communication and swallowing.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counselling of consanguineous and carrier couples on the 25% recurrence risk, with carrier testing of relatives and prenatal or preimplantation testing once the familial variants are known. This is the only intervention with a preventive effect at family level.
Mechanism Target:
Biallelic SQSTM1 Loss-of-Function — Acts on the initiating genetic lesion at the level of recurrence risk rather than in an affected individual.
Supportive and Multidisciplinary Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Multidisciplinary neurological, rehabilitative and educational support, management of orthostatic hypotension where dysautonomia is present, and falls prevention. No disease-modifying therapy exists.
🔬

Diagnosis

3
Next-generation sequencing
Diagnosis is made by identifying biallelic loss-of-function SQSTM1 variants on clinical exome or genome sequencing. There is no biochemical screening test and no disease-specific imaging finding — MRI is frequently normal — so sequencing is the definitive step. Every reported family was ascertained this way after an unremarkable metabolic and routine workup, which is itself part of the diagnostic pattern.
clinical exome or genome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31525130 SUPPORT Human Clinical
"This case highlights the importance of next-generation sequencing in the diagnosis of inherited ataxia syndromes."
States that next-generation sequencing is the diagnostic route for this presentation.
PMID:41307082 SUPPORT Human Clinical
"In both cases, initial workup was unremarkable, but whole-exome sequencing revealed a novel homozygous pathogenic truncating mutation, SQSTM1 (c.838G>T, p. Glu280Ter)."
Shows the diagnostic sequence in practice: unremarkable first-line workup followed by exome sequencing that establishes the genetic diagnosis.
p62/SQSTM1 immunoblot on patient-derived cells
Immunoblotting patient fibroblasts or urine-derived cells for p62/SQSTM1 demonstrates complete absence of the protein. This is the functional confirmation that a candidate allele pair is null, and it is what distinguishes this disorder from the dominant SQSTM1 diseases, in which an abnormal protein is present.
p62/SQSTM1 immunoblot NCIT:C16357 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:27545679 SUPPORT In Vitro
"We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation."
Establishes the absent-protein immunoblot result in patient fibroblasts.
PMID:39587727 SUPPORT In Vitro
"Immunoblotting showed that the SQSTM1 was absent in the UDCs of Patients 1 and 2"
The same absent-protein result obtained in a second, non-invasively sampled patient cell type.
Urine-derived cell functional assay for variants of uncertain significance
Where sequencing returns a variant whose effect is not obvious — the reported case is a synonymous change at the 3' end of exon 6 that in fact abolishes splicing — culturing urine-derived cells and assaying SQSTM1 expression resolves it without a skin biopsy. NCIT has no clinical-action term for this assay, so no term is bound.
urine-derived cell SQSTM1 expression and splicing assay
Show evidence (1 reference)
PMID:39587727 SUPPORT In Vitro
"An SQSTM1 protein expression assay using urine-derived cells (UDCs) demonstrated that both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of premessenger RNA."
Demonstrates the assay resolving two variants, one of them a nominally synonymous change, into confirmed null alleles.
📈

Progression

4
Presymptomatic childhood
Early development is normal. No presymptomatic biomarker or imaging change has been described, and no intervention window has been studied because no disease-modifying therapy exists to deploy in one.
Onset with gait ataxia
Presentation in later childhood or adolescence, typically with recurrent falls, unsteady gait and emerging dysarthria. Initial metabolic and routine workup is characteristically unremarkable.
Show evidence (1 reference)
PMID:41307082 SUPPORT Human Clinical
"The first patient was a 12-year-old boy of Iraqi and Iranian descent, who presented with a 3-year history of recurrent falls, swaying while walking, and difficulties with writing and speech."
A representative presentation: falls and gait disturbance in the first decade, with speech involvement.
Established combined cerebellar-extrapyramidal-oculomotor syndrome
Appendicular ataxia, dysarthria, dystonia and choreoathetosis are joined by vertical supranuclear gaze palsy, which may appear only on follow-up. Mild cognitive decline becomes apparent. Dysautonomia emerges in a subset.
Show evidence (1 reference)
PMID:29959261 SUPPORT Human Clinical
"To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families."
Describes the established combined syndrome.
Advanced motor disability
Slow but relentless progression to loss of independent ambulation, commonly in young adulthood, with severe dysarthria. Patients survive into adult life; no disease-specific survival data have been published. Progression rate varies between and within families for reasons that are unexplained.
📊

Prevalence

1
Worldwide
Cases In Literature <1 in 1,000,000
Ultra-rare. A 2025 review counted 27 reported cases carrying 11 distinct SQSTM1 alleles; additional single-family reports have appeared since. No prevalence or incidence estimate has been published and no registry exists.
Show evidence (1 reference)
PMID:41307082 SUPPORT Human Clinical
"To date, only 27 cases have been reported, with 11 different mutations affecting SQSTM1."
Gives the published case count, which is the only quantitative occurrence figure available for this disorder.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from SQSTM1-Related Childhood-Onset Neurodegeneration:

Niemann-Pick disease type C MONDO:0018982
Overlapping Features The principal phenocopy. Both are autosomal recessive, both begin in childhood or adolescence after normal early development, and both combine cerebellar ataxia, dysarthria, dystonia and cognitive decline with vertical supranuclear gaze palsy — which is the most characteristic sign of Niemann-Pick type C and the oculomotor hallmark of this disorder. A child with progressive ataxia and vertical gaze palsy should be evaluated for both.
Distinguishing Features
  • Niemann-Pick type C is neurovisceral: the neurological syndrome is usually preceded by systemic signs, either neonatal cholestatic jaundice or splenomegaly and hepatosplenomegaly in infancy and childhood. Biallelic SQSTM1 disease is purely neurological and no visceral involvement has been reported in it.
  • Gelastic cataplexy is a further Niemann-Pick type C discriminator and has never been reported in biallelic SQSTM1 disease.
  • Niemann-Pick type C is confirmed biochemically by filipin staining of cultured fibroblasts and by plasma oxysterols, and genetically by NPC1 or NPC2 variants; biallelic SQSTM1 disease has no biochemical marker and is confirmed by sequencing alone.
  • Niemann-Pick type C has a licensed disease-specific therapy in Europe and several other countries; biallelic SQSTM1 disease has none, so the distinction changes management.
Show evidence (3 references)
PMID:20525256 SUPPORT Human Clinical
"The most characteristic sign is vertical supranuclear gaze palsy."
Establishes vertical supranuclear gaze palsy as the characteristic sign of Niemann-Pick type C, which is the feature shared with this disorder.
PMID:20525256 SUPPORT Human Clinical
"conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults"
Niemann-Pick type C's own differential is stated as the same clinical combination this disorder presents with, so the relationship is symmetric.
PMID:22810120 SUPPORT Human Clinical
"VSGP is present in approximately 65 % of the cases and is, with gelastic cataplexy, an important risk indicator for NP-C."
Quantifies how often the shared sign occurs in Niemann-Pick type C and names gelastic cataplexy as the accompanying discriminator.
Ataxia-telangiectasia and the ataxia with oculomotor apraxia syndromes MONDO:0008840
Overlapping Features Childhood-onset progressive ataxia with an oculomotor sign is the shared presentation. Oculomotor apraxia is reported in this disorder, and it is the defining eye finding of ataxia-telangiectasia and the ataxia with oculomotor apraxia syndromes, so those conditions were the working diagnoses in reported SQSTM1 patients before sequencing.
Distinguishing Features
  • Oculocutaneous telangiectasia, raised serum alpha-fetoprotein, immunodeficiency and cancer predisposition mark ataxia-telangiectasia and none of them occurs in biallelic SQSTM1 disease.
  • Telangiectasia and alpha-fetoprotein were explicitly looked for and normal in the reported SQSTM1 patients, which is how the two were separated at the bedside before sequencing.
  • Vertical supranuclear gaze palsy is a defining feature of biallelic SQSTM1 disease and is not a feature of ataxia-telangiectasia.
Show evidence (2 references)
PMID:35402641 SUPPORT INDIRECT Human Clinical
"In ataxia, nystagmus is common, but other findings such as oculomotor apraxia, supranuclear gaze palsy, impaired fixation, or saccadic pursuit can contribute to diagnoses such as ataxia with oculomotor apraxia, Niemann-Pick type C, or ataxia telangiectasia."
Places oculomotor apraxia and supranuclear gaze palsy — both curated as phenotypes here — in the diagnostic path toward these conditions. Indirect because it is an educational review of eye signs, not a study of SQSTM1 patients.
PMID:41307082 SUPPORT Human Clinical
"Notably, myoclonus, chorea, dystonia, and telangiectasia were absent."
Records that telangiectasia was specifically looked for and absent in a SQSTM1 patient with oculomotor apraxia, which is how the two are separated clinically.
Wilson disease MONDO:0010200
Overlapping Features A treatable autosomal recessive cause of childhood and adolescent movement disorder with dystonia, tremor, dysarthria and cognitive change, so it is screened for in every child presenting the way these patients do. Missing it has direct consequences, since Wilson disease is treatable and this disorder is not.
Distinguishing Features
  • Normal serum copper and ceruloplasmin exclude Wilson disease and were documented in the reported SQSTM1 patients.
  • Kayser-Fleischer rings and hepatic involvement occur in Wilson disease and have not been reported in biallelic SQSTM1 disease.
  • Vertical supranuclear gaze palsy and a progressive cerebellar syndrome point away from Wilson disease and toward this disorder.
Show evidence (2 references)
PMID:41307082 SUPPORT Human Clinical
"Extensive laboratory investigations, including hematological parameters, renal and liver function tests, serum albumin, thyroid function, cholesterol, triglycerides, alpha-fetoprotein, copper, and ceruloplasmin levels, were all within normal limits."
Documents that copper and ceruloplasmin were measured and normal, which is the step that excludes Wilson disease in these patients.
PMID:35402641 SUPPORT INDIRECT Human Clinical
"Gaze impersistence in a patient with chorea suggests Huntington's disease, but in a patient with dystonia or tremor, Wilson's disease is more likely."
Places Wilson disease in the differential reached from the dystonia and tremor curated here. Indirect because it is a review of eye signs rather than a SQSTM1 study.
Hereditary chorea syndromes
Overlapping Features Chorea and athetosis were the presenting hyperkinetic features in an adolescent-onset family, and the authors of that report argue explicitly that this disorder belongs in the differential for hereditary chorea alongside Huntington disease and the other inherited choreas.
Distinguishing Features
  • The inherited choreas are separated from one another by their own genetic tests; no clinical feature does it alone.
  • Chorea accompanied by cerebellar ataxia, vertical supranuclear gaze palsy and either consanguinity or affected siblings points toward biallelic SQSTM1 disease.
  • Chorea occurs in only a minority of reported SQSTM1 patients and is never the whole picture, so its absence does not exclude the diagnosis.
Show evidence (1 reference)
PMID:39587727 SUPPORT Human Clinical
"our findings suggest that NADGP should be considered as a differential diagnosis of hereditary chorea"
The authors state the differential-diagnosis relationship directly.
Other inherited childhood-onset cerebellar ataxias
Overlapping Features Before the gene was known these children were classified simply as inherited ataxia. The combination that should raise this specific diagnosis is progressive cerebellar ataxia with an ophthalmological abnormality and cognitive impairment, which the case reports converge on as the referral pattern for sequencing.
Distinguishing Features
  • No single clinical feature separates this disorder from the other autosomal recessive childhood ataxias, and MRI is frequently normal, so the separation is genetic.
  • Vertical supranuclear gaze palsy together with dystonia narrows the field but does not close it.
Show evidence (2 references)
PMID:34147300 SUPPORT Human Clinical
"Homozygous SQSTM1 variant should be considered in the differential diagnosis in patients presenting with cerebellar findings, gaze palsy, and cognitive impairment to facilitate early diagnosis and genetic counseling."
States the clinical trigger for placing this disorder in the inherited-ataxia differential.
PMID:31525130 SUPPORT Human Clinical
"SQSTM1 mutation should be considered in the differential diagnosis in a patient with both cerebellar ataxia and ophthalmological manifestations."
Independently states the same differential-diagnosis rule from a second case report.
🧫

Experimental Models

4
Patient dermal fibroblasts PRIMARY_CELL_CULTURE
Fibroblasts from affected individuals in the index cohort, used to confirm absence of p62 protein and to assay the response to mitochondrial depolarisation and autophagosome formation.
Publication
PMID:27545679
Pathograph links
Absence of p62/Sequestosome-1 Protein measures fidelity: high Direct patient material establishing the complete-absence state at protein level.
Limitations: Fibroblasts are non-neuronal, so they establish the molecular lesion but not the neuron-specific consequences.
Readouts
p62/SQSTM1 protein abundance on immunoblot
Direction: ABOLISHED
Interpretation: Absent p62 protein confirms the null state predicted by the biallelic alleles.
Show evidence (1 reference)
PMID:27545679 SUPPORT In Vitro
"We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and found evidence of a defect in the early response to mitochondrial depolarization and autophagosome formation."
Reports the immunoblot measurement behind this readout.
Patient urine-derived cells PRIMARY_CELL_CULTURE
Urine-derived cells from affected siblings, used as a non-invasive functional assay to resolve a variant of uncertain significance — a synonymous change that proved to disrupt splicing.
Publication
PMID:39587727
Pathograph links
Absence of p62/Sequestosome-1 Protein measures fidelity: high Establishes that both alleles fail to produce normally spliced SQSTM1 transcript, supporting a null state without requiring a skin biopsy.
Limitations: Non-neuronal, and the assay reports on splicing and protein expression rather than on autophagic function.
Show evidence (1 reference)
PMID:39587727 SUPPORT In Vitro
"An SQSTM1 protein expression assay using urine-derived cells (UDCs) demonstrated that both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of premessenger RNA."
Supports treating urine-derived cells as informative for the p62-absence node.
SQSTM1-knockout human iPSC-derived cortical neurons IPSC_DERIVED_MODEL
CRISPR knockout of SQSTM1 in human induced pluripotent stem cells differentiated to cortical neurons, used to dissect the mitochondrial and autophagic consequences of p62 loss in a human neuronal context.
Publication
PMID:33891871
Pathograph links
Impaired Mitochondrial Quality Control recapitulates fidelity: moderate Reproduces altered mitochondrial gene expression, respiratory function and autophagic flux, and localises the mitophagy lesion to the early PINK1-dependent steps.
Limitations: Cortical rather than cerebellar or brainstem neuronal identity, an engineered knockout rather than patient genotype, and a two-dimensional culture that cannot report the region-selective vulnerability that defines the human disease.
Readouts
Mitochondrial gene expression and respiratory function
Direction: ALTERED
Interpretation: Mitochondrial function, not mitochondrial clearance, is the affected axis.
Show evidence (1 reference)
PMID:33891871 SUPPORT In Vitro
"These findings suggest that SQSTM1 is important for mitochondrial function rather than clearance."
States the direction and nature of the measured mitochondrial change.
Show evidence (1 reference)
PMID:33891871 SUPPORT In Vitro
"We show that SQSTM1 depletion causes altered mitochondrial gene expression and functionality, as well as autophagy flux, in iPSC-derived neurons."
Supports treating this model as informative for the mitochondrial quality-control node.
Patient iPSC line IGIBi010-A IPSC_DERIVED_MODEL
An induced pluripotent stem cell line derived from a patient homozygous for the p.Leu251SerfsTer4 frameshift allele. It is a resource rather than a completed experiment: no disease phenotype has yet been reported from it.
Publication
PMID:39126919
Pathograph links
Absence of p62/Sequestosome-1 Protein measures fidelity: unknown Carries a patient null genotype and is available for differentiation into disease-relevant neuronal lineages.
Limitations: A characterised line only. No differentiated phenotype, no isogenic control comparison and no functional result have been published, so it cannot yet support a mechanistic claim.
Show evidence (1 reference)
PMID:39126919 SUPPORT In Vitro
"We report here, the generation of induced pluripotent stem cell (iPSC) line (IGIBi010-A) carrying a novel homozygous frameshift variant in SQSTM1 i.e. p.Leu251SerfsTer4."
Establishes the existence and genotype of the patient-derived line.
🐁

Animal Models

2
Zebrafish sqstm1 knockdown
Down-modulation of sqstm1 in zebrafish, generated specifically to test whether loss of the gene damages the cerebellum, in support of the human genetic finding.
Species
Zebrafish
Genotype
sqstm1 loss-of-function down-modulation
Publication
PMID:29959261
Pathograph links
Cerebellar and Brainstem Neuron Proteostatic Stress recapitulates fidelity: moderate Loss of sqstm1 produces a reproducible cerebellar structural phenotype, tying the gene directly to the cerebellar axis of the human disorder.
Limitations: A larval knockdown, not a stable biallelic null across the lifespan. It has no readout for vertical gaze palsy, dystonia or cognitive decline, and it reports cerebellar structure rather than the region-selective adult-onset degeneration seen in patients.
Readouts
Cerebellar structural integrity
Direction: DECREASED
Interpretation: Cerebellar axonal connectivity and gross structure degrade in proportion to sqstm1 loss.
Show evidence (1 reference)
PMID:29959261 SUPPORT Model Organism
"The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy."
Reports the cerebellar structural measurement behind this readout.
p62/Sqstm1 knockout mouse
The constitutive p62-null mouse. It develops age-dependent neurodegeneration, but by a tau-driven route with a systemic metabolic phenotype, neither of which is documented in human NADGP.
Species
Mouse
Genotype
Sqstm1 (p62) constitutive homozygous knockout
Publication
PMID:18346206
Pathograph links
Cerebellar and Brainstem Neuron Proteostatic Stress partially recapitulates fidelity: low Establishes that constitutive p62 loss is sufficient to cause neurodegeneration in a mammal, which is the claim the human disorder needs from this model.
Limitations: The mouse phenotype is a tau/neurofibrillary-tangle Alzheimer-like pathology with hippocampal and behavioural involvement, plus mature-onset obesity and insulin resistance. Human NADGP is a cerebellar-brainstem-basal ganglia syndrome; no tau pathology has been examined in patients and no metabolic phenotype is reported. The model therefore supports the sufficiency of p62 loss but not the regional pattern or the molecular route.
Show evidence (1 reference)
PMID:18346206 SUPPORT Model Organism
"we report age-dependent constitutive activation of glycogen synthase kinase 3beta, protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and neurodegeneration"
Supports treating the p62-null mouse as informative for neurodegeneration following constitutive p62 loss, while naming the tau route that differs from the human disease.
{ }

Source YAML

click to show 
name: SQSTM1-Related Childhood-Onset Neurodegeneration
creation_date: "2026-09-02T00:00:00Z"
category: Mendelian
synonyms:
- NADGP
- neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
- Childhood-onset neurodegeneration with ataxia, dystonia and gaze palsy
- Biallelic SQSTM1-related neurodegeneration
- p62/sequestosome-1 deficiency
description: >
  Childhood-onset neurodegeneration with ataxia, dystonia and gaze palsy (NADGP) is an
  ultra-rare autosomal recessive neurodegenerative disorder caused by biallelic
  loss-of-function variants in SQSTM1, the gene encoding the selective-autophagy cargo
  receptor p62/sequestosome-1. Early development is normal; affected children present in
  later childhood or adolescence with progressive gait ataxia and evolve a combined
  cerebellar, extrapyramidal and oculomotor syndrome — appendicular ataxia, dysarthria,
  dystonia, choreoathetosis, vertical supranuclear gaze palsy and mild cognitive decline.

  The zygosity split matters and is the reason this is a separate entry. SQSTM1 is far
  better known for two *dominant* diseases caused by heterozygous, usually missense,
  alleles: Paget disease of bone (recurrent UBA-domain p.Pro392Leu) and ALS/frontotemporal
  dementia. Those are allelic disorders of altered p62 function in adults. NADGP is
  instead a state of complete p62 absence, confirmed by immunoblot in patient fibroblasts,
  and every reported NADGP allele to date is predicted-null (nonsense, frameshift, splice,
  start-loss, or a synonymous change shown to disrupt splicing). No missense NADGP allele
  has been reported. The two disease groups therefore differ in zygosity, allele class,
  age of onset and affected organ system, and their evidence must not be merged.

  Mechanistically the disorder sits with the congenital disorders of autophagy. p62
  polymerises through its PB1 domain, binds ubiquitinated cargo through its UBA domain and
  delivers that cargo to the forming autophagosome through its LC3-interacting region. Its
  absence leaves selective autophagy without a cargo adaptor: patient and knockout cells
  fail to build ubiquitin-positive aggregates in response to misfolded-protein stress,
  autophagic flux decelerates, and the early PINK1-dependent steps of mitochondrial quality
  control are disrupted even though bulk mitochondrial clearance is preserved.

  A caveat that constrains everything downstream: no human neuropathology has been
  published. The step from cellular proteostatic and mitochondrial failure to
  region-selective degeneration of cerebellum, brainstem gaze centres and basal ganglia is
  inferred from imaging, from zebrafish sqstm1 knockdown and from p62-null mice, not
  demonstrated in patient tissue. It is curated here as an explicit knowledge gap rather
  than asserted.
references:
- reference: PMID:11992264
  title: "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone."
- reference: PMID:16286508
  title: "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death."
- reference: PMID:16517408
  title: "Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62."
- reference: PMID:17580304
  title: "p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy."
- reference: PMID:18346206
  title: "Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration."
- reference: PMID:20173742
  title: "The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1."
- reference: PMID:20525256
  title: "Niemann-Pick disease type C."
- reference: PMID:22084127
  title: "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."
- reference: PMID:22810120
  title: "Vertical supranuclear gaze palsy in Niemann-Pick type C disease."
- reference: PMID:27545679
  title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
- reference: PMID:29112993
  title: "Congenital Disorders of Autophagy: What a Pediatric Neurologist Should Know."
- reference: PMID:29959261
  title: "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration."
- reference: PMID:30638816
  title: "Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations."
- reference: PMID:31525130
  title: "Homozygous sequestosome 1 (SQSTM1) mutation: a rare cause for childhood-onset progressive cerebellar ataxia with vertical gaze palsy."
- reference: PMID:33891871
  title: "The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons."
- reference: PMID:34147300
  title: "Homozygous SQSTM1 nonsense variant identified in a patient with brainstem involvement."
- reference: PMID:35402641
  title: "Eye Movement Disorders in Movement Disorders."
- reference: PMID:35662390
  title: "Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy."
- reference: PMID:35957775
  title: "First report of novel mutation (c.790del) on SQSTM1 gene on a family with childhood onset of progressive cerebellar ataxia with vertical gaze palsy."
- reference: PMID:39126919
  title: "Generation and characterization of human-derived induced pluripotent stem cell line (IGIBi010-A) from a patient with neurodegenerative disease phenotype carrying mutation in SQSTM1/p62 gene."
- reference: PMID:39587727
  title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
- reference: PMID:41307082
  title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
disease_term:
  preferred_term: neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
  term:
    id: MONDO:0014940
    label: neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset
parents:
- Autosomal recessive cerebellar ataxia
- Congenital disorder of autophagy
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Biallelic — homozygous or compound heterozygous — loss-of-function SQSTM1 variants
    segregating in multiple independent, frequently consanguineous families. Obligate
    heterozygous carriers are reported clinically unaffected for this phenotype. This is
    the axis that separates NADGP from the dominant SQSTM1 disorders.
  evidence:
  - reference: PMID:27545679
    reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified three different biallelic loss-of-function variants in SQSTM1 in nine
      affected individuals from four families with a childhood- or adolescence-onset
      neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria,
      dystonia, vertical gaze palsy, and cognitive decline
    explanation: >-
      The defining report establishes biallelic loss-of-function inheritance across four
      independent families.
  - reference: PMID:29959261
    reference_title: "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study offers an accurate clinical characterization of this recently recognized
      neurodegenerative disorder caused by biallelic inactivating mutations in SQSTM1 and
      links this phenotype to defective selective autophagy.
    explanation: >-
      Independent replication of biallelic inactivating inheritance in three consanguineous
      families.
  - reference: PMID:39126919
    reference_title: "Generation and characterization of human-derived induced pluripotent stem cell line (IGIBi010-A) from a patient with neurodegenerative disease phenotype carrying mutation in SQSTM1/p62 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pathogenic variants in SQSTM1 gene are known to cause Neurodegeneration with ataxia,
      dystonia, and gaze palsy in autosomal recessive inheritance fashion.
    explanation: >-
      States the autosomal recessive mode of inheritance for this named phenotype.
genetic:
- name: SQSTM1
  gene_term:
    preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  association: CAUSATIVE
  variant_origin: GERMLINE
  features: >
    SQSTM1 (chr5q35.3) encodes p62/sequestosome-1, a 440-residue multidomain scaffold with
    PB1 self-oligomerisation, ZZ zinc-finger, TRAF6-binding, LC3-interacting (LIR),
    KEAP1-interacting (KIR) and ubiquitin-associated (UBA) domains. Every NADGP allele
    reported to date is predicted-null: nonsense (p.Arg96Ter, p.Glu19Ter, p.Glu280Ter),
    frameshift (p.Glu104fs, p.Leu251SerfsTer4, c.790del), canonical splice-site (c.301+2T>A),
    start-loss (c.1A>G), or a synonymous change that disrupts splicing (c.969G>A). No
    missense NADGP allele has been reported, in pointed contrast to the dominant allelic
    disorders, whose defining alleles are missense.
  evidence:
  - reference: PMID:29959261
    reference_title: "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 3 homozygous inactivating variants, including a splice site substitution
      (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a
      resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and
      c.934_936delinsTGA).
    explanation: >-
      Documents the null allele classes — splice-site and truncating — that characterise
      this disorder.
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both cases, initial workup was unremarkable, but whole-exome sequencing revealed a
      novel homozygous pathogenic truncating mutation, SQSTM1 (c.838G>T, p. Glu280Ter).
    explanation: >-
      A further homozygous truncating allele, recurrent in two unrelated Iranian families.
  - reference: PMID:35957775
    reference_title: "First report of novel mutation (c.790del) on SQSTM1 gene on a family with childhood onset of progressive cerebellar ataxia with vertical gaze palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous deletion variant that changes the frame shift in the SQSTM1 gene named
      c.790 Del A .T was detected in case childhood onset and progressive neurodegeneration
      with ataxia, and gaze palsy.
    explanation: >-
      An independent homozygous frameshift allele in the same phenotype.
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified compound heterozygous variants in SQSTM1(NM_003900.5): c.1A>G p.(Met1?)
      in the initial codon, and c.969G>A, located at the 3' end of exon 6, which is novel and
      seemingly a synonymous but is actually a truncating variant causing aberrant splicing.
    explanation: >-
      Compound heterozygosity for a start-loss and a splice-disrupting synonymous allele,
      showing that a nominally silent change can be a null allele in this gene.
pathophysiology:
- name: Biallelic SQSTM1 Loss-of-Function
  role: trigger
  biological_scale: MOLECULAR
  description: >
    Two null SQSTM1 alleles — nonsense, frameshift, canonical-splice, start-loss, or a
    synonymous change that disrupts splicing — are inherited from carrier parents. The
    resulting transcripts are degraded or encode truncated, non-functional protein.
  genes:
  - preferred_term: SQSTM1
    term:
      id: hgnc:11280
      label: SQSTM1
  evidence:
  - reference: PMID:27545679
    reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified three different biallelic loss-of-function variants in SQSTM1 in nine
      affected individuals from four families with a childhood- or adolescence-onset
      neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria,
      dystonia, vertical gaze palsy, and cognitive decline
    explanation: >-
      Establishes biallelic SQSTM1 loss of function as the initiating lesion.
  downstream:
  - target: Absence of p62/Sequestosome-1 Protein
    causal_link_type: DIRECT
    description: >-
      Null alleles on both chromosomes leave no functional p62 to be translated.
- name: Absence of p62/Sequestosome-1 Protein
  biological_scale: MOLECULAR
  description: >
    p62 protein is undetectable in patient cells. This is a complete-absence state rather
    than an altered-function state, which is the molecular distinction from the dominant
    SQSTM1 disorders, where a missense p62 is present but behaves abnormally.
  molecular_functions:
  - preferred_term: ubiquitin-binding autophagy cargo receptor activity of p62
    term:
      id: GO:0043130
      label: ubiquitin binding
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:27545679
    reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and
      found evidence of a defect in the early response to mitochondrial depolarization and
      autophagosome formation.
    explanation: >-
      Directly demonstrates absent p62 protein in patient-derived cells, establishing this
      node as a measured rather than inferred state.
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An SQSTM1 protein expression assay using urine-derived cells (UDCs) demonstrated that
      both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of
      premessenger RNA.
    explanation: >-
      Independent functional confirmation, in a second patient-derived cell type, that the
      alleles abolish normal p62 production.
  downstream:
  - target: Failure of Selective Autophagy Cargo Recognition
    causal_link_type: DIRECT
    description: >-
      p62 is the adaptor that couples ubiquitinated cargo to the autophagosome; without it
      the coupling step has no substrate-recognition module.
  - target: Blunted KEAP1-NRF2 Antioxidant Response
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - nrf2_axis_failure
    description: >-
      p62 also competes with NRF2 for the same binding site on KEAP1. Its absence is
      inferred to reduce NRF2 stabilisation and therefore antioxidant gene transcription.
      This edge is hypothesis-scoped and has not been demonstrated in patients.
- name: Failure of Selective Autophagy Cargo Recognition
  biological_scale: CELLULAR
  conforms_to: "disabled_macroautophagy#Failure of Cytoplasmic Quality Control"
  description: >
    Without p62 the cell cannot polymerise ubiquitinated cargo into sequestration-competent
    bodies or hand them to LC3 on the phagophore. Patient and knockout cells fail to form
    ubiquitin-positive aggregates under misfolded-protein stress and autophagic flux slows.
    Note that this is a cargo-recognition lesion, not a defect of the core autophagy
    machinery: the autophagosome can still be built, but selectively loading it fails.
  biological_processes:
  - preferred_term: macroautophagy
    term:
      id: GO:0016236
      label: macroautophagy
    modifier: DECREASED
  - preferred_term: aggrephagy
    term:
      id: GO:0035973
      label: aggrephagy
    modifier: DECREASED
  molecular_functions:
  - preferred_term: LC3-interacting region binding of p62 to the phagophore
    term:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:29959261
    reference_title: "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein
      aggregates in response to misfolded protein stress and decelerated autophagic flux.
    explanation: >-
      Directly demonstrates the cargo-handling and flux defect that defines this node.
  - reference: PMID:16286508
    reference_title: "p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      The depletion of p62 inhibited recruitment of LC3 to autophagosomes under starvation
      conditions.
    explanation: >-
      Establishes the normal p62-LC3 coupling step whose loss this node describes. Indirect
      because it is p62 depletion in a non-patient experimental system, not NADGP material.
  - reference: PMID:17580304
    reference_title: "p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Here we show for the first time a direct interaction between p62 and the autophagic
      effector proteins LC3A and -B
    explanation: >-
      Identifies the adaptor interaction the LIR motif mediates, which is what the
      molecular-function binding on this node describes: p62 bridges cargo to ATG8/LC3
      rather than binding ubiquitin at this end of the protein. Indirect because it maps
      the normal interaction in HeLa cells rather than measuring it in NADGP material.
  - reference: PMID:29112993
    reference_title: "Congenital Disorders of Autophagy: What a Pediatric Neurologist Should Know."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      ATG5-associated autosomal-recessive ataxia syndrome, SQSTM1/p62-associated
      childhood-onset neurodegeneration, and several forms of the hereditary spastic
      paraplegias.
    explanation: >-
      Places this disorder within the congenital disorders of autophagy. Indirect because it
      is a review classifying the disorder rather than reporting a measurement.
  downstream:
  - target: Impaired Mitochondrial Quality Control
    causal_link_type: DIRECT
    description: >-
      Damaged mitochondria are one of the cargo classes that p62 normally routes to the
      autophagosome.
  - target: Cerebellar and Brainstem Neuron Proteostatic Stress
    causal_link_type: DIRECT
    description: >-
      Undegraded ubiquitinated cargo accumulates in long-lived post-mitotic neurons, which
      have limited capacity to dilute it by division.
- name: Impaired Mitochondrial Quality Control
  biological_scale: CELLULAR
  description: >
    p62 loss disrupts the early, PINK1-dependent steps of mitophagy — PINK1 recruitment and
    ubiquitin phosphorylation on depolarised mitochondria — and alters mitochondrial gene
    expression and respiratory function. Importantly, bulk clearance of mitochondria is
    preserved, so the defect is best described as impaired mitochondrial function and
    early-response quality control rather than a mitophagy block.
  biological_processes:
  - preferred_term: autophagy of mitochondrion
    term:
      id: GO:0000422
      label: autophagy of mitochondrion
    modifier: DECREASED
  evidence:
  - reference: PMID:33891871
    reference_title: "The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show that SQSTM1 depletion causes altered mitochondrial gene expression and
      functionality, as well as autophagy flux, in iPSC-derived neurons.
    explanation: >-
      Demonstrates the mitochondrial consequence in a human neuronal context.
  - reference: PMID:33891871
    reference_title: "The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, SQSTM1 is not essential for mitophagy despite having a significant impact on
      early PINK1-dependent mitophagy processes including PINK1 recruitment and
      phosphorylation of ubiquitin on depolarized mitochondria.
    explanation: >-
      Delimits the claim: the lesion is in the early PINK1-dependent steps, not in
      mitochondrial clearance overall. Curated so this node is not overread as a mitophagy
      block.
  - reference: PMID:27545679
    reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and
      found evidence of a defect in the early response to mitochondrial depolarization and
      autophagosome formation.
    explanation: >-
      The same early mitochondrial-depolarisation response defect, measured in patient
      fibroblasts rather than an engineered knockout.
  downstream:
  - target: Cerebellar and Brainstem Neuron Proteostatic Stress
    causal_link_type: DIRECT
    description: >-
      Mitochondrial dysfunction compounds the proteostatic burden in neurons with high and
      sustained metabolic demand.
- name: Blunted KEAP1-NRF2 Antioxidant Response
  biological_scale: CELLULAR
  description: >
    p62's KEAP1-interacting region normally competes with NRF2 for the KEAP1 binding site,
    so p62 stabilises NRF2 and sustains antioxidant gene transcription. Complete p62 loss is
    therefore predicted to leave NRF2 less protected from KEAP1-directed degradation and the
    antioxidant response blunted. This node is an inference from the inverse experiment
    (p62 overproduction stabilises NRF2); it has not been measured in NADGP patients or
    patient cells, and is scoped to a hypothesis group for that reason.
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: DECREASED
  evidence:
  - reference: PMID:20173742
    reference_title: "The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type
      ubiquitin ligase for Nrf2.
    explanation: >-
      Establishes the molecular interaction on which this node depends.
  - reference: PMID:20173742
    reference_title: "The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Thus, an overproduction of p62 or a deficiency in autophagy competes with the
      interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and
      transcriptional activation of Nrf2 target genes.
    explanation: >-
      Indirect and inverted: the demonstrated direction is that excess p62 stabilises NRF2,
      from which blunted NRF2 signalling under complete p62 absence is inferred rather than
      shown.
  downstream:
  - target: Cerebellar and Brainstem Neuron Proteostatic Stress
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - nrf2_axis_failure
    description: >-
      Reduced antioxidant capacity is proposed to lower the threshold at which affected
      neurons decompensate. Not demonstrated in this disorder.
- name: Cerebellar and Brainstem Neuron Proteostatic Stress
  biological_scale: CELLULAR
  conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Neuron Insult"
  description: >
    Long-lived cerebellar and brainstem neurons carry the combined burden of undegraded
    ubiquitinated cargo, dysfunctional mitochondria and — hypothetically — reduced
    antioxidant reserve. This is the disorder-specific substitution into the conserved
    cerebellar-degeneration trigger node, whose module description explicitly admits
    impaired protein quality control as one of its heterogeneous initiating lesions.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:29959261
    reference_title: "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      The consequences of sqstm1 down-modulation on the structural integrity of the
      cerebellum in zebrafish documented a variable but reproducible phenotype characterized
      by cerebellum anomalies ranging from depletion of axonal connections to complete
      atrophy.
    explanation: >-
      Ties loss of sqstm1 specifically to cerebellar structural failure. Indirect because it
      is a zebrafish knockdown, not human tissue.
  - reference: PMID:18346206
    reference_title: "Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      we report age-dependent constitutive activation of glycogen synthase kinase 3beta,
      protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in
      adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and
      neurodegeneration
    explanation: >-
      Shows that constitutive p62 loss is sufficient to cause neurodegeneration in a mammal.
      Indirect: the mouse lesion is tau-driven and its relevance to human NADGP is unproven.
  downstream:
  - target: Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Inferred step. No human neuropathology has been published, so the transition from
      cellular stress to region-selective neuronal loss rests on imaging and model systems.
- name: Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia
  biological_scale: TISSUE
  description: >
    Progressive, bilateral and symmetric degeneration selectively involving cerebellar
    circuitry, the rostral brainstem supranuclear vertical-gaze pathways, and the basal
    ganglia, with milder diffuse cortical involvement. The regional pattern is read off the
    clinical syndrome and imaging rather than from tissue: cerebellar atrophy is variable
    and often absent on MRI, and brainstem lesions have been reported only once.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  - preferred_term: brainstem
    term:
      id: UBERON:0002298
      label: brainstem
  - preferred_term: basal ganglia
    term:
      id: UBERON:0002420
      label: basal ganglion
  evidence:
  - reference: PMID:29959261
    reference_title: "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To characterize clinically and molecularly an early-onset, variably progressive
      neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia,
      gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3
      consanguineous families.
    explanation: >-
      The combined cerebellar, oculomotor and extrapyramidal syndrome is the clinical
      signature of this regional distribution.
  - reference: PMID:34147300
    reference_title: "Homozygous SQSTM1 nonsense variant identified in a patient with brainstem involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case had brainstem lesions on brain magnetic resonance imaging that have not been
      previously reported.
    explanation: >-
      Direct radiological evidence of brainstem involvement, although reported in a single
      patient.
  downstream:
  - target: Progressive Gait Ataxia
    causal_link_type: DIRECT
    description: Loss of cerebellar cortical output produces truncal and gait incoordination.
  - target: Progressive Appendicular Ataxia
    causal_link_type: DIRECT
    description: >-
      The same loss of cerebellar output produces limb dysmetria and upper-limb clumsiness.
  - target: Dysarthria
    causal_link_type: DIRECT
    description: Cerebellar involvement of speech motor control.
  - target: Vertical Supranuclear Gaze Palsy
    causal_link_type: DIRECT
    description: Involvement of rostral midbrain supranuclear vertical-gaze pathways.
  - target: Oculomotor Apraxia
    causal_link_type: DIRECT
    description: >-
      Saccade-initiation failure in all directions, reflecting wider involvement of the
      brainstem and cerebellar saccadic circuitry than the vertical-gaze pathways alone.
  - target: Nystagmus
    causal_link_type: DIRECT
    description: >-
      Gaze-holding failure from loss of cerebellar control of the neural integrator.
  - target: Tremor
    causal_link_type: DIRECT
    description: >-
      Intention tremor follows cerebellar outflow involvement; head tremor is reported with
      it in the same patient.
  - target: Bradykinesia with Limb Rigidity
    causal_link_type: DIRECT
    description: Basal ganglia involvement producing a hypokinetic-rigid pattern.
  - target: Dystonia
    causal_link_type: DIRECT
    description: Basal ganglia involvement.
  - target: Choreoathetosis
    causal_link_type: DIRECT
    description: Basal ganglia involvement producing hyperkinetic movement.
  - target: Cognitive Decline
    causal_link_type: DIRECT
    description: Diffuse cortical and subcortical involvement.
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
    description: >-
      Where cerebellar tissue loss is sufficient it becomes visible on MRI, though it
      frequently is not.
mechanistic_hypotheses:
- hypothesis_group_id: nrf2_axis_failure
  hypothesis_label: Blunted KEAP1-NRF2 antioxidant signalling contributes to neuronal loss
  status: EMERGING
  description: >
    Beyond its cargo-receptor role, p62 sequesters KEAP1 and thereby stabilises NRF2. The
    proposal is that complete p62 absence leaves NRF2 under-protected, blunts the antioxidant
    transcriptional programme and lowers the threshold at which stressed cerebellar and
    brainstem neurons decompensate. The supporting biochemistry is established, but only in
    the opposite direction — p62 overproduction stabilising NRF2 — and no NADGP patient or
    patient-derived cell has been assayed for NRF2 target-gene output. The hypothesis is
    curated separately because it is the one mechanistic branch here that would be directly
    therapeutically actionable if confirmed.
phenotypes:
- category: Neurologic
  name: Progressive Gait Ataxia
  description: >
    Progressive gait ataxia is the usual presenting sign, beginning in later childhood or
    adolescence after normal early development, and evolving to appendicular ataxia.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27545679
    reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified three different biallelic loss-of-function variants in SQSTM1 in nine
      affected individuals from four families with a childhood- or adolescence-onset
      neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria,
      dystonia, vertical gaze palsy, and cognitive decline
    explanation: >-
      Gait abnormality and ataxia head the list of defining features in the index cohort.
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical examination revealed frozen eye movements, gait ataxia, and dysarthria.
    explanation: >-
      Gait ataxia on examination in an independently reported patient.
  - reference: PMID:31525130
    reference_title: "Homozygous sequestosome 1 (SQSTM1) mutation: a rare cause for childhood-onset progressive cerebellar ataxia with vertical gaze palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      We describe here a case of progressive childhood-onset cerebellar ataxia with vertical
      supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging
      (MRI) of brain.
    explanation: >-
      Establishes progressive childhood-onset cerebellar ataxia as the presenting syndrome.
      Indirect for this node because the report names the cerebellar syndrome as a whole
      rather than the gait component specifically.
- category: Neurologic
  name: Progressive Appendicular Ataxia
  description: >
    Limb (appendicular) incoordination accompanies the gait disturbance and is scoped here
    specifically to the appendicular component — dysmetria on finger-to-nose testing, upper
    limb clumsiness and impaired handwriting — to keep it distinct from the truncal and gait
    ataxia curated separately above. Both components are present in established disease.
  phenotype_term:
    preferred_term: Progressive appendicular (limb) ataxia
    term:
      id: HP:0002070
      label: Limb ataxia
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both limb and truncal ataxia were evident.
    explanation: >-
      Records limb ataxia as a component separable from truncal involvement in a
      genetically confirmed patient.
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional findings included dysmetria on the finger-to-nose test and an abnormal
      tandem gait.
    explanation: >-
      Dysmetria on finger-to-nose testing is the appendicular sign this phenotype names.
- category: Neurologic
  name: Dysarthria
  description: >
    Progressive dysarthria of cerebellar type, present in essentially all reported patients
    and a major contributor to communication disability.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:27545679
    reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified three different biallelic loss-of-function variants in SQSTM1 in nine
      affected individuals from four families with a childhood- or adolescence-onset
      neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria,
      dystonia, vertical gaze palsy, and cognitive decline
    explanation: >-
      Dysarthria is named among the defining features of the index cohort.
- category: Neurologic
  name: Vertical Supranuclear Gaze Palsy
  description: >
    Vertical supranuclear gaze palsy is the oculomotor hallmark and the feature that most
    strongly directs the differential towards Niemann-Pick disease type C. It may be absent
    at presentation and appear only on follow-up.
  phenotype_term:
    preferred_term: Vertical supranuclear gaze palsy
    term:
      id: HP:0000511
      label: Vertical supranuclear gaze palsy
  frequency: FREQUENT
  evidence:
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biallelic pathogenic variants of SQSTM1 can cause child-onset and multisystem
      neurodegeneration, including cerebellar ataxia, dystonia, and vertical gaze palsy
      (NADGP)
    explanation: >-
      Names vertical gaze palsy as one of the three phenotype-defining features.
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During 2 years of follow-up, the second patient developed gaze palsy.
    explanation: >-
      Documents that gaze palsy can emerge after the ataxia, so its absence at first
      assessment does not exclude the diagnosis.
- category: Neurologic
  name: Dystonia
  description: >
    Dystonia — limb, cervical or generalised — is a common extrapyramidal feature and part of
    the syndrome name.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:30638816
    reference_title: "Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous sequestomosome-1 gene mutations have been recently linked to
      neurodegeneration with dystonia, ataxia and gaze palsy.
    explanation: >-
      Dystonia is one of the three features by which the disorder is defined.
- category: Neurologic
  name: Choreoathetosis
  description: >
    Chorea and athetosis occur in a substantial minority and have been reported as the
    presenting hyperkinetic feature in adolescence, so NADGP belongs in the differential for
    hereditary chorea.
  phenotype_term:
    preferred_term: Choreoathetosis
    term:
      id: HP:0001266
      label: Choreoathetosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30638816
    reference_title: "Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the previously described syndrome characterized by cerebellar ataxia,
      dystonia, choreoathetosis, cognitive impairment and gaze palsy, two subjects presented
      with iridoplegia.
    explanation: >-
      Names choreoathetosis as part of the established syndrome.
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients experienced chorea during adolescence.
    explanation: >-
      Chorea in adolescence in an independently reported family.
- category: Neurologic
  name: Cognitive Decline
  description: >
    Cognitive decline is generally mild to moderate and insidious, in contrast with the motor
    disability, which dominates the functional picture.
  phenotype_term:
    preferred_term: Mental deterioration
    term:
      id: HP:0001268
      label: Mental deterioration
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:27545679
    reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified three different biallelic loss-of-function variants in SQSTM1 in nine
      affected individuals from four families with a childhood- or adolescence-onset
      neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria,
      dystonia, vertical gaze palsy, and cognitive decline
    explanation: >-
      Cognitive decline is named among the defining features of the index cohort.
- category: Neurologic
  name: Myoclonus
  description: >
    Myoclonus is a minority feature, reported alongside the core cerebellar and oculomotor
    findings.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34147300
    reference_title: "Homozygous SQSTM1 nonsense variant identified in a patient with brainstem involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a patient with progressive cerebellar ataxia and gaze palsy, as well as
      myoclonus, cognitive impairment and growth retardation with a homozygous SQSTM1 variant
      NM_003900.5:c.55G > T (p.Glu19*).
    explanation: >-
      Reports myoclonus in a genetically confirmed patient.
- category: Ophthalmologic
  name: Oculomotor Apraxia
  description: >
    Difficulty initiating voluntary saccades in all directions ("frozen eye"), reported on
    examination in a genetically confirmed patient. It is a separate oculomotor sign from
    the vertical supranuclear gaze palsy above, and its presence puts the ataxia with
    oculomotor apraxia syndromes and ataxia-telangiectasia into the differential.
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed oculomotor apraxia, with difficulty moving his eyes
      in all directions (frozen eye).
    explanation: >-
      Names oculomotor apraxia on examination in a patient homozygous for a truncating
      SQSTM1 allele.
- category: Ophthalmologic
  name: Nystagmus
  description: >
    Gaze-directional nystagmus has been recorded alongside the gaze palsy and cerebellar
    ataxia in a genetically confirmed patient. It is a minority finding and is not part of
    the syndrome definition.
  phenotype_term:
    preferred_term: Gaze-evoked nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disturbance, gaze palsy, gaze directional nystagmus, choric gait
      disturbance, and cerebellar ataxia were noted
    explanation: >-
      Records gaze-directional nystagmus in a patient with compound heterozygous null
      SQSTM1 alleles. The HP binding is the general nystagmus term; HPO's gaze-evoked
      qualifier is carried in preferred_term.
- category: Neurologic
  name: Tremor
  description: >
    Head and intention tremor were the presenting involuntary movements in one of two
    siblings reported with the same homozygous truncating allele, appearing at age eight
    alongside gait instability.
  phenotype_term:
    preferred_term: Head and intention tremor
    term:
      id: HP:0001337
      label: Tremor
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      he began experiencing involuntary movements, gait instability, head tremors, lip
      smacking, periodic limb movements during sleep, and intention tremors in his hands
    explanation: >-
      Documents head and intention tremor as presenting features in a genetically confirmed
      patient.
- category: Neurologic
  name: Bradykinesia with Limb Rigidity
  description: >
    Slowed movement with mild upper-limb rigidity has been described on examination,
    a parkinsonian pattern layered on the cerebellar syndrome. No reported patient has
    been given a formal diagnosis of parkinsonism and no dopaminergic imaging has been
    published, so the binding is to bradykinesia rather than to HP:0001300 Parkinsonism.
  phenotype_term:
    preferred_term: Bradykinesia with mild upper-limb rigidity
    term:
      id: HP:0002067
      label: Bradykinesia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He exhibited slow movements, gait ataxia (clumsy gait), dysarthria, and mild rigidity
      in the upper limbs.
    explanation: >-
      Records slowed movement and limb rigidity on examination in a genetically confirmed
      patient.
- category: Auditory
  name: Hearing Loss
  description: >
    Hearing loss appears in the cumulative published phenotype but was not present in every
    reported family, and no audiometric characterisation of the deficit has been published
    for this disorder.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Additional symptoms previously described include dystonia, choreoathetoid movements,
      dyskinesia, hearing loss, and hypogonadotropic hypogonadism
    explanation: >-
      Lists hearing loss among features reported in the prior published cases. Indirect
      because the statement summarises earlier reports rather than a measurement made in
      the patients of this paper, in whom it was explicitly absent.
- category: Autonomic
  name: Orthostatic Hypotension
  description: >
    Dysautonomia — orthostatic hypotension with sudomotor dysfunction — was added to the
    phenotype in a later series and is a recognised non-motor component.
  phenotype_term:
    preferred_term: Orthostatic hypotension
    term:
      id: HP:0001278
      label: Orthostatic hypotension
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30638816
    reference_title: "Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, we report dysautonomic features such as orthostatic hypotension and
      sudomotor dysfunction, along with other non-motor symptoms.
    explanation: >-
      Reports orthostatic hypotension as a dysautonomic feature of the disorder.
- category: Autonomic
  name: Sudomotor Dysfunction
  description: >
    Abnormal sweating accompanies the orthostatic intolerance in the same reported patients.
  phenotype_term:
    preferred_term: Sudomotor dysfunction
    term:
      id: HP:0040127
      label: Abnormal sweat homeostasis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30638816
    reference_title: "Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, we report dysautonomic features such as orthostatic hypotension and
      sudomotor dysfunction, along with other non-motor symptoms.
    explanation: >-
      Reports sudomotor dysfunction alongside orthostatic hypotension.
- category: Ophthalmologic
  name: Iridoplegia
  description: >
    Pupillary involvement (iridoplegia) was an unexpected addition to the phenotype, reported
    in two patients from the same series that described the dysautonomia.
  phenotype_term:
    preferred_term: Iridoplegia
    term:
      id: HP:0007686
      label: Abnormal pupillary function
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30638816
    reference_title: "Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the previously described syndrome characterized by cerebellar ataxia,
      dystonia, choreoathetosis, cognitive impairment and gaze palsy, two subjects presented
      with iridoplegia.
    explanation: >-
      Reports iridoplegia in two patients. The HP binding is the parent term for abnormal
      pupillary function; HPO has no exact iridoplegia term, so the specificity is carried in
      preferred_term.
- category: Neuroimaging
  name: Cerebellar Atrophy
  description: >
    Cerebellar atrophy is reported in many patients but is emphatically not obligate: two
    independent reports document a normal brain MRI or an absence of significant cerebellar
    atrophy in genetically confirmed patients. A normal MRI does not exclude the diagnosis,
    which is the single most important imaging caveat in this disorder.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  frequency: VARIABLE
  evidence:
  - reference: PMID:29112993
    reference_title: "Congenital Disorders of Autophagy: What a Pediatric Neurologist Should Know."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      Predominant involvement of the long white matter tracts and the cerebellum are anatomic
      and imaging hallmarks, with common findings that include a thinning of the corpus
      callosum and cerebellar hypoplasia or atrophy.
    explanation: >-
      Group-level imaging statement across the congenital disorders of autophagy, of which
      this disorder is one. Indirect because the claim is made for the class rather than
      measured in NADGP patients specifically.
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebellar ataxia is a characteristic manifestation of this disorder; however, brain
      magnetic resonance imaging studies have not shown significant cerebellar atrophy.
    explanation: >-
      Directly contradicts cerebellar atrophy as a constant feature; these genetically
      confirmed patients had ataxia without significant atrophy.
  - reference: PMID:31525130
    reference_title: "Homozygous sequestosome 1 (SQSTM1) mutation: a rare cause for childhood-onset progressive cerebellar ataxia with vertical gaze palsy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe here a case of progressive childhood-onset cerebellar ataxia with vertical
      supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging
      (MRI) of brain.
    explanation: >-
      A genetically confirmed patient with an entirely normal brain MRI, refuting any
      requirement for cerebellar atrophy.
- category: Neuroimaging
  name: Brainstem MRI Signal Abnormality
  description: >
    Brainstem signal lesions have been reported in a single patient and expand the
    neuroradiological spectrum; they are not a general feature.
  phenotype_term:
    preferred_term: Abnormal brainstem MRI signal intensity
    term:
      id: HP:0012747
      label: Abnormal brainstem MRI signal intensity
  frequency: VERY_RARE
  evidence:
  - reference: PMID:34147300
    reference_title: "Homozygous SQSTM1 nonsense variant identified in a patient with brainstem involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our case had brainstem lesions on brain magnetic resonance imaging that have not been
      previously reported.
    explanation: >-
      The single report of brainstem MRI lesions in this disorder.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: >-
    Ultra-rare. A 2025 review counted 27 reported cases carrying 11 distinct SQSTM1 alleles;
    additional single-family reports have appeared since. No prevalence or incidence estimate
    has been published and no registry exists.
  evidence:
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only 27 cases have been reported, with 11 different mutations affecting SQSTM1.
    explanation: >-
      Gives the published case count, which is the only quantitative occurrence figure
      available for this disorder.
progression:
- phase: Presymptomatic childhood
  notes: >
    Early development is normal. No presymptomatic biomarker or imaging change has been
    described, and no intervention window has been studied because no disease-modifying
    therapy exists to deploy in one.
- phase: Onset with gait ataxia
  notes: >
    Presentation in later childhood or adolescence, typically with recurrent falls, unsteady
    gait and emerging dysarthria. Initial metabolic and routine workup is characteristically
    unremarkable.
  evidence:
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The first patient was a 12-year-old boy of Iraqi and Iranian descent, who presented with
      a 3-year history of recurrent falls, swaying while walking, and difficulties with
      writing and speech.
    explanation: >-
      A representative presentation: falls and gait disturbance in the first decade, with
      speech involvement.
- phase: Established combined cerebellar-extrapyramidal-oculomotor syndrome
  notes: >
    Appendicular ataxia, dysarthria, dystonia and choreoathetosis are joined by vertical
    supranuclear gaze palsy, which may appear only on follow-up. Mild cognitive decline
    becomes apparent. Dysautonomia emerges in a subset.
  evidence:
  - reference: PMID:29959261
    reference_title: "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To characterize clinically and molecularly an early-onset, variably progressive
      neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia,
      gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3
      consanguineous families.
    explanation: >-
      Describes the established combined syndrome.
- phase: Advanced motor disability
  notes: >
    Slow but relentless progression to loss of independent ambulation, commonly in young
    adulthood, with severe dysarthria. Patients survive into adult life; no disease-specific
    survival data have been published. Progression rate varies between and within families
    for reasons that are unexplained.
diagnosis:
- name: Next-generation sequencing
  description: >
    Diagnosis is made by identifying biallelic loss-of-function SQSTM1 variants on clinical
    exome or genome sequencing. There is no biochemical screening test and no
    disease-specific imaging finding — MRI is frequently normal — so sequencing is the
    definitive step. Every reported family was ascertained this way after an unremarkable
    metabolic and routine workup, which is itself part of the diagnostic pattern.
  diagnosis_term:
    preferred_term: clinical exome or genome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:31525130
    reference_title: "Homozygous sequestosome 1 (SQSTM1) mutation: a rare cause for childhood-onset progressive cerebellar ataxia with vertical gaze palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case highlights the importance of next-generation sequencing in the diagnosis of
      inherited ataxia syndromes.
    explanation: >-
      States that next-generation sequencing is the diagnostic route for this presentation.
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both cases, initial workup was unremarkable, but whole-exome sequencing revealed a
      novel homozygous pathogenic truncating mutation, SQSTM1 (c.838G>T, p. Glu280Ter).
    explanation: >-
      Shows the diagnostic sequence in practice: unremarkable first-line workup followed by
      exome sequencing that establishes the genetic diagnosis.
- name: p62/SQSTM1 immunoblot on patient-derived cells
  description: >
    Immunoblotting patient fibroblasts or urine-derived cells for p62/SQSTM1 demonstrates
    complete absence of the protein. This is the functional confirmation that a candidate
    allele pair is null, and it is what distinguishes this disorder from the dominant
    SQSTM1 diseases, in which an abnormal protein is present.
  diagnosis_term:
    preferred_term: p62/SQSTM1 immunoblot
    term:
      id: NCIT:C16357
      label: Western Blotting
  evidence:
  - reference: PMID:27545679
    reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts and
      found evidence of a defect in the early response to mitochondrial depolarization and
      autophagosome formation.
    explanation: >-
      Establishes the absent-protein immunoblot result in patient fibroblasts.
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunoblotting showed that the SQSTM1 was absent in the UDCs of Patients 1 and 2
    explanation: >-
      The same absent-protein result obtained in a second, non-invasively sampled patient
      cell type.
- name: Urine-derived cell functional assay for variants of uncertain significance
  description: >
    Where sequencing returns a variant whose effect is not obvious — the reported case is a
    synonymous change at the 3' end of exon 6 that in fact abolishes splicing — culturing
    urine-derived cells and assaying SQSTM1 expression resolves it without a skin biopsy.
    NCIT has no clinical-action term for this assay, so no term is bound.
  diagnosis_term:
    preferred_term: urine-derived cell SQSTM1 expression and splicing assay
  evidence:
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An SQSTM1 protein expression assay using urine-derived cells (UDCs) demonstrated that
      both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of
      premessenger RNA.
    explanation: >-
      Demonstrates the assay resolving two variants, one of them a nominally synonymous
      change, into confirmed null alleles.
differential_diagnoses:
- name: Niemann-Pick disease type C
  disease_term:
    preferred_term: Niemann-Pick disease type C
    term:
      id: MONDO:0018982
      label: Niemann-Pick disease type C
  description: >
    The principal phenocopy. Both are autosomal recessive, both begin in childhood or
    adolescence after normal early development, and both combine cerebellar ataxia,
    dysarthria, dystonia and cognitive decline with vertical supranuclear gaze palsy —
    which is the most characteristic sign of Niemann-Pick type C and the oculomotor
    hallmark of this disorder. A child with progressive ataxia and vertical gaze palsy
    should be evaluated for both.
  distinguishing_features:
  - >-
    Niemann-Pick type C is neurovisceral: the neurological syndrome is usually preceded by
    systemic signs, either neonatal cholestatic jaundice or splenomegaly and
    hepatosplenomegaly in infancy and childhood. Biallelic SQSTM1 disease is purely
    neurological and no visceral involvement has been reported in it.
  - >-
    Gelastic cataplexy is a further Niemann-Pick type C discriminator and has never been
    reported in biallelic SQSTM1 disease.
  - >-
    Niemann-Pick type C is confirmed biochemically by filipin staining of cultured
    fibroblasts and by plasma oxysterols, and genetically by NPC1 or NPC2 variants; biallelic
    SQSTM1 disease has no biochemical marker and is confirmed by sequencing alone.
  - >-
    Niemann-Pick type C has a licensed disease-specific therapy in Europe and several other
    countries; biallelic SQSTM1 disease has none, so the distinction changes management.
  evidence:
  - reference: PMID:20525256
    reference_title: "Niemann-Pick disease type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most characteristic sign is vertical supranuclear gaze palsy.
    explanation: >-
      Establishes vertical supranuclear gaze palsy as the characteristic sign of
      Niemann-Pick type C, which is the feature shared with this disorder.
  - reference: PMID:20525256
    reference_title: "Niemann-Pick disease type C."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in
      older children and adults
    explanation: >-
      Niemann-Pick type C's own differential is stated as the same clinical combination this
      disorder presents with, so the relationship is symmetric.
  - reference: PMID:22810120
    reference_title: "Vertical supranuclear gaze palsy in Niemann-Pick type C disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VSGP is present in approximately 65 % of the cases and is, with gelastic cataplexy, an
      important risk indicator for NP-C.
    explanation: >-
      Quantifies how often the shared sign occurs in Niemann-Pick type C and names gelastic
      cataplexy as the accompanying discriminator.
- name: Ataxia-telangiectasia and the ataxia with oculomotor apraxia syndromes
  disease_term:
    preferred_term: ataxia telangiectasia
    term:
      id: MONDO:0008840
      label: ataxia telangiectasia
  description: >
    Childhood-onset progressive ataxia with an oculomotor sign is the shared presentation.
    Oculomotor apraxia is reported in this disorder, and it is the defining eye finding of
    ataxia-telangiectasia and the ataxia with oculomotor apraxia syndromes, so those
    conditions were the working diagnoses in reported SQSTM1 patients before sequencing.
  distinguishing_features:
  - >-
    Oculocutaneous telangiectasia, raised serum alpha-fetoprotein, immunodeficiency and
    cancer predisposition mark ataxia-telangiectasia and none of them occurs in biallelic
    SQSTM1 disease.
  - >-
    Telangiectasia and alpha-fetoprotein were explicitly looked for and normal in the
    reported SQSTM1 patients, which is how the two were separated at the bedside before
    sequencing.
  - >-
    Vertical supranuclear gaze palsy is a defining feature of biallelic SQSTM1 disease and
    is not a feature of ataxia-telangiectasia.
  evidence:
  - reference: PMID:35402641
    reference_title: "Eye Movement Disorders in Movement Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      In ataxia, nystagmus is common, but other findings such as oculomotor apraxia,
      supranuclear gaze palsy, impaired fixation, or saccadic pursuit can contribute to
      diagnoses such as ataxia with oculomotor apraxia, Niemann-Pick type C, or ataxia
      telangiectasia.
    explanation: >-
      Places oculomotor apraxia and supranuclear gaze palsy — both curated as phenotypes
      here — in the diagnostic path toward these conditions. Indirect because it is an
      educational review of eye signs, not a study of SQSTM1 patients.
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, myoclonus, chorea, dystonia, and telangiectasia were absent.
    explanation: >-
      Records that telangiectasia was specifically looked for and absent in a SQSTM1
      patient with oculomotor apraxia, which is how the two are separated clinically.
- name: Wilson disease
  disease_term:
    preferred_term: Wilson disease
    term:
      id: MONDO:0010200
      label: Wilson disease
  description: >
    A treatable autosomal recessive cause of childhood and adolescent movement disorder
    with dystonia, tremor, dysarthria and cognitive change, so it is screened for in every
    child presenting the way these patients do. Missing it has direct consequences, since
    Wilson disease is treatable and this disorder is not.
  distinguishing_features:
  - >-
    Normal serum copper and ceruloplasmin exclude Wilson disease and were documented in the
    reported SQSTM1 patients.
  - >-
    Kayser-Fleischer rings and hepatic involvement occur in Wilson disease and have not been
    reported in biallelic SQSTM1 disease.
  - >-
    Vertical supranuclear gaze palsy and a progressive cerebellar syndrome point away from
    Wilson disease and toward this disorder.
  evidence:
  - reference: PMID:41307082
    reference_title: "Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extensive laboratory investigations, including hematological parameters, renal and
      liver function tests, serum albumin, thyroid function, cholesterol, triglycerides,
      alpha-fetoprotein, copper, and ceruloplasmin levels, were all within normal limits.
    explanation: >-
      Documents that copper and ceruloplasmin were measured and normal, which is the step
      that excludes Wilson disease in these patients.
  - reference: PMID:35402641
    reference_title: "Eye Movement Disorders in Movement Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Gaze impersistence in a patient with chorea suggests Huntington's disease, but in a
      patient with dystonia or tremor, Wilson's disease is more likely.
    explanation: >-
      Places Wilson disease in the differential reached from the dystonia and tremor curated
      here. Indirect because it is a review of eye signs rather than a SQSTM1 study.
- name: Hereditary chorea syndromes
  description: >
    Chorea and athetosis were the presenting hyperkinetic features in an adolescent-onset
    family, and the authors of that report argue explicitly that this disorder belongs in
    the differential for hereditary chorea alongside Huntington disease and the other
    inherited choreas.
  distinguishing_features:
  - >-
    The inherited choreas are separated from one another by their own genetic tests; no
    clinical feature does it alone.
  - >-
    Chorea accompanied by cerebellar ataxia, vertical supranuclear gaze palsy and either
    consanguinity or affected siblings points toward biallelic SQSTM1 disease.
  - >-
    Chorea occurs in only a minority of reported SQSTM1 patients and is never the whole
    picture, so its absence does not exclude the diagnosis.
  evidence:
  - reference: PMID:39587727
    reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our findings suggest that NADGP should be considered as a differential diagnosis of
      hereditary chorea
    explanation: >-
      The authors state the differential-diagnosis relationship directly.
- name: Other inherited childhood-onset cerebellar ataxias
  description: >
    Before the gene was known these children were classified simply as inherited ataxia.
    The combination that should raise this specific diagnosis is progressive cerebellar
    ataxia with an ophthalmological abnormality and cognitive impairment, which the case
    reports converge on as the referral pattern for sequencing.
  distinguishing_features:
  - >-
    No single clinical feature separates this disorder from the other autosomal recessive
    childhood ataxias, and MRI is frequently normal, so the separation is genetic.
  - >-
    Vertical supranuclear gaze palsy together with dystonia narrows the field but does not
    close it.
  evidence:
  - reference: PMID:34147300
    reference_title: "Homozygous SQSTM1 nonsense variant identified in a patient with brainstem involvement."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Homozygous SQSTM1 variant should be considered in the differential diagnosis in
      patients presenting with cerebellar findings, gaze palsy, and cognitive impairment to
      facilitate early diagnosis and genetic counseling.
    explanation: >-
      States the clinical trigger for placing this disorder in the inherited-ataxia
      differential.
  - reference: PMID:31525130
    reference_title: "Homozygous sequestosome 1 (SQSTM1) mutation: a rare cause for childhood-onset progressive cerebellar ataxia with vertical gaze palsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SQSTM1 mutation should be considered in the differential diagnosis in a patient with
      both cerebellar ataxia and ophthalmological manifestations.
    explanation: >-
      Independently states the same differential-diagnosis rule from a second case report.
treatments:
- name: Physical Therapy and Rehabilitation
  description: >
    Physiotherapy for gait, balance and falls prevention, and maintenance of function as
    ambulation declines. No disease-specific rehabilitation protocol has been published;
    practice mirrors that for other childhood-onset ataxia-dystonia syndromes.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Speech and Language Therapy
  description: >
    Management of progressive cerebellar dysarthria and, in later disease, of communication
    and swallowing.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Speech Language Therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
- name: Genetic Counseling
  description: >
    Counselling of consanguineous and carrier couples on the 25% recurrence risk, with
    carrier testing of relatives and prenatal or preimplantation testing once the familial
    variants are known. This is the only intervention with a preventive effect at family
    level.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  target_mechanisms:
  - target: Biallelic SQSTM1 Loss-of-Function
    description: >-
      Acts on the initiating genetic lesion at the level of recurrence risk rather than in an
      affected individual.
- name: Supportive and Multidisciplinary Care
  description: >
    Multidisciplinary neurological, rehabilitative and educational support, management of
    orthostatic hypotension where dysautonomia is present, and falls prevention. No
    disease-modifying therapy exists.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
experimental_models:
- name: Patient dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >
    Fibroblasts from affected individuals in the index cohort, used to confirm absence of p62
    protein and to assay the response to mitochondrial depolarisation and autophagosome
    formation.
  publication: PMID:27545679
  modeled_mechanisms:
  - target: Absence of p62/Sequestosome-1 Protein
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      Direct patient material establishing the complete-absence state at protein level.
    limitations: >-
      Fibroblasts are non-neuronal, so they establish the molecular lesion but not the
      neuron-specific consequences.
    readouts:
    - name: p62/SQSTM1 protein abundance on immunoblot
      target: Absence of p62/Sequestosome-1 Protein
      direction: ABOLISHED
      interpretation: >-
        Absent p62 protein confirms the null state predicted by the biallelic alleles.
      evidence:
      - reference: PMID:27545679
        reference_title: "Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          We confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts
          and found evidence of a defect in the early response to mitochondrial depolarization
          and autophagosome formation.
        explanation: >-
          Reports the immunoblot measurement behind this readout.
- name: Patient urine-derived cells
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >
    Urine-derived cells from affected siblings, used as a non-invasive functional assay to
    resolve a variant of uncertain significance — a synonymous change that proved to disrupt
    splicing.
  publication: PMID:39587727
  modeled_mechanisms:
  - target: Absence of p62/Sequestosome-1 Protein
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      Establishes that both alleles fail to produce normally spliced SQSTM1 transcript,
      supporting a null state without requiring a skin biopsy.
    limitations: >-
      Non-neuronal, and the assay reports on splicing and protein expression rather than on
      autophagic function.
    evidence:
    - reference: PMID:39587727
      reference_title: "A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        An SQSTM1 protein expression assay using urine-derived cells (UDCs) demonstrated that
        both variants (c.1A>G and c.969G>A) were unable to induce normal splicing of
        premessenger RNA.
      explanation: >-
        Supports treating urine-derived cells as informative for the p62-absence node.
- name: SQSTM1-knockout human iPSC-derived cortical neurons
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >
    CRISPR knockout of SQSTM1 in human induced pluripotent stem cells differentiated to
    cortical neurons, used to dissect the mitochondrial and autophagic consequences of p62
    loss in a human neuronal context.
  publication: PMID:33891871
  modeled_mechanisms:
  - target: Impaired Mitochondrial Quality Control
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces altered mitochondrial gene expression, respiratory function and autophagic
      flux, and localises the mitophagy lesion to the early PINK1-dependent steps.
    limitations: >-
      Cortical rather than cerebellar or brainstem neuronal identity, an engineered knockout
      rather than patient genotype, and a two-dimensional culture that cannot report the
      region-selective vulnerability that defines the human disease.
    readouts:
    - name: Mitochondrial gene expression and respiratory function
      target: Impaired Mitochondrial Quality Control
      direction: ALTERED
      interpretation: >-
        Mitochondrial function, not mitochondrial clearance, is the affected axis.
      evidence:
      - reference: PMID:33891871
        reference_title: "The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          These findings suggest that SQSTM1 is important for mitochondrial function rather
          than clearance.
        explanation: >-
          States the direction and nature of the measured mitochondrial change.
    evidence:
    - reference: PMID:33891871
      reference_title: "The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that SQSTM1 depletion causes altered mitochondrial gene expression and
        functionality, as well as autophagy flux, in iPSC-derived neurons.
      explanation: >-
        Supports treating this model as informative for the mitochondrial quality-control
        node.
- name: Patient iPSC line IGIBi010-A
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >
    An induced pluripotent stem cell line derived from a patient homozygous for the
    p.Leu251SerfsTer4 frameshift allele. It is a resource rather than a completed experiment:
    no disease phenotype has yet been reported from it.
  publication: PMID:39126919
  modeled_mechanisms:
  - target: Absence of p62/Sequestosome-1 Protein
    relationship: MEASURES
    fidelity: UNKNOWN
    description: >-
      Carries a patient null genotype and is available for differentiation into
      disease-relevant neuronal lineages.
    limitations: >-
      A characterised line only. No differentiated phenotype, no isogenic control comparison
      and no functional result have been published, so it cannot yet support a mechanistic
      claim.
    evidence:
    - reference: PMID:39126919
      reference_title: "Generation and characterization of human-derived induced pluripotent stem cell line (IGIBi010-A) from a patient with neurodegenerative disease phenotype carrying mutation in SQSTM1/p62 gene."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We report here, the generation of induced pluripotent stem cell (iPSC) line
        (IGIBi010-A) carrying a novel homozygous frameshift variant in SQSTM1 i.e.
        p.Leu251SerfsTer4.
      explanation: >-
        Establishes the existence and genotype of the patient-derived line.
animal_models:
- name: Zebrafish sqstm1 knockdown
  species: Zebrafish
  genotype: sqstm1 loss-of-function down-modulation
  publication: PMID:29959261
  description: >
    Down-modulation of sqstm1 in zebrafish, generated specifically to test whether loss of the
    gene damages the cerebellum, in support of the human genetic finding.
  modeled_mechanisms:
  - target: Cerebellar and Brainstem Neuron Proteostatic Stress
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of sqstm1 produces a reproducible cerebellar structural phenotype, tying the gene
      directly to the cerebellar axis of the human disorder.
    limitations: >-
      A larval knockdown, not a stable biallelic null across the lifespan. It has no readout
      for vertical gaze palsy, dystonia or cognitive decline, and it reports cerebellar
      structure rather than the region-selective adult-onset degeneration seen in patients.
    readouts:
    - name: Cerebellar structural integrity
      target: Cerebellar and Brainstem Neuron Proteostatic Stress
      direction: DECREASED
      interpretation: >-
        Cerebellar axonal connectivity and gross structure degrade in proportion to sqstm1
        loss.
      evidence:
      - reference: PMID:29959261
        reference_title: "Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The consequences of sqstm1 down-modulation on the structural integrity of the
          cerebellum in zebrafish documented a variable but reproducible phenotype
          characterized by cerebellum anomalies ranging from depletion of axonal connections
          to complete atrophy.
        explanation: >-
          Reports the cerebellar structural measurement behind this readout.
- name: p62/Sqstm1 knockout mouse
  species: Mouse
  genotype: Sqstm1 (p62) constitutive homozygous knockout
  publication: PMID:18346206
  description: >
    The constitutive p62-null mouse. It develops age-dependent neurodegeneration, but by a
    tau-driven route with a systemic metabolic phenotype, neither of which is documented in
    human NADGP.
  modeled_mechanisms:
  - target: Cerebellar and Brainstem Neuron Proteostatic Stress
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Establishes that constitutive p62 loss is sufficient to cause neurodegeneration in a
      mammal, which is the claim the human disorder needs from this model.
    limitations: >-
      The mouse phenotype is a tau/neurofibrillary-tangle Alzheimer-like pathology with
      hippocampal and behavioural involvement, plus mature-onset obesity and insulin
      resistance. Human NADGP is a cerebellar-brainstem-basal ganglia syndrome; no tau
      pathology has been examined in patients and no metabolic phenotype is reported. The
      model therefore supports the sufficiency of p62 loss but not the regional pattern or
      the molecular route.
    evidence:
    - reference: PMID:18346206
      reference_title: "Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we report age-dependent constitutive activation of glycogen synthase kinase 3beta,
        protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in
        adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and
        neurodegeneration
      explanation: >-
        Supports treating the p62-null mouse as informative for neurodegeneration following
        constitutive p62 loss, while naming the tau route that differs from the human disease.
discussions:
- discussion_id: nadgp_no_human_neuropathology
  kind: KNOWLEDGE_GAP
  prompt: >-
    Which neuronal populations actually degenerate in NADGP, and does the pathology match the
    cerebellar-brainstem-basal ganglia pattern inferred from the clinical syndrome?
  attaches_to:
  - "pathophysiology#Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia"
  rationale: >-
    No autopsy neuropathology has been published for this disorder. The regional map curated
    on that node is read off the clinical syndrome, off MRI that is frequently normal, and off
    model systems — it is not a tissue observation. In particular, Purkinje cell loss is
    assumed rather than shown, which is why this entry conforms only to the trigger node of
    the cerebellar Purkinje degeneration module and not to its degeneration node. Any curator
    tempted to strengthen that edge should note that the evidence to do so does not yet exist.
  proposed_experiments:
  - experiment_id: nadgp_postmortem_neuropathology
    name: Post-mortem neuropathological characterisation of NADGP
    description: >-
      Systematic neuropathological examination of a NADGP brain — cerebellar cortex and deep
      nuclei, rostral midbrain vertical-gaze centres, striatum and pallidum — with
      quantification of Purkinje and granule cell density, ubiquitin and p62 immunostaining,
      and assessment of tau and iron deposition.
    would_support:
    - "pathophysiology#Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia"
    supporting_outcome:
    - >-
      Selective loss of Purkinje and granule neurons with midbrain and striatal involvement,
      matching the clinical syndrome.
    refuting_outcome:
    - >-
      Preserved cerebellar cortical neurons with the pathology localising elsewhere, which
      would require the regional model curated here to be rewritten.
- discussion_id: nadgp_mouse_human_mismatch
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do the defining phenotypes of the p62-null mouse — tau hyperphosphorylation with
    neurofibrillary tangles, and mature-onset obesity with insulin resistance — occur in
    humans with complete p62 absence?
  attaches_to:
  - "pathophysiology#Cerebellar and Brainstem Neuron Proteostatic Stress"
  - "animal_models#Mouse"
  rationale: >-
    The p62-null mouse is the only constitutive mammalian model of this genotype, and it is a
    poor phenotypic match. It develops an Alzheimer-like tauopathy with hippocampal
    involvement, memory impairment and depression-like behaviour, and separately a mature-onset
    obesity and insulin-resistance syndrome. Human NADGP presents in childhood as a cerebellar,
    extrapyramidal and oculomotor disorder; no tau pathology has been looked for in patients
    because no tissue exists, and no metabolic phenotype has been reported in any published
    family. This is evidence that exists in a model whose translational validity is the open
    question, not absent evidence. It matters practically: the tau result has been used to
    argue that p62 is a general anti-tauopathy factor, and importing that framing into NADGP
    would assert a mechanism no patient observation supports.
  evidence:
  - reference: PMID:16517408
    reference_title: "Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We report here that p62(-/-) mice develop mature-onset obesity, leptin resistance, as
      well as impaired glucose and insulin intolerance.
    explanation: >-
      Documents the mouse metabolic phenotype that has no counterpart in the human disorder.
  - reference: PMID:35662390
    reference_title: "Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In PS19 mice deficient in p62 (PS19/p62-KO), increased accumulation of phosphorylated
      tau, acceleration of neuronal loss, and exacerbation of neuroinflammation were observed
      in the hippocampus as compared with PS19 mice.
    explanation: >-
      Reinforces the mouse tau-centred framing of p62 loss, which is the framing this
      mismatch warns against importing into NADGP.
  proposed_experiments:
  - experiment_id: nadgp_tau_and_metabolic_phenotyping
    name: Tau and metabolic phenotyping of NADGP patients
    description: >-
      Prospective assessment of plasma and CSF phosphorylated-tau species and, where feasible,
      tau PET in genetically confirmed NADGP patients, alongside structured metabolic
      phenotyping for obesity, glucose intolerance and insulin resistance.
    would_refute:
    - "animal_models#Mouse"
    supporting_outcome:
    - >-
      Elevated phosphorylated tau and a metabolic syndrome in patients, which would upgrade
      the mouse from a poor to a fair model.
    refuting_outcome:
    - >-
      Normal tau biomarkers and normal metabolic phenotype, confirming that the mouse
      phenotypes are species-specific and must not be curated as human mechanism.
- discussion_id: nadgp_heterozygote_risk
  kind: KNOWLEDGE_GAP
  prompt: >-
    Are heterozygous carriers of a NADGP truncating allele at increased risk of Paget disease
    of bone or of ALS/frontotemporal dementia, the dominant SQSTM1 disorders?
  attaches_to:
  - "genetic#SQSTM1"
  - "inheritance#Autosomal recessive inheritance"
  rationale: >-
    The dominant SQSTM1 disorders are caused predominantly by missense alleles — the recurrent
    UBA-domain p.Pro392Leu in Paget disease, and missense variants in ALS cohorts — whereas
    every NADGP allele reported is a null. Whether a single null allele confers any risk of the
    dominant phenotypes is unknown: NADGP parents are reported unaffected, but they are young
    relative to the age of onset of Paget disease and ALS and no cohort has been followed. The
    answer determines whether carrier relatives identified during cascade testing need
    surveillance, and it also bears on whether the dominant diseases are haploinsufficiency or
    altered-function disorders.
  evidence:
  - reference: PMID:11992264
    reference_title: "Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Screening SQSTM1/p62 for mutations led to the identification of a recurrent
      nonconservative change (P392L) flanking the ubiquitin-associated domain (UBA) (position
      394-440) of the protein that was not present in 291 control individuals.
    explanation: >-
      Establishes that the dominant Paget allele is a specific UBA-domain missense change, not
      a null — the contrast that makes carrier risk an open rather than settled question.
  - reference: PMID:22084127
    reference_title: "SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15
      patients (6 with familial ALS and 9 with sporadic ALS).
    explanation: >-
      Shows the ALS-associated allele spectrum is predominantly heterozygous missense,
      reinforcing the allele-class distinction from NADGP.
  proposed_experiments:
  - experiment_id: nadgp_carrier_cohort_surveillance
    name: Longitudinal surveillance of obligate NADGP carriers
    description: >-
      Assembly of a multi-family cohort of obligate heterozygous carriers of NADGP null alleles
      with longitudinal bone turnover markers, skeletal imaging and neurological assessment,
      compared against age-matched non-carrier relatives.
    would_support:
    - "genetic#SQSTM1"
notes: >-
  Lump/split decision: curated as a standalone DISEASE entry, not as a subtype of any
  existing SQSTM1 entry. The split is by zygosity and allele class. Paget_Disease_of_Bone is
  already curated in this KB and is caused by heterozygous, recurrent UBA-domain missense
  alleles acting in adult bone; ALS/FTD3 is likewise a dominant, predominantly missense,
  adult-onset condition. NADGP is biallelic null, childhood-onset, and neurological, with a
  demonstrated complete-absence protein state that the dominant disorders do not share. The
  two groups have different age of onset, different affected organ system, different allele
  class and different molecular consequence, so a has_subtypes relationship on either
  dominant entry would misstate all four.

  Coverage check performed against kb/ before curating, since a grep hit is not coverage.
  SQSTM1/hgnc:11280 already appears in Paget_Disease_of_Bone (causal, dominant),
  Amyotrophic_Lateral_Sclerosis (on a mechanism node listing autophagy-receptor genes),
  Huntington_Disease (genetic entry with association Pathophysiological Role, not causal),
  and kb/groupings/Macroautophagy_Deficiency_Disorders.yaml (as the representative
  autophagy-receptor gene on the ALS member). MONDO:0014940 was bound nowhere. Elsewhere in
  kb/ — including Myofibrillar_Myopathy and Spinocerebellar_Ataxia_Autosomal_Recessive_31 —
  SQSTM1 appears as the p62 protein in mechanism prose, not as a causal gene. So this entry
  is the first causal binding of SQSTM1 to a recessive phenotype in the KB.

  Module conformance. Two edges are declared and both are deliberate.
  `disabled_macroautophagy#Failure of Cytoplasmic Quality Control` is declared on the
  cargo-recognition node: p62 is the canonical selective-autophagy cargo receptor, and the
  Macroautophagy_Deficiency_Disorders grouping already names SQSTM1 as the representative
  autophagy-receptor gene for exactly this failure point.
  `cerebellar_purkinje_degeneration#Cerebellar Neuron Insult` is declared on the neuronal
  stress node because that module's trigger explicitly admits "impaired protein quality
  control" as one of its heterogeneous initiating lesions and its scope covers autosomal
  recessive ataxias. Conformance is deliberately NOT declared to that module's `Purkinje
  Neuron Degeneration` node: no human neuropathology exists for this disorder, so Purkinje
  cell loss is inferred and not demonstrated. See the nadgp_no_human_neuropathology
  discussion. Conformance to `disabled_macroautophagy#Autophagy Machinery Decline` is also
  not declared — that node is framed as age-associated decline of autophagic capacity, and
  this is a congenital genetic null with no defect in the core machinery.

  Deliberately not curated. No `datasets:` block: no NADGP omics dataset was identified and
  a dataset accession found by searching the gene alone would surface the dominant SQSTM1
  diseases rather than this one, which is the named-entity-confusion trap for this gene. No
  `clinical_trials:` block: no interventional trial for biallelic SQSTM1 disease was found.
  No `environmental:` block: this disorder has no reported environmental contributor,
  trigger or modifier.

  A treatment claim that could not be evidenced. The one published treatment narrative
  (PMID:40728085, de Almeida Marcelino et al.) reports non-response to levodopa/carbidopa,
  baclofen, trihexyphenidyl and tetrabenazine. That record exposes neither abstract nor full
  text in the reference cache, so there is no quotable substring and the claim is recorded
  here in notes rather than curated as a treatment with fabricated evidence. Several other
  case reports in this literature (PMID:38279634, PMID:38532471, PMID:41482852,
  PMID:41708390, PMID:42014241, PMID:42403283) are correspondence-format publications with
  no abstract in the cache and were likewise not used as evidence.

  Orphanet has no dedicated ORPHA code for this entity that could be located, so no ORPHA
  evidence row is cited. The prevalence record is therefore anchored on a published case
  count rather than an Orphanet epidemiology class.

  GeneReviews. Searched PubMed on 2026-09-02 via E-utilities. `SQSTM1[Title] AND
  GeneReviews[Book]` returns nothing; `GeneReviews AND SQSTM1` across all fields returns a
  single record, PMID:20301623 "Amyotrophic Lateral Sclerosis Overview", which covers the
  dominant SQSTM1 disorder and not this recessive entity; and `GeneReviews AND
  ("neurodegeneration with ataxia, dystonia, and gaze palsy" OR NADGP)` returns nothing.
  There is therefore no GeneReviews chapter to tag in `references:`, and the absence is a
  finding rather than an omission — this entity has ~30 published patients and no chapter
  has been commissioned. Re-run the query when the case count grows.

  Phenotypes left out for want of a quotable source. The deep-research report lists urinary
  incontinence and bilateral internuclear ophthalmoplegia in the phenotypic tail. Neither is
  curated: no cached reference in this PR contains the word "incontinence", and the single
  internuclear-ophthalmoplegia report is one of the correspondence-format publications whose
  cache body is empty. Both should be added when a citable source is available.
📚

References & Deep Research

References

22
PMID:11992264
Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone.
No top-level findings curated for this source.
PMID:16286508
p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death.
No top-level findings curated for this source.
PMID:16517408
Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62.
No top-level findings curated for this source.
PMID:17580304
p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy.
No top-level findings curated for this source.
PMID:18346206
Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration.
No top-level findings curated for this source.
PMID:20173742
The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1.
No top-level findings curated for this source.
PMID:20525256
Niemann-Pick disease type C.
No top-level findings curated for this source.
PMID:22084127
SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.
No top-level findings curated for this source.
PMID:22810120
Vertical supranuclear gaze palsy in Niemann-Pick type C disease.
No top-level findings curated for this source.
PMID:27545679
Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy.
No top-level findings curated for this source.
PMID:29112993
Congenital Disorders of Autophagy: What a Pediatric Neurologist Should Know.
No top-level findings curated for this source.
PMID:29959261
Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration.
No top-level findings curated for this source.
PMID:30638816
Beyond dystonia and ataxia: Expanding the phenotype of SQSTM1 mutations.
No top-level findings curated for this source.
PMID:31525130
Homozygous sequestosome 1 (SQSTM1) mutation: a rare cause for childhood-onset progressive cerebellar ataxia with vertical gaze palsy.
No top-level findings curated for this source.
PMID:33891871
The role of SQSTM1 (p62) in mitochondrial function and clearance in human cortical neurons.
No top-level findings curated for this source.
PMID:34147300
Homozygous SQSTM1 nonsense variant identified in a patient with brainstem involvement.
No top-level findings curated for this source.
PMID:35402641
Eye Movement Disorders in Movement Disorders.
No top-level findings curated for this source.
PMID:35662390
Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy.
No top-level findings curated for this source.
PMID:35957775
First report of novel mutation (c.790del) on SQSTM1 gene on a family with childhood onset of progressive cerebellar ataxia with vertical gaze palsy.
No top-level findings curated for this source.
PMID:39126919
Generation and characterization of human-derived induced pluripotent stem cell line (IGIBi010-A) from a patient with neurodegenerative disease phenotype carrying mutation in SQSTM1/p62 gene.
No top-level findings curated for this source.
PMID:39587727
A Novel Synonymous Variant in SQSTM1 Causes Neurodegeneration With Ataxia, Dystonia, and Gaze Palsy Revealed by Urine-Derived Cells-Based Functional Analysis.
No top-level findings curated for this source.
PMID:41307082
Novel SQSTM1 (c.838G>T) Mutation Identified in Two Unrelated Cases of Cerebellar Ataxia and Gaze Palsy.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Lump/split decision: curated as a standalone DISEASE entry, not as a subtype of any existing SQSTM1 entry. The split is by zygosity and allele class. Paget_Disease_of_Bone is already curated in this KB and is caused by heterozygous, recurrent UBA-domain missense alleles acting in adult bone; ALS/FTD3 is likewise a dominant, predominantly missense, adult-onset condition. NADGP is biallelic null, childhood-onset, and neurological, with a demonstrated complete-absence protein state that the dominant disorders do not share. The two groups have different age of onset, different affected organ system, different allele class and different molecular consequence, so a has_subtypes relationship on either dominant entry would misstate all four. Coverage check performed against kb/ before curating, since a grep hit is not coverage. SQSTM1/hgnc:11280 already appears in Paget_Disease_of_Bone (causal, dominant), Amyotrophic_Lateral_Sclerosis (on a mechanism node listing autophagy-receptor genes), Huntington_Disease (genetic entry with association Pathophysiological Role, not causal), and kb/groupings/Macroautophagy_Deficiency_Disorders.yaml (as the representative autophagy-receptor gene on the ALS member). MONDO:0014940 was bound nowhere. Elsewhere in kb/ — including Myofibrillar_Myopathy and Spinocerebellar_Ataxia_Autosomal_Recessive_31 — SQSTM1 appears as the p62 protein in mechanism prose, not as a causal gene. So this entry is the first causal binding of SQSTM1 to a recessive phenotype in the KB. Module conformance. Two edges are declared and both are deliberate. `disabled_macroautophagy#Failure of Cytoplasmic Quality Control` is declared on the cargo-recognition node: p62 is the canonical selective-autophagy cargo receptor, and the Macroautophagy_Deficiency_Disorders grouping already names SQSTM1 as the representative autophagy-receptor gene for exactly this failure point. `cerebellar_purkinje_degeneration#Cerebellar Neuron Insult` is declared on the neuronal stress node because that module's trigger explicitly admits "impaired protein quality control" as one of its heterogeneous initiating lesions and its scope covers autosomal recessive ataxias. Conformance is deliberately NOT declared to that module's `Purkinje Neuron Degeneration` node: no human neuropathology exists for this disorder, so Purkinje cell loss is inferred and not demonstrated. See the nadgp_no_human_neuropathology discussion. Conformance to `disabled_macroautophagy#Autophagy Machinery Decline` is also not declared — that node is framed as age-associated decline of autophagic capacity, and this is a congenital genetic null with no defect in the core machinery. Deliberately not curated. No `datasets:` block: no NADGP omics dataset was identified and a dataset accession found by searching the gene alone would surface the dominant SQSTM1 diseases rather than this one, which is the named-entity-confusion trap for this gene. No `clinical_trials:` block: no interventional trial for biallelic SQSTM1 disease was found. No `environmental:` block: this disorder has no reported environmental contributor, trigger or modifier. A treatment claim that could not be evidenced. The one published treatment narrative (PMID:40728085, de Almeida Marcelino et al.) reports non-response to levodopa/carbidopa, baclofen, trihexyphenidyl and tetrabenazine. That record exposes neither abstract nor full text in the reference cache, so there is no quotable substring and the claim is recorded here in notes rather than curated as a treatment with fabricated evidence. Several other case reports in this literature (PMID:38279634, PMID:38532471, PMID:41482852, PMID:41708390, PMID:42014241, PMID:42403283) are correspondence-format publications with no abstract in the cache and were likewise not used as evidence. Orphanet has no dedicated ORPHA code for this entity that could be located, so no ORPHA evidence row is cited. The prevalence record is therefore anchored on a published case count rather than an Orphanet epidemiology class. GeneReviews. Searched PubMed on 2026-09-02 via E-utilities. `SQSTM1[Title] AND GeneReviews[Book]` returns nothing; `GeneReviews AND SQSTM1` across all fields returns a single record, PMID:20301623 "Amyotrophic Lateral Sclerosis Overview", which covers the dominant SQSTM1 disorder and not this recessive entity; and `GeneReviews AND ("neurodegeneration with ataxia, dystonia, and gaze palsy" OR NADGP)` returns nothing. There is therefore no GeneReviews chapter to tag in `references:`, and the absence is a finding rather than an omission — this entity has ~30 published patients and no chapter has been commissioned. Re-run the query when the case count grows. Phenotypes left out for want of a quotable source. The deep-research report lists urinary incontinence and bilateral internuclear ophthalmoplegia in the phenotypic tail. Neither is curated: no cached reference in this PR contains the word "incontinence", and the single internuclear-ophthalmoplegia report is one of the correspondence-format publications whose cache body is empty. Both should be added when a citable source is available.

Edit: address CHANGES_REQUESTED review on PR #10655 (reference titles, references block, GO binding, diagnosis, differential diagnoses) · 2026-09-03T03:57:11Z · View source

Addressed the five blocking items and two of the three suggestions from the automated review of PR #10655 (comment 5519767878). No content the reviewer commended was undone. RESEARCH INPUT (restated for accuracy): research/SQSTM1-Related_Childhood-Onset_Neurodegeneration-deep-research-claude_code.md was produced by the claude_code provider, NOT by falcon. Falcon was the requested provider and failed with ProviderBillingError HTTP 402; the run fell back to claude_code via the documented --fallback path, recorded in the report frontmatter as fell_back: true. It was used as a lead only in this session as in the create session. BLOCKING 1 - reference_title. Every evidence item now carries reference_title. Values were read programmatically out of each references_cache/*.md frontmatter rather than typed, which is the failure mode #9138 documents (correct PMID, verified snippet, invented title). 77 evidence items now carry one; the file had 55 at review time and gained 22 with the new diagnosis, differential_diagnoses and phenotype content. just check-reference-titles OK, no new sub-0.85 titles. BLOCKING 2 - top-level references: block. Added, listing all 22 cited references with cache-derived titles, generated by the same script. GeneReviews: searched PubMed 2026-09-02 via E-utilities. 'SQSTM1[Title] AND GeneReviews[Book]' returns 0. 'GeneReviews AND SQSTM1' across all fields returns exactly one record, PMID:20301623 'Amyotrophic Lateral Sclerosis Overview', which covers the dominant SQSTM1 disorder, not this recessive entity. 'GeneReviews AND (\"neurodegeneration with ataxia, dystonia, and gaze palsy\" OR NADGP)' returns 0. There is no chapter to tag, so no tags: [GeneReviews] entry was added; the searches and their results are recorded in entry notes so the next curator does not repeat them. The reviewer could not run this check (PubMed blocked in its environment) and marked it N/A; it is now resolved rather than assumed. BLOCKING 3 - wrong GO binding. The reviewer was right. GO:0043130 'ubiquitin binding' on the node 'Failure of Selective Autophagy Cargo Recognition' was attached to preferred_term 'LC3-interacting region binding of p62 to the phagophore'; the LIR binds ATG8/LC3, and ubiquitin binding is the UBA domain at the C-terminus. Rebound to GO:0030674 'protein-macromolecule adaptor activity' (verified present in cache/go/terms.csv with that exact label). The separate GO:0043130 binding on 'Absence of p62/Sequestosome-1 Protein', whose preferred_term is 'ubiquitin-binding autophagy cargo receptor activity of p62', is correct and was left alone. PMID:17580304 (Pankiv 2007), already cached in this PR but uncited, is now cited on that node with the direct-interaction sentence, graded IN_VITRO/INDIRECT because it maps the normal interaction in HeLa cells rather than measuring it in NADGP material. BLOCKING 4 - diagnosis: section. Three entries, all from cached references. Next-generation sequencing (NCIT:C101295 Whole Exome Sequencing) with PMID:31525130 and PMID:41307082; p62/SQSTM1 immunoblot on patient-derived cells (NCIT:C16357 Western Blotting, resolved online during term validation and now cached in cache/ncit/terms.csv and the treatmentactionterm enum cache) with PMID:27545679 and PMID:39587727; and the urine-derived-cell splicing/expression assay for VUS resolution with PMID:39587727, deliberately left with no term: because NCIT has no clinical-action term for that assay and a free-text preferred_term is the documented fallback. BLOCKING 5 - differential_diagnoses: section. Five entries. Niemann-Pick disease type C (MONDO:0018982) is the principal phenocopy and is what the prose at the vertical-gaze-palsy phenotype was already gesturing at; it is now a structured entry with distinguishing_features covering the neurovisceral onset, gelastic cataplexy, filipin/oxysterol confirmation and the licensed therapy, evidenced by two newly fetched references (PMID:20525256 Vanier Orphanet review, PMID:22810120 Salsano VSGP review). Also added: ataxia-telangiectasia and the ataxia with oculomotor apraxia syndromes (MONDO:0008840), reached from the oculomotor apraxia phenotype added in this same session and separated by the normal alpha-fetoprotein and absent telangiectasia explicitly documented in PMID:41307082; Wilson disease (MONDO:0010200), separated by the normal copper and ceruloplasmin in the same paper; hereditary chorea syndromes, which PMID:39587727 states directly; and other inherited childhood-onset cerebellar ataxias, from PMID:34147300 and PMID:31525130. PMID:35402641 (Eye Movement Disorders in Movement Disorders) was fetched to evidence the oculomotor route into these differentials. SUGGESTION 6 - minority phenotypes. Added five, each with an exact quote: Oculomotor Apraxia (HP:0000657), Nystagmus (HP:0000639), Tremor (HP:0001337), Bradykinesia with Limb Rigidity (HP:0002067), Hearing Loss (HP:0000365). Bradykinesia rather than HP:0001300 Parkinsonism deliberately: no reported patient carries a formal parkinsonism diagnosis and no dopaminergic imaging has been published, so the narrower defensible term was chosen and the reasoning recorded in the phenotype description. Urinary incontinence and bilateral internuclear ophthalmoplegia were NOT added: no cached reference in this PR contains the word 'incontinence', and the internuclear-ophthalmoplegia report is one of the correspondence-format publications with an empty cache body. Both omissions are recorded in entry notes so they are re-checked rather than forgotten. SUGGESTION 7 - Progressive Gait Ataxia vs Progressive Cerebellar Ataxia overlap. Scoped rather than merged. 'Progressive Cerebellar Ataxia' (HP:0002073) was renamed 'Progressive Appendicular Ataxia' and rebound to HP:0002070 Limb ataxia, with new limb-specific evidence (PMID:39587727 'Both limb and truncal ataxia were evident.'; PMID:41307082 finger-to-nose dysmetria) replacing the two generic cerebellar-ataxia quotes, one of which moved to Progressive Gait Ataxia graded directness: INDIRECT and the other of which already lived on Cerebellar Atrophy. This also fixed a pathograph defect the review did not catch: the old node had no incoming edge and was an orphan in the causal graph. The rename broke nothing because no downstream target referenced it; a downstream edge from 'Regional Neurodegeneration of Cerebellum, Brainstem and Basal Ganglia' was added for it and for the four new movement/oculomotor phenotypes. Hearing Loss was left unconnected because no source localises it. PRESERVED DELIBERATELY: the treatment non-response narrative stays in notes rather than being given a manufactured snippet (PMID:40728085 and its DOI record are both content-empty); the two REFUTE items on Cerebellar Atrophy; the nrf2_axis_failure EMERGING hypothesis scoping; and the withheld cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration conformance with its KNOWLEDGE_GAP. CACHE HYGIENE: three references were fetched (PMID:20525256, PMID:22810120, PMID:35402641). PMID:20525256 was already tracked as abstract_only and the fetch upgraded it to full_text_pdf, producing 1935 lines of unrelated churn; it was restored with git restore and both snippets taken from it were re-verified against the original abstract-only body. A one-line frontmatter churn on PMID:17580304 was likewise restored. Only the two genuinely new cache files are committed. VALIDATION (all run, real output read): just validate PASS with 77/77 snippets verified; just validate-terms PASS; just count-verified-snippets 77/77; just check-duplicate-keys OK; just check-entity-refs OK; just check-causal-targets OK, no new breakage; just check-qualifier-terms OK and check-qualifier-terms-online OK with 97 CURIEs resolved; just check-enum-values OK; just check-reference-titles OK; just check-snippet-grading OK; just check-folded-hyphens, check-snippet-length, check-title-snippets all OK with no new entries; just check-term-cache-integrity OK; just validate-disorders PASS, exit 0. All 22 cited references are PMIDs, so the validate-disorders DOI-prefix skip does not apply to this entry and no --unskip-prefix pass was needed.

Create: SQSTM1-Related_Childhood-Onset_Neurodegeneration (NADGP, MONDO:0014940) · 2026-09-03T03:03:25Z · View source

Curated the biallelic, childhood-onset SQSTM1 entity (NADGP, MONDO:0014940) as a standalone DISEASE entry, replacing the seed-stub placeholder at the same path and consuming stubs/Neurodegeneration_With_Ataxia_Dystonia_And_Gaze_Palsy_Childhood-onset.yaml. LUMP/SPLIT DECISION: DISEASE, split from the dominant SQSTM1 disorders by zygosity and allele class. Paget_Disease_of_Bone is already curated and is the only KB entry where SQSTM1 (hgnc:11280) is a causal genetic: binding; it is dominant, adult-onset, skeletal, and caused by UBA-domain missense alleles (verified against PMID:11992264). NADGP is biallelic-null, childhood-onset and neurological, with complete absence of p62 protein demonstrated by immunoblot in patient fibroblasts (PMID:27545679). No missense NADGP allele has been reported. A has_subtypes relationship on either dominant entry would misstate onset, organ system, allele class and molecular consequence. COVERAGE CHECK (verified by hand, not trusted from the issue): MONDO:0014940 was bound nowhere in kb/. The issue asserted SQSTM1 appears elsewhere only as the p62 protein; that is close but not exact. hgnc:11280 appears as a causal gene in Paget_Disease_of_Bone only. Amyotrophic_Lateral_Sclerosis carries hgnc:11280 inside a pathophysiology node's genes: list but SQSTM1 is NOT in its genetic: section at all. Huntington_Disease carries it in genetic: with association 'Pathophysiological Role', not causal. Macroautophagy_Deficiency_Disorders carries it as the representative autophagy-receptor gene on its ALS member. Myofibrillar_Myopathy mentions a digenic SQSTM1-TIA1 combination in prose only; Spinocerebellar_Ataxia_Autosomal_Recessive_31 uses p62/SQSTM1 as a mechanism node (cargo receptor accumulating in ATG7 deficiency). This entry is therefore the first causal binding of SQSTM1 to a recessive phenotype in the KB. RESEARCH INPUT: research/SQSTM1-Related_Childhood-Onset_Neurodegeneration-deep-research-claude_code.md. This report was produced by the claude_code provider, NOT by falcon. The requested provider was falcon; that attempt failed with ProviderBillingError HTTP 402 (account out of credits) and the run fell back to claude_code via the documented --fallback path, which the report frontmatter records as fell_back: true with provider_attempts. just preflight-dr with --strict returned PASS (SQSTM1 mentioned 30 times, OMIM 617145 present). The report was treated as a lead only: every snippet was re-derived by hand from the cached reference files, and the report's four self-flagged unsupported quotes (PMID:31525130, PMID:33891871, PMID:29959261) were not copied. One report claim was rejected outright: it cited PMID:18346206 for 'elevated oxidative stress demonstrated in p62-null mice', which that abstract does not state; only the tau/neurofibrillary-tangle/neurodegeneration claim was used. MODULE CONFORMANCE: two edges declared. disabled_macroautophagy#Failure of Cytoplasmic Quality Control on the cargo-recognition node, and cerebellar_purkinje_degeneration#Cerebellar Neuron Insult on the neuronal stress node (that module's trigger explicitly admits impaired protein quality control as an initiating lesion and its scope covers autosomal recessive ataxias). Deliberately NOT declared: cerebellar_purkinje_degeneration#Purkinje Neuron Degeneration, because no human neuropathology exists for this disorder so Purkinje loss is inferred rather than shown; and disabled_macroautophagy#Autophagy Machinery Decline, which is framed as age-associated decline rather than a congenital null. NUANCES CURATED RATHER THAN FLATTENED: Cerebellar Atrophy carries one INDIRECT group-level SUPPORT (PMID:29112993) plus two REFUTE items (PMID:39587727, PMID:31525130) documenting genetically confirmed patients with normal MRI or no significant atrophy, since a normal MRI does not exclude the diagnosis. The KEAP1-NRF2 branch is scoped to a mechanistic_hypotheses group (nrf2_axis_failure, status EMERGING) with INDIRECT evidence, because the demonstrated direction (PMID:20173742) is inverted: p62 overproduction stabilises NRF2, and blunted NRF2 under p62 absence is an inference not measured in patients. Three discussions record the open questions: no human neuropathology (KNOWLEDGE_GAP), the p62-null mouse tau/obesity phenotypes absent from human NADGP (HUMAN_MODEL_MISMATCH), and heterozygous carrier risk for the dominant allelic diseases (KNOWLEDGE_GAP). DELIBERATELY NOT CURATED: no datasets: block (a gene-only dataset search would surface the dominant SQSTM1 diseases, which is the named-entity-confusion trap here); no clinical_trials: block (no interventional trial found for biallelic SQSTM1 disease); no environmental: block (no reported contributor). The one published treatment narrative (PMID:40728085) reporting non-response to levodopa/carbidopa, baclofen, trihexyphenidyl and tetrabenazine is recorded in entry notes rather than as a treatment claim, because that record exposes neither abstract nor full text in the cache and so has no quotable substring. Six further correspondence-format case reports (PMID:38279634, PMID:38532471, PMID:41482852, PMID:41708390, PMID:42014241, PMID:42403283) likewise have empty cache bodies and were not used as evidence. No dedicated ORPHA code for this entity could be located, so prevalence is anchored on a published case count (PMID:41307082, 27 cases) rather than an Orphanet epidemiology class. VALIDATION (all run, real output): just validate PASS with 55/55 snippets verified; just validate-terms PASS; just count-verified-snippets 55/55; just check-duplicate-keys OK; just check-entity-refs OK; just check-causal-targets OK (no new breakage); just check-qualifier-terms OK (entry uses no qualifiers, so check-qualifier-terms-online was not required); just check-enum-values OK; just check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading all OK with no new entries; just validate-disorders PASS (exit 0). All 55 references are PMIDs, so the validate-disorders DOI-prefix skip does not apply to this entry.

Claude Code ▸
SQSTM1-Related Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy (NADGP) — Comprehensive Research Report
claude-fable-5[1m], claude-haiku-4-5-20251001 21 citations 2026-09-02T18:00:28.311848

SQSTM1-Related Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy (NADGP) — Comprehensive Research Report

Prepared: 2026-09-02. All PMIDs below were verified against PubMed E-utilities during this session unless explicitly flagged as "background-knowledge citation — re-verify." Quotes are drawn from abstracts/records as retrieved and should be re-verified verbatim against just fetch-reference output before being used as evidence snippet values.

1. Disease Information

Overview. Childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP) is an ultra-rare, autosomal recessive, slowly progressive neurodegenerative disorder caused by biallelic loss-of-function variants in SQSTM1, the gene encoding the multifunctional autophagy adaptor/signaling scaffold protein p62/sequestosome-1. Affected individuals are typically normal in early childhood and present between ~7 and 15 years of age with progressive gait ataxia; the disorder then evolves to a combined cerebellar–extrapyramidal–oculomotor syndrome with dysarthria, dystonia, chorea/athetosis, vertical supranuclear gaze palsy, and mild cognitive decline. It was first delineated by Haack et al. (2016), who reported "childhood- or adolescence-onset neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline" in nine individuals from four families (PMID:27545679).

Identifiers.

Resource Identifier
OMIM #617145 (NADGP); gene SQSTM1 601530
MONDO MONDO:0014940 (as cross-referenced in ClinVar records for this condition; verify against current MONDO release before binding)
Orphanet No dedicated ORPHA code identified in this search; the entity may be subsumed under Orphanet's autosomal recessive cerebellar ataxia classification. Flag as a gap rather than inventing one.
ICD-10 / ICD-11 No disease-specific code; classifiable under G11.- (hereditary ataxia) / 8A03 hereditary ataxias
ClinVar condition "Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset" (multiple RCV records; see §4)

Synonyms. NADGP; neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset; SQSTM1-related childhood-onset neurodegeneration; biallelic SQSTM1-related neurodegeneration. (Muto et al. use the phrase "early-onset, variably progressive neurodegeneration"; one 2025 case report uses "NDAGP".)

Data provenance. All information is aggregated from disease-level resources (OMIM, ClinVar, GTR) and per-family primary case reports/series (~15 publications, ~35–45 reported patients); there are no EHR-scale or registry-scale data for this disease.

2. Etiology

Causal factor. Purely genetic: biallelic (homozygous or compound heterozygous) germline loss-of-function variants in SQSTM1 (chr5q35.3). Haack et al. "identified three different biallelic loss-of-function variants in SQSTM1 in nine affected individuals from four families" and "confirmed absence of the SQSTM1/p62 protein in affected individuals' fibroblasts" (PMID:27545679). Muto et al. independently identified "three homozygous inactivating variants" in 11 individuals from consanguineous families (PMID:29959261). Complete absence of p62 protein is the established disease mechanism.

Genetic risk factors. Carrier parents (obligate heterozygotes for LOF alleles) are reported clinically unaffected in the NADGP literature. Consanguinity is the dominant epidemiological risk factor: most reported families are consanguineous (Muto's cohort explicitly so; subsequent single-family reports from Iran, India, Turkey, Peru, the Philippines and elsewhere are largely homozygous). Note that heterozygous SQSTM1 variants — typically missense (classically p.Pro392Leu in the UBA domain) — cause allelic dominant disorders (Paget disease of bone 3, OMIM 167250; frontotemporal dementia/ALS 3, OMIM 616437; see §4), but these are distinct mechanisms (altered/dominant-negative function vs complete loss) and there is no evidence that NADGP-type truncating-allele carriers develop them at elevated rates; this genotype–phenotype boundary is an open question worth recording as a knowledge gap.

Environmental risk/protective factors. None known; no environmental trigger, modifier, or protective exposure has been reported. Gene–environment interaction data: none (CTD lists SQSTM1 chemical interactions only in non-disease contexts).

Protective genetic factors. None identified; no modifier genes reported. Phenotypic variability between and within families (rate of progression, presence of dystonia vs chorea, imaging findings) is documented (PMID:29959261) but unexplained.

3. Phenotypes

Core frequencies from the index series of 9 patients (PMID:27545679): gait abnormality 9/9, ataxia (mostly upper-limb) 9/9, dysarthria 9/9, dystonia 7/9, vertical gaze palsy 7/9, mild cognitive decline 7/9. Suggested HP terms below are leads; HP:0000511 and HP:0000657 were verified against OLS this session, others should be checked before binding.

Phenotype Type Onset / course Frequency Suggested HP term
Gait ataxia (usual presenting sign) Sign 7–15 y; progressive ~100% HP:0002066 Gait ataxia
Cerebellar ataxia incl. upper-limb/appendicular Sign Childhood–adolescence; progressive ~100% HP:0001251 Cerebellar ataxia
Dysarthria Sign Progressive ~100% HP:0001260 Dysarthria
Vertical supranuclear gaze palsy Sign "onset between 7 and 15 years of age" (OMIM synopsis); may appear on follow-up after ataxia (PMID:41307082) ~75–80% HP:0000511 Vertical supranuclear gaze palsy (OLS-verified)
Dystonia (limb, cervical, generalized) Sign Progressive ~70–80% HP:0001332 Dystonia
Cognitive decline (mild–moderate) Sign/behavioral Insidious, progressive ~75% HP:0001268 Mental deterioration
Chorea / athetosis / dyskinesia Sign Variable Common (Muto, Zúñiga-Ramírez, Masuko) HP:0002072 Chorea; HP:0002305 Athetosis
Myoclonus Sign Variable Minority (PMID:34147300; PMID:42403283) HP:0001336 Myoclonus
Nystagmus; oculomotor apraxia Sign Variable Minority HP:0000639 Nystagmus; HP:0000657 Oculomotor apraxia (OLS-verified)
Bilateral internuclear ophthalmoplegia Sign Reported once (2026) Rare HP term for INO — verify
Iridoplegia (pupillary involvement) Sign Reported in 2 patients Rare (PMID:30638816)
Dysautonomia: orthostatic hypotension, sudomotor dysfunction Sign Later course Minority HP:0001278 Orthostatic hypotension (verify)
Urinary incontinence Symptom Variable presenting feature Minority HP:0000020 Urinary incontinence (verify)
Mild hearing loss Sign Variable "Some patients" (OMIM synopsis) HP:0000365 Hearing impairment (verify)
Tremor, parkinsonian features Sign Later course Minority HP:0001337 Tremor; HP:0001300 Parkinsonism (verify)
Growth retardation Physical Single case Rare (PMID:34147300)
Cerebellar atrophy (MRI) Imaging/lab Variable — present in many, absent in others Variable HP:0001272 Cerebellar atrophy (verify)
Brainstem signal lesions (MRI) Imaging Single case Rare (PMID:34147300)

Quality-of-life impact. No formal QoL instruments (EQ-5D/SF-36/PROMIS) have been applied. Functional impact is inferred from motor milestones: "Many patients are wheelchair-bound eventually" (OMIM-derived synopsis), typically by young adulthood; dysarthria impairs communication; cognitive decline is generally mild, and patients survive into adult life.

Supporting quotes: Muto et al. describe "a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline" (PMID:29959261). Zúñiga-Ramírez et al. add "dysautonomic features such as orthostatic hypotension and sudomotor dysfunction" (PMID:30638816). Vedartham et al. document "progressive childhood-onset cerebellar ataxia with vertical supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging (brain)" (PMID:31525130) — i.e., normal MRI does not exclude the diagnosis.

4. Genetic/Molecular Information

Causal gene. SQSTM1 (sequestosome 1; hgnc:11280 — verify lowercase-prefix form against the repo cache; OMIM 601530; chr5q35.3). Encodes p62, a 440-aa multidomain scaffold: PB1 (self-oligomerization), ZZ zinc finger (RIP1/N-degron binding), TB (TRAF6), LIR (LC3-interacting region), KIR (KEAP1-interacting region), and UBA (ubiquitin-associated) domains.

Pathogenic variants (all germline; ACMG pathogenic/likely pathogenic in ClinVar for the NADGP condition). Every NADGP allele reported to date is predicted-null (nonsense, frameshift, canonical splice, start-loss, or splice-disrupting synonymous):

  • c.286C>T (p.Arg96Ter) — ClinVar RCV000256198 (Haack 2016)
  • c.311_312del (p.Glu104fs) — RCV000256191 (Haack 2016)
  • c.175dup (p.Arg59fs) — RCV001264728
  • c.301+2T>A — RCV001815052 (Muto 2018)
  • c.875_876insT (p.Ser294fs) — RCV001815054 (Muto 2018)
  • c.969+1G>C — RCV003340920
  • c.1135_1138del (p.Glu379fs) — RCV002282804
  • c.784_820del (p.Gly262fs) — RCV002252670
  • c.55G>T (nonsense; patient with brainstem lesions) — PMID:34147300
  • c.790del (frameshift) — PMID:35957775
  • c.838G>T (p.Glu280Ter; two unrelated Iranian boys) — PMID:41307082
  • c.1A>G (start-loss) in trans with c.969G>A — a synonymous variant shown by urine-derived-cell functional analysis to cause aberrant splicing (PMID:39587727)
  • p.Leu251SerfsTer4 (frameshift; iPSC line IGIBi010-A derived from this patient) — PMID:39126919
  • Additional novel biallelic/homozygous frameshift variants: Peruvian family (PMID:38532471), Indian patient (PMID:38279634), Filipino adolescent (PMID:41708390), subacute-onset German-reported case (PMID:40728085)

Functional consequence. Complete loss of function/protein absence, confirmed by immunoblot in patient fibroblasts (PMID:27545679) and urine-derived cells (PMID:39587727). No missense NADGP allele is reported — an important genotype–phenotype observation, since missense alleles instead cause the dominant allelic disorders.

Allelic (heterozygous) disorders — distinct diseases, do not merge: - Paget disease of bone 3 (OMIM 167250) — recurrent p.Pro392Leu and other UBA-domain missense variants (Laurin et al. 2002, AJHG; PMID:11992264 — background-knowledge citation, re-verify). - Frontotemporal dementia and/or ALS 3 (FTDALS3, OMIM 616437) — heterozygous SQSTM1 variants in ALS/FTD cohorts (Fecto et al. 2011, Arch Neurol; PMID:22084127 — background-knowledge citation, re-verify). - A digenic distal myopathy with rimmed vacuoles involving SQSTM1 plus TIA1 variants has been reported (no verified PMID captured this session).

Allele frequency. NADGP alleles are individually absent or ultra-rare in gnomAD (consistent with private, family-specific LOF variants); no founder allele has been established, although recurrence of c.838G>T in two unrelated Iranian families suggests a possible regional founder effect (PMID:41307082).

Modifier genes, epigenetics, chromosomal abnormalities. None reported. No large deletions/CNVs of SQSTM1 reported in NADGP to date; no epigenetic disease mechanism described.

5. Environmental Information

Not applicable in the causal sense: NADGP is fully genetic with no known environmental, lifestyle, or infectious contributors, triggers, or modifiers. (Mechanistically, p62 sits on the KEAP1–NRF2 oxidative-stress response axis, so oxidative stressors are a plausible but undemonstrated modifier — record only as a hypothesis/knowledge gap, not as an environmental factor.)

6. Mechanism / Pathophysiology

Causal chain (ordered; steps 4–6 are partially inferred from model systems)

  1. Biallelic LOF variants in SQSTM1 (nonsense/frameshift/splice/start-loss) lead to nonsense-mediated decay or truncated non-functional transcripts, resulting in complete absence of p62 protein in patient cells (demonstrated: fibroblast immunoblot, PMID:27545679; urine-derived cells, PMID:39587727).
  2. Loss of p62 adaptor function leads to failure of selective autophagy cargo handling: p62 normally polymerizes via PB1, binds ubiquitinated cargo via UBA, and delivers it to autophagosomes via LIR–LC3 binding (background: Bjørkøy 2005, PMID:16286508; Pankiv 2007, PMID:17580304 — background-knowledge citations, re-verify). In patient/knockout cells this manifests as (branch a) "impaired production of ubiquitin-positive protein aggregates" and decelerated autophagic flux (PMID:29959261), and (branch b) a "defect in the early response to mitochondrial depolarization and autophagosome formation" (PMID:27545679).
  3. Defective mitochondrial quality control — in SQSTM1-knockout human iPSC-derived cortical neurons, "SQSTM1 depletion causes altered mitochondrial gene expression and functionality, as well as autophagy flux"; SQSTM1 "affects early processes of PINK1-dependent mitophagy but is dispensable for mitochondria clearance" (PMID:33891871). This results in impaired mitochondrial respiration/homeostasis in neurons (demonstrated in vitro; inferred in patients).
  4. Loss of p62's KEAP1-sequestering function is inferred to lead to blunted NRF2-dependent antioxidant transcription and heightened oxidative stress (background: Komatsu 2010, p62–KEAP1–NRF2 axis, PMID:20173742 — background-knowledge citation, re-verify; elevated oxidative stress demonstrated in p62-null mice, PMID:18346206). Inferred, not demonstrated in patients.
  5. Chronic proteostatic + mitochondrial + redox failure results in dysfunction and degeneration of vulnerable neuronal populations — cerebellar circuitry (Purkinje/granule neurons), brainstem supranuclear gaze centers (rostral midbrain), and basal ganglia. Zebrafish loss-of-function modeling shows "variable cerebellar anomalies ranging from axonal depletion to complete atrophy" (PMID:29959261 — model organism); p62-null mice accumulate hyperphosphorylated tau with neurodegeneration, synaptic deficits, and memory impairment (PMID:18346206 — model organism; human relevance inferred).
  6. Regional neurodegeneration leads to the clinical phenotype: cerebellar damage → ataxia/dysarthria; midbrain supranuclear pathway involvement → vertical gaze palsy; basal ganglia involvement (with reported iron deposition on MRI in some patients) → dystonia/chorea/parkinsonism; diffuse involvement → cognitive decline.

Note on directness: no NADGP autopsy neuropathology has been published; the cellular-to-regional mapping (step 5→6) rests on imaging, model organisms, and analogy — a genuine HUMAN_MODEL_MISMATCH/knowledge-gap candidate. Notably, human p62 deficiency does not phenocopy the mouse (no reported obesity/insulin resistance in patients vs PMID:16517408 mice; tau status in patients unknown vs PMID:18346206 mice).

Checklist mapping. Molecular pathways: macroautophagy/selective autophagy (suggest GO:0016236 macroautophagy, GO:0000422 mitophagy, GO:0035973 aggrephagy — verify), KEAP1–NRF2, NF-κB and mTORC1 scaffolding roles of p62 (background). Cellular processes: autophagosome assembly (GO:0000045 — verify), mitochondrial organization, response to oxidative stress (GO:0034599 — verify). Protein dysfunction: absence of a scaffold, not misfolding/aggregation. Subcellular compartments: autophagosome (GO:0005776), mitochondrion (GO:0005739). Cell types: suggest CL:0000121 Purkinje cell, cerebellar granule cell, cortical neuron (verify IDs). Immune involvement: none reported clinically. Molecular profiling: iPSC-neuron transcriptomics show altered mitochondrial respiratory gene expression (PMID:33891871); no patient proteomics/metabolomics published.

7. Anatomical Structures Affected

  • Primary: central nervous system. Cerebellum (atrophy in many patients, but can be radiologically normal — PMID:31525130; suggest UBERON:0002037 cerebellum); brainstem/midbrain supranuclear vertical-gaze pathways (clinical VSGP; brainstem MRI lesions in one case, PMID:34147300; suggest UBERON:0002298 brainstem — verify); basal ganglia (dystonia/chorea; reported iron deposition on imaging in some patients — OMIM-derived synopsis; suggest UBERON:0010011/UBERON:0002420 — verify); cerebral cortex (cognitive decline).
  • Secondary: autonomic nervous system (orthostatic hypotension, sudomotor dysfunction — PMID:30638816); auditory system (mild hearing loss in some); iris/pupillary pathways (iridoplegia, PMID:30638816).
  • Tissue/cell level: neurons broadly; presumed cerebellar Purkinje/granule neurons and brainstem oculomotor-control neurons (inferred; no human histopathology).
  • Subcellular: autophagosomes, mitochondria, ubiquitinated protein inclusions (absent/failed to form in p62-null cells).
  • Lateralization: bilateral, symmetric.

8. Temporal Development

  • Onset: childhood to adolescence, typically 7–15 years (PMID:27545679); occasionally earlier-childhood or subacute presentation (PMID:40728085). Development before onset is normal.
  • Onset pattern: insidious and chronic in most; one subacute-onset case reported (PMID:40728085).
  • Progression: slow but relentless; "variably progressive" between families (PMID:29959261). Gait ataxia → appendicular ataxia, dysarthria, gaze palsy, extrapyramidal features → loss of independent ambulation ("wheelchair-bound as young adults" in several patients). Cognitive decline is generally mild.
  • Course pattern: chronic progressive; no remissions, no episodic course reported. Lifelong.
  • Critical periods: none defined; no presymptomatic intervention window has been studied (no therapy exists to deploy in one).

9. Inheritance and Population

  • Inheritance: autosomal recessive; 25% recurrence risk per pregnancy for carrier couples. Penetrance of biallelic LOF appears complete in reported families (all homozygotes symptomatic), with variable expressivity in severity/progression rate (PMID:29959261). No anticipation (not a repeat-expansion disorder), no germline mosaicism reported.
  • Epidemiology: prevalence unknown; ultra-rare — approximately 35–45 patients from ~20 families reported worldwide (2016–2026). Suggested prevalence class for KB purposes: BELOW_1_IN_1000000 with measure_type: CASES_IN_LITERATURE semantics; no incidence data.
  • Populations reported: families from Europe, Turkey/Middle East, Iran (≥3 families; recurrent c.838G>T in two — possible founder effect, PMID:41307082, PMID:35957775), India (PMID:31525130, PMID:38279634, PMID:39126919), Mexico (PMID:30638816), Peru (PMID:38532471), Japan (PMID:39587727), Philippines (PMID:41708390). Consanguinity is frequent.
  • Sex ratio: both sexes affected; no skew evident in the small case corpus.
  • Carrier frequency: not established; individual alleles are private/ultra-rare in gnomAD.

10. Diagnostics

  • Genetic testing (definitive): exome/genome sequencing or hereditary ataxia / complex movement-disorder gene panels including SQSTM1; single-gene sequencing where a familial variant is known. Clinical tests for NADGP are registered in NCBI GTR (e.g., GTR test 578425, prenatal sequence analysis of all coding exons). Vedartham et al. explicitly "emphasize the diagnostic utility of next-generation sequencing in inherited ataxia" (PMID:31525130). CMA/karyotype/FISH/mtDNA/repeat testing: not informative for this disease (useful only in the differential workup).
  • Functional confirmation: absence of p62 on immunoblot in patient fibroblasts (PMID:27545679); urine-derived cell splicing/protein analysis validated a synonymous variant of uncertain significance (PMID:39587727) — a practical, minimally invasive functional assay for VUS resolution in this gene.
  • Imaging: brain MRI — cerebellar atrophy in many; normal MRI does not exclude the diagnosis (PMID:31525130; PMID:39587727 noted chorea/ataxia "without significant cerebellar atrophy"); brainstem lesions rarely (PMID:34147300); basal ganglia iron deposition reported in some (OMIM-derived synopsis) — relevant to the NBIA differential.
  • Biomarkers/labs: none disease-specific; routine metabolic workup is typically unremarkable.
  • Differential diagnosis: Niemann-Pick disease type C (the closest phenocopy — childhood ataxia + vertical supranuclear gaze palsy + dystonia + cognitive decline; distinguish by filipin/oxysterols/NPC1-NPC2 testing), juvenile PSP-like presentations, NBIA disorders (when iron deposition present), ataxia-telangiectasia and AOA1/2 (oculomotor apraxia), Wilson disease, autosomal recessive cerebellar ataxias (ARSACS, Friedreich), other congenital disorders of autophagy (EPG5/Vici, WDR45/BPAN, ATG5-related ataxia — PMID:29112993).
  • Screening: not in newborn-screening panels; carrier and prenatal testing available for known familial variants (GTR).

11. Outcome/Prognosis

  • Survival: no formal survival data; patients survive into adulthood; no disease-specific mortality figures published. Life expectancy impact unknown.
  • Function/morbidity: progressive motor disability dominates — loss of independent ambulation in young adulthood for many ("Many patients are wheelchair-bound eventually"); progressive dysarthria; mild-moderate cognitive impairment; dysautonomia in a subset. No published EQ-5D/SF-36/PROMIS data.
  • Complications: those of chronic neurodisability (falls, dysarthria-related communication impairment, possible dysphagia); orthostatic hypotension where dysautonomia present.
  • Recovery potential: none; neurodegeneration is irreversible and no disease-modifying therapy exists.
  • Prognostic factors/biomarkers: none established. Inter-familial variability in progression is documented (PMID:29959261) but unexplained; no genotype–severity correlation is possible when all alleles are null.

12. Treatment

There is no disease-modifying or approved therapy. Management is entirely supportive/symptomatic; "No treatment has been reported but physical therapy, speech therapy, and special education may be of benefit" (OMIM-derived synopsis).

  • Pharmacotherapy (symptomatic, largely empirical, often ineffective): in the best-documented treatment narrative, "treatment with methylprednisolone, oral penicillin and levodopa/carbidopa led to no improvement, and over the years, treatment with baclofen, trihexyphenidyl and tetrabenazine had no effect on the movement disorder" (PMID:40728085) — i.e., documented non-response to levodopa and standard anti-dystonia/anti-chorea agents. Suggested KB modeling: treatments with supports: REFUTE-style evidence on efficacy claims, or supportive-care entries only. NCIT suggestions: NCIT:C15986 Pharmacotherapy (with CHEBI agents levodopa, baclofen, trihexyphenidyl, tetrabenazine where curated), NCIT:C15302 Physical Therapy, NCIT:C159273 Speech Therapy (verify), NCIT:C15315 Rehabilitation, NCIT:C15747 Supportive Care, NCIT:C15240 Genetic Counseling.
  • Advanced therapeutics: no gene therapy, ASO, cell therapy, or targeted therapy exists or is in trials. Conceptually, gene replacement is attractive (recessive LOF, single gene) but p62 dosage is a concern given dominant gain-of-function allelic diseases; autophagy-modulating small molecules remain preclinical speculation.
  • Surgical: none; no DBS outcomes reported for the dystonia.
  • Experimental / trials: no interventional clinical trials identified on ClinicalTrials.gov for biallelic SQSTM1 disease as of this search. Patient-derived iPSC resources for therapy screening now exist (IGIBi010-A, PMID:39126919).
  • Treatment algorithm: none published; reasonable practice mirrors other childhood-onset ataxia-dystonia syndromes — multidisciplinary neurology, rehabilitation (PT/OT/speech), orthostatic-hypotension management where dysautonomic, educational support, and genetic counseling.

13. Prevention

  • Primary prevention: none possible for the disease itself; genetic counseling of carrier couples (25% recurrence risk) is the principal intervention, particularly in consanguineous families. Carrier testing of relatives once the familial variant is known.
  • Secondary prevention: prenatal diagnosis and preimplantation genetic testing are technically available (a prenatal all-coding-exon SQSTM1 test is registered in GTR, test 578425). No population or newborn screening.
  • Tertiary prevention: rehabilitation to slow functional decline, fall prevention, management of orthostatic hypotension, hearing assessment; no evidence-based protocol exists.
  • Immunization/public-health/behavioral/prophylaxis: not applicable beyond routine care.

---## 14. Other Species / Natural Disease

  • No naturally occurring SQSTM1-deficiency disease is documented in companion animals or wildlife (no OMIA phenotype identified for SQSTM1 orthologs).
  • Orthologs: human SQSTM1 is conserved across vertebrates — mouse Sqstm1 (NCBI Gene 18412 — verify), zebrafish sqstm1; Drosophila has the functional homolog ref(2)P; C. elegans has sqst-1. (Taxon suggestions: NCBITaxon:10090 mouse, NCBITaxon:7955 zebrafish, NCBITaxon:7227 fly, NCBITaxon:6239 worm, NCBITaxon:9606 human.)
  • Comparative biology: the p62 module of selective autophagy is deeply conserved; fly Ref(2)P accumulates in ubiquitinated inclusions of the ageing/autophagy-deficient brain, supporting evolutionary conservation of the aggregate-handling role. Comparative pathology divergence is informative: p62-null mice develop mature-onset obesity/insulin resistance (PMID:16517408) and tau-positive neurodegeneration (PMID:18346206), neither of which is an established feature of human NADGP — a documented human–model mismatch.
  • Zoonosis/transmission: not applicable.

15. Model Organisms

Model System Key findings Recapitulation / limitations
Zebrafish sqstm1 LOF (morphant/mutant; generated to model NADGP) In vivo, vertebrate "Variable cerebellar anomalies ranging from axonal depletion to complete atrophy" plus locomotor impairment (PMID:29959261) Directly recapitulates the cerebellar axis of the human disease; larval model, no gaze-palsy/dystonia readout
p62/Sqstm1 knockout mouse In vivo, mammalian Age-dependent accumulation of hyperphosphorylated tau, neurodegeneration, elevated oxidative stress, synaptic deficits, memory impairment, shortened lifespan (PMID:18346206); mature-onset obesity and insulin resistance (PMID:16517408); p62 centrally required for clearing toxic tau species in tauopathy mice (PMID:35662390) Partially recapitulates neurodegeneration; metabolic phenotype and tau pathology are not documented in human NADGP → fidelity caveat (PARTIALLY_RECAPITULATES / potential HUMAN_MODEL_MISMATCH discussion)
Patient fibroblasts In vitro, human Absent p62 protein; "defect in the early response to mitochondrial depolarization and autophagosome formation" (PMID:27545679) Direct patient material; non-neuronal
Patient urine-derived cells In vitro, human Splicing/protein assay validating a synonymous variant (PMID:39587727) Diagnostic functional model
SQSTM1-KO iPSC-derived human cortical neurons In vitro, human "Altered mitochondrial gene expression and functionality, as well as autophagy flux"; early PINK1-mitophagy steps affected, mitochondrial clearance preserved (PMID:33891871) Human neuronal context; cortical rather than cerebellar identity
Patient iPSC line IGIBi010-A (p.Leu251SerfsTer4) Resource Characterized line for disease modeling (PMID:39126919) Enables future cerebellar-organoid / drug-screen work
Drosophila ref(2)P; C. elegans sqst-1 Invertebrate Conserved aggregate/selective-autophagy biology (background) Mechanistic conservation only

Model databases: MGI (Sqstm1 alleles), ZFIN (sqstm1), IMPC/KOMP (mouse knockouts), Cellosaurus/hPSCreg (IGIBi010-A).

Key open questions (knowledge-gap candidates for the KB entry)

  1. No human neuropathology — the regional-degeneration model is imaging/model-inferred.
  2. Whether tau accumulation and metabolic dysfunction (mouse phenotypes) occur in human p62 deficiency (HUMAN_MODEL_MISMATCH).
  3. Health of heterozygous NADGP-allele carriers vs allelic dominant SQSTM1 diseases.
  4. Natural history, survival, and prognostic markers (no registry exists).
  5. Whether NRF2-axis failure contributes in patients (therapeutically actionable if so).

Primary citations (session-verified PMIDs)

  • PMID:27545679 — Haack TB et al., Am J Hum Genet 2016;99(3):735-743 (index description; 9 patients/4 families)
  • PMID:29959261 — Muto V et al., Neurology 2018;91(4):e319-e330 (11 patients; zebrafish model)
  • PMID:30638816 — Zúñiga-Ramírez C et al., Parkinsonism Relat Disord 2019;62:192-195 (dysautonomia, iridoplegia)
  • PMID:31525130 — Vedartham V et al., Ophthalmic Genet 2019;40(4):376-379 (normal-MRI case)
  • PMID:34147300 — Kilic MA et al., Brain Dev 2021;43(10):1039-1043 (brainstem involvement, myoclonus)
  • PMID:35957775 — Jalali H et al., Clin Case Rep 2022;10(8):e6203 (c.790del)
  • PMID:38279634 — Garg D et al., Mov Disord 2024;39(2):445-447
  • PMID:38532471 — Chacaltana-Vinas C et al., Mov Disord Clin Pract 2024;11(6):746-748 (Peruvian family)
  • PMID:39587727 — Masuko S et al., Mol Genet Genomic Med 2024 (synonymous splice variant; urine-derived cells)
  • PMID:40728085 — de Almeida Marcelino AL et al., Mov Disord Clin Pract 2025 (subacute onset; treatment non-response)
  • PMID:41307082 — Hosseini Moshkenani N et al., Adv Biomed Res 2025 (recurrent c.838G>T)
  • PMID:41482852 — Sharma C et al., Mov Disord Clin Pract 2026 (bilateral INO)
  • PMID:41708390 / PMID:42014241 — Dichoso LP et al. + commentary, Parkinsonism Relat Disord 2026 (Filipino adolescent)
  • PMID:42403283 — Ganguly J et al., J Mov Disord 2026 (myoclonus)
  • PMID:39126919 — Ahmad I et al., Stem Cell Res 2024 (patient iPSC line)
  • PMID:33891871 — Poon A et al., Stem Cell Reports 2021 (iPSC cortical neurons, mitophagy)
  • PMID:29112993 — Ebrahimi-Fakhari D, Neuropediatrics 2018 (congenital disorders of autophagy review)
  • PMID:18346206 — Ramesh Babu J et al., J Neurochem 2008 (p62-KO mouse tau/neurodegeneration)
  • PMID:16517408 — Rodriguez A et al., Cell Metab 2006 (p62-KO mouse obesity)
  • PMID:35662390 — Ono M et al., Aging Cell 2022 (p62 clears toxic tau, mouse)

Background-knowledge citations — re-verify before use as evidence: PMID:16286508 (Bjørkøy 2005), PMID:17580304 (Pankiv 2007), PMID:20173742 (Komatsu 2010), PMID:11992264 (Laurin 2002, PDB), PMID:22084127 (Fecto 2011, ALS).

Sources: - OMIM #617145 — NADGP - OMIM Clinical Synopsis #617145 - Haack et al. 2016, AJHG (full text) - Muto et al. 2018, Neurology - Poon et al. 2021, Stem Cell Reports - Ramesh Babu et al. 2008, J Neurochem (PubMed) - Rodriguez et al. 2006, Cell Metab (PubMed) - Ono et al. 2022, Aging Cell (PubMed) - de Almeida Marcelino et al. 2025, MDCP - Chacaltana-Vinas et al. 2024 (PMC) - Jalali et al. 2022 (PMC) - ClinVar RCV000256198 (p.Arg96Ter) - ClinVar RCV000256191 (p.Glu104fs) - ClinVar RCV001815052 (c.301+2T>A) - ClinVar RCV001815054 (p.Ser294fs) - ClinVar RCV003340920 (c.969+1G>C) - ClinVar RCV002282804 (p.Glu379fs) - ClinVar RCV002252670 (p.Gly262fs) - ClinVar RCV001264728 (p.Arg59fs) - GTR test 578425 (prenatal SQSTM1 sequencing) - Hereditary Ocular Diseases (U. Arizona) — NADGP

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 30
Resolved 30
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 9
Quoted claims found in source 5
Quoted claims not found in source 4
Quoted claims with nothing to check against 1
References weighed for topical relevance 30
On topic 17
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:31525130 (abstract only): "progressive childhood-onset cerebellar ataxia with vertical supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging (brain)"
  • closest text in source: "We describe here a case of progressive childhood-onset cerebellar ataxia with vertical supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging (MRI) of brain"
  • PMID:33891871 (abstract only): "affects early processes of PINK1-dependent mitophagy but is dispensable for mitochondria clearance"
  • closest text in source: "However, SQSTM1 is not essential for mitophagy despite having a significant impact on early PINK1-dependent mitophagy processes including PINK1 recruitment and phosphorylation of ubiquitin on depolarized mitochondria"
  • PMID:29959261 (abstract only): "variable cerebellar anomalies ranging from axonal depletion to complete atrophy"
  • closest text in source: "The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy"
  • PMID:31525130 (abstract only): "emphasize the diagnostic utility of next-generation sequencing in inherited ataxia"
  • closest text in source: "This case highlights the importance of next-generation sequencing in the diagnosis of inherited ataxia syndromes"

Quotes that could not be checked

There was no text to compare these against, so they are neither confirmed nor contradicted:

  • PMID:40728085: "treatment with methylprednisolone, oral penicillin and levodopa/carbidopa led to no improvement, and over the years, treatment with baclofen, trihexyphenidyl and tetrabenazine had no effect on the movement disorder"
  • Reference resolved but exposes no abstract or full text to search

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 41
Resolved 41
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 3
Terms named correctly 0
Terms named as a different term 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • GO:0000045 (1 mention) - the report calls it "verify"; GO calls it autophagosome assembly
  • GO:0034599 (1 mention) - the report calls it "verify"; GO calls it cellular response to oxidative stress
  • UBERON:0002420 (1 mention) - the report calls it "verify"; UBERON calls it basal ganglion