Neuronal Intranuclear Inclusion Disease

Mendelian MONDO:0011327 Pathograph 10 Show in embeddings browser Trinucleotide Repeat Disorder Neurodegenerative Disease

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive, multisystem neurodegenerative disorder defined pathologically by eosinophilic, ubiquitin- and SUMO1-positive intranuclear inclusions in neurons and glia throughout the central, peripheral, and autonomic nervous systems and also in visceral and somatic cells (adipocytes, dermal fibroblasts, sweat gland cells). It is caused by a non-coding GGC repeat expansion in the 5' region of the human-specific gene NOTCH2NLC. The expanded repeat sits inside a small upstream open reading frame and is translated into a toxic polyglycine protein, uN2CpolyG, which accumulates in the inclusions — placing NIID in the "polyG diseases" alongside FXTAS (FMRpolyG) rather than in the translated CAG/polyglutamine family. Clinical expression is strikingly heterogeneous: adult sporadic disease is usually dementia-dominant with miosis, ataxia, and episodes of unconsciousness, whereas early-onset familial disease is usually limb-weakness-dominant with sensory disturbance and bladder dysfunction. The radiologic hallmark — high signal at the corticomedullary junction on diffusion-weighted MRI — together with skin biopsy has converted NIID from a post-mortem diagnosis into an antemortem one, and the disease is now thought to be substantially underdiagnosed.

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1
Mappings
2
Inheritance
8
Pathophys.
1
Histopath.
14
Phenotypes
2
Hypotheses
2
Gaps
10
Pathograph
1
Genes
1
Variants
2
Medical Actions
🔗

Mappings

NCIT
NCIT:C122655 Neuronal Intranuclear Inclusion Disease
skos:exactMatch MONDO:0011327
MONDO:0011327 lists NCIT:C122655 as a cross-reference and the two terms denote the same disease entity. The NCIT definition is dated in one respect — it describes NIID as "usually affects children", which predates the recognition (PMID:27797808) that adult-onset disease dominates the ascertained population once skin biopsy is used — but the entity is the same, so the mapping is exact rather than close.
NCIT
NCIT:C122655 Neuronal Intranuclear Inclusion Disease
skos:exactMatch MONDO:0011327
MONDO:0011327 lists NCIT:C122655 as a cross-reference and the two terms denote the same disease entity. The NCIT definition is dated in one respect — it describes NIID as "usually affects children", which predates the recognition (PMID:27797808) that adult-onset disease dominates the ascertained population once skin biopsy is used — but the entity is the same, so the mapping is exact rather than close.
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Familial NIID segregates as an autosomal dominant trait: linkage analysis in large multiplex families mapped the locus to chromosome 1p, and the NOTCH2NLC GGC repeat expansion was found in all affected members of those families.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:31332381 SUPPORT Human Clinical
"By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members."
Co-segregation of the expansion with affected status in a large multiplex family supports dominant transmission of familial NIID.
PMID:31178126 SUPPORT Human Clinical
"Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1"
Supports a single Mendelian locus for familial NIID at 1p13.3-q23.1 (the NOTCH2NLC region). Note that linkage mapping alone does not establish the mode of inheritance; dominance rests on the co-segregation evidence in the item above and on the pedigrees in this same study.
Sporadic HP:0003745
Most reported NIID cases are sporadic rather than familial, although the same GGC repeat expansion is found in sporadic cases; sporadic and familial cases differ systematically in age at onset and in dominant clinical presentation.
Sporadic
Show evidence (2 references)
PMID:31332381 SUPPORT Human Clinical
"The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases."
Documents that the reported NIID case series is composed mostly of sporadic cases.
PMID:31178126 SUPPORT Human Clinical
"The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported."
Confirms that NIID occurs in both familial and sporadic forms.
◈

Mechanistic Hypotheses

2
Canonical uORF-Translated Polyglycine (uN2CpolyG) Proteotoxicity Model
canonical_un2cpolyg_proteotoxicity_model CANONICAL
Evidence balance 2 support
The dominant model holds that the pathogenic species in NIID is a protein, not the RNA. The expanded GGC repeat lies within a small upstream open reading frame (uN2C) in the NOTCH2NLC 5' UTR; translation through the expanded repeat produces a polyglycine-containing protein, uN2CpolyG, which misfolds, accumulates in the nucleus, and forms the eosinophilic ubiquitin-positive intranuclear inclusions that define the disease. Expression of uN2CpolyG alone is sufficient to cause inclusion formation, neuronal loss, locomotor impairment, and premature death in mice, which is the key causal (rather than merely correlative) evidence for this arm. The model is directly parallel to FMRpolyG in FXTAS and defines a class of polyG diseases.
Pathograph links
NOTCH2NLC 5' UTR GGC Repeat Expansion -> uORF Translation of the Polyglycine Protein uN2CpolyG DIRECT The expanded repeat lies within an upstream open reading frame and is translated through, generating the polyglycine protein.
uORF Translation of the Polyglycine Protein uN2CpolyG -> Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation DIRECT uN2CpolyG accumulates in the nucleus and is a constituent of the intranuclear inclusions.
Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation -> Progressive Neuronal Dysfunction and Loss DIRECT Nuclear accumulation of the polyglycine protein is proteotoxic to long-lived postmitotic neurons.
Show evidence (2 references)
PMID:33887199 SUPPORT In Vitro
"We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG."
Establishes the uORF-translation route from the expanded GGC repeat to the polyglycine protein that is the proposed pathogenic species.
PMID:33887199 SUPPORT Model Organism
"Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals."
Mouse expression of the polyglycine protein alone reproduces neurodegeneration, supporting a causal rather than epiphenomenal role.
Expanded-Repeat RNA Gain-of-Function Model
repeat_rna_gain_of_function_model ALTERNATIVE
Evidence balance 3 support
A non-exclusive alternative arm proposes that the expanded GGC/CGG repeat is also pathogenic at the RNA level, as it is in other non-coding repeat expansion disorders (FXTAS, myotonic dystrophy): expanded-repeat sense and antisense transcripts accumulate and may sequester RNA-binding proteins. Patient-derived fibroblasts show abnormal antisense transcripts that are absent from unaffected individuals, and the disease gene was found by explicitly reasoning from the clinical and neuroimaging similarity to FMR1 CGG-repeat FXTAS. A necessary precondition for this arm is satisfied: the expanded repeat is not hypermethylated even above 200 repeats and NOTCH2NLC expression is unchanged in carriers, so — unlike full-mutation FMR1 — the locus is not silenced and repeat-containing transcript continues to be made. That is permissive, not demonstrative: it shows the substrate exists without showing it is toxic. The relative contribution of RNA toxicity versus uN2CpolyG proteotoxicity in human NIID brain is not resolved.
Pathograph links
NOTCH2NLC 5' UTR GGC Repeat Expansion -> Expanded-Repeat Transcript Accumulation DIRECT Transcription across the expanded repeat yields abnormal sense and antisense repeat-containing transcripts.
Expanded-Repeat Transcript Accumulation -> Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation INDIRECT UNKNOWN INTERMEDIATES Postulated RNA-mediated route to nuclear inclusion pathology, by analogy with RNA-binding-protein sequestration in other non-coding repeat expansion disorders.
Show evidence (3 references)
PMID:31332381 SUPPORT In Vitro
"We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals."
Patient-specific abnormal antisense transcripts are the primary evidence offered for an RNA-level arm of NIID pathogenesis.
PMID:31332380 SUPPORT Human Clinical
"Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1"
The clinical/radiologic parallel to FXTAS, itself a canonical non-coding repeat RNA gain-of-function disorder, motivates the RNA-toxicity arm.
PMID:31178126 SUPPORT INDIRECT Human Clinical
"the expanded GGC repeat does not alter the expression of NOTCH2NLC and that the GGC repeat RNA could potentially play a role in the molecular pathogenesis of NIID"
INDIRECT — unchanged expression of the unmethylated expanded allele establishes that repeat-containing RNA is still produced (a precondition for RNA toxicity) but does not demonstrate that the RNA is itself pathogenic; the authors state it only as a possibility.
?

Discussions and Knowledge Gaps

2
Why does the same non-coding NOTCH2NLC GGC repeat expansion produce phenotypes as different as dementia-dominant adult NIID, early-onset limb-weakness familial NIID, oculopharyngodistal myopathy type 3, parkinsonism, and Alzheimer-disease-like presentations — and what (repeat length, repeat interruption/impurity, methylation, somatic instability, modifier loci) determines which a given carrier develops?
KNOWLEDGE GAP OPEN gap_niid_notch2nlc_genotype_phenotype
Attached to
pathophysiology#NOTCH2NLC 5' UTR GGC Repeat Expansion pathophysiology#Multisystem Neurological Decline
A single lesion class producing a spectrum this wide means allele identity alone cannot be prognostic. The gap is clinically consequential: it blocks counseling of expansion-positive relatives, and it determines whether NIID, OPDM3, and NOTCH2NLC-associated parkinsonism should be curated as one entity or several. The proposal of an umbrella NIID-related disorders category is an explicit acknowledgement that the boundary is unresolved.
Proposed experiments
Pooled NOTCH2NLC expansion genotype-phenotype correlation
exp_niid_pooled_genotype_phenotype
Relate repeat length, repeat purity/interruption, and methylation status to presenting syndrome (NIID dementia-dominant vs NIID limb-weakness vs OPDM3 vs parkinsonism) across a pooled multi-ancestry cohort of expansion carriers.
Tissue-resolved somatic instability and uN2CpolyG burden
exp_niid_tissue_resolved_polyg_burden
Measure somatic repeat instability and uN2CpolyG protein burden in brain versus skeletal muscle from carriers with divergent phenotypes, testing whether tissue-specific expansion or translation efficiency explains the NIID/OPDM3 split.
Show evidence (2 references)
PMID:31178126 SUPPORT Human Clinical
"Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC."
The authors' proposal of an umbrella category is direct evidence that the entity boundaries and genotype-phenotype relationship are unresolved.
PMID:31332380 SUPPORT Human Clinical
"These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases."
Frames the same repeat motif as generating a broad clinical spectrum, which is the substance of this gap.
In human NIID brain, how much of the pathology is driven by the uN2CpolyG polyglycine protein versus by the expanded-repeat RNA itself?
INTERPRETATION OPEN interp_niid_rna_versus_protein_toxicity
Attached to
pathophysiology#uORF Translation of the Polyglycine Protein uN2CpolyG pathophysiology#Expanded-Repeat Transcript Accumulation
The two mechanistic arms curated here are not mutually exclusive and rest on asymmetric evidence: the protein arm has a sufficiency experiment (uN2CpolyG expression alone causes neuronal loss in mice), whereas the RNA arm rests on patient-specific abnormal antisense transcripts in fibroblasts plus analogy to FXTAS. Resolving the balance matters therapeutically, because repeat-RNA-directed strategies (for example antisense oligonucleotides) and polyG-directed strategies target different steps.
Show evidence (2 references)
PMID:33887199 SUPPORT Model Organism
"Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals."
The sufficiency result that makes the protein arm the stronger of the two.
PMID:31332381 SUPPORT INDIRECT In Vitro
"We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals."
The observation supporting an RNA arm; INDIRECT because it is correlative, in fibroblasts rather than brain, and does not establish toxicity.
⚙

Pathophysiology

8
NOTCH2NLC 5' UTR GGC Repeat Expansion
The initiating lesion is an expanded non-coding GGC (CGG) trinucleotide repeat in the 5' region of NOTCH2NLC, a human-specific gene that arose by segmental duplication of NOTCH2. The expansion was identified independently by two long-read-sequencing studies and by a targeted repeat search, in familial and sporadic NIID alike. Because the repeat is non-coding, the mechanism is not loss of NOTCH2NLC function but a gain-of-function acting through the expanded repeat itself.
Canonical uORF-Translated Polyglycine (uN2CpolyG) Proteotoxicity Model Expanded-Repeat RNA Gain-of-Function Model
NOTCH2NLC hgnc:53924 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves abnormal NOTCH2NLC (hgnc:53924). hgnc:53924 is a gene from the HUGO Gene Nomenclature Committee. ⚠ ABNORMAL
Downstream
uORF Translation of the Polyglycine Protein uN2CpolyG The expanded repeat lies within an upstream open reading frame and is translated through, generating the polyglycine protein. Canonical uORF-Translated Polyglycine (uN2CpolyG) Proteotoxicity Model
Expanded-Repeat Transcript Accumulation Transcription across the expanded repeat yields abnormal sense and antisense repeat-containing transcripts. Expanded-Repeat RNA Gain-of-Function Model
Show evidence (3 references)
PMID:31332381 SUPPORT Human Clinical
"This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease."
Establishes the NOTCH2NLC GGC repeat expansion as the causal lesion of NIID.
PMID:31178126 SUPPORT Human Clinical
"We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC."
Independent replication of the causal repeat expansion in a separate NIID cohort.
PMID:31332380 SUPPORT Human Clinical
"we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID"
Third independent identification of the non-coding repeat expansion as the NIID mutation.
uORF Translation of the Polyglycine Protein uN2CpolyG
The expanded GGC repeat is embedded in a small upstream open reading frame (uN2C) in the NOTCH2NLC 5' UTR. Translation of that uORF reads through the expanded repeat and produces uN2CpolyG, a protein carrying a long polyglycine tract. This is the same class of event as RAN/uORF translation of FMRpolyG from the FMR1 CGG premutation in FXTAS, and it is what makes NIID a polyglycine rather than a polyglutamine disease.
Canonical uORF-Translated Polyglycine (uN2CpolyG) Proteotoxicity Model
translation GO:0006412 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal translation (GO:0006412). GO:0006412 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation uN2CpolyG accumulates in the nucleus and is a constituent of the intranuclear inclusions. Canonical uORF-Translated Polyglycine (uN2CpolyG) Proteotoxicity Model
Show evidence (2 references)
PMID:33887199 SUPPORT In Vitro
"We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG."
Directly demonstrates uORF translation of the expanded repeat into the polyglycine protein.
PMID:33887199 SUPPORT Human Clinical
"NIID is caused by an expansion of GGC repeats in the 5' UTR of the NOTCH2NLC (N2C) gene."
Confirms the 5' UTR location of the expansion that places it within the upstream ORF.
Expanded-Repeat Transcript Accumulation
Transcription across the expanded repeat produces abnormal repeat-containing transcripts, including antisense transcripts detectable in patient fibroblasts but not in cells from unaffected individuals. By analogy with FXTAS and other non-coding repeat expansion disorders, such transcripts are candidate mediators of an RNA gain-of-function arm; their contribution in human NIID brain remains unquantified.
Expanded-Repeat RNA Gain-of-Function Model
gene expression GO:0010467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal gene expression (GO:0010467). GO:0010467 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation Postulated RNA-mediated route to nuclear inclusion pathology, by analogy with RNA-binding-protein sequestration in other non-coding repeat expansion disorders. Expanded-Repeat RNA Gain-of-Function Model
Show evidence (1 reference)
PMID:31332381 SUPPORT In Vitro
"We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals."
Demonstrates patient-specific abnormal antisense transcripts arising from the expanded locus.
Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation
The defining pathological lesion is an eosinophilic, hyaline, ubiquitin- and SUMO1-positive intranuclear inclusion. NIID is a systemic inclusion-body disease: inclusions occur in neurons and glia of the central, peripheral, and autonomic nervous systems, in visceral organs, and in somatic cells of the skin — adipocytes, fibroblasts, and sweat gland cells — where they are ultrastructurally identical to those in neurons. This node conforms to the conserved misfolded-protein aggregation step of the proteostasis module, substituting uN2CpolyG as the aggregating species and the widely distributed neuronal, glial, and somatic cells as the affected populations.
Canonical uORF-Translated Polyglycine (uN2CpolyG) Proteotoxicity Model
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. glial cell CL:0000125 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glial cell (CL:0000125). CL:0000125 is a cell type from the Cell Ontology. dermal fibroblast CL:0002551 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves dermal fibroblast, annotated with fibroblast of dermis (CL:0002551). CL:0002551 is a cell type from the Cell Ontology. adipocyte CL:0000136 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves adipocyte (CL:0000136). CL:0000136 is a cell type from the Cell Ontology. sweat gland epithelial cell CL:1000448 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves sweat gland epithelial cell, annotated with epithelial cell of sweat gland (CL:1000448). CL:1000448 is a cell type from the Cell Ontology.
inclusion body assembly GO:0070841 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inclusion body assembly (GO:0070841). GO:0070841 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Progressive Neuronal Dysfunction and Loss Nuclear accumulation of the polyglycine protein is proteotoxic to long-lived postmitotic neurons. Canonical uORF-Translated Polyglycine (uN2CpolyG) Proteotoxicity Model
Show evidence (5 references)
PMID:21411744 SUPPORT Human Clinical
"In NIID skin biopsy samples, intranuclear inclusions were observed in adipocytes, fibroblasts, and sweat gland cells."
Establishes the somatic (skin) cell types carrying the inclusions.
PMID:21411744 SUPPORT Human Clinical
"These inclusions were stained with both anti-ubiquitin and anti-SUMO1 antibodies."
Documents the ubiquitin/SUMO1 immunoprofile of the inclusions.
PMID:21411744 SUPPORT Human Clinical
"Electron microscopy revealed that the features of the intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells were identical to those of neuronal cells."
Shows the somatic and neuronal inclusions are the same lesion, supporting a single systemic aggregation process.
+ 2 more references
Progressive Neuronal Dysfunction and Loss
Proteotoxic nuclear accumulation of uN2CpolyG produces progressive neuronal dysfunction and neuronal loss. The strongest causal evidence is from mouse models expressing uN2CpolyG, which develop neuronal cell loss, locomotor impairment, and premature death; the corresponding human evidence is the slowly progressive neurodegenerative course.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
neuron apoptotic process GO:0051402 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased neuron apoptotic process (GO:0051402). GO:0051402 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Corticomedullary-Junction Leukoencephalopathy Neuronal and glial injury is accompanied by the characteristic white-matter abnormality at the corticomedullary junction.
Peripheral and Autonomic Nerve Involvement Inclusion-bearing peripheral and autonomic neurons develop conduction abnormality and clinical neuropathy.
Multisystem Neurological Decline Cumulative neuronal loss produces the progressive clinical syndrome.
Show evidence (3 references)
PMID:33887199 SUPPORT Model Organism
"Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals."
Mouse model evidence that the polyglycine protein causes neuronal loss and progressive neurological impairment.
PMID:33887199 SUPPORT In Vitro
"These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID."
States the authors' causal chain from polyglycine translation to inclusions and neurodegeneration.
PMID:27797808 SUPPORT Human Clinical
"Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs."
Establishes the slowly progressive neurodegenerative course in humans.
Corticomedullary-Junction Leukoencephalopathy
NIID produces a distinctive leukoencephalopathy whose radiologic signature is high signal intensity along the corticomedullary junction on diffusion-weighted MRI. In a 57-case adult-onset series this finding was present in both sporadic and familial cases and in all dementia-dominant cases, and it is the single strongest imaging clue to the diagnosis. NIID therefore belongs in the differential diagnosis of adult leukoencephalopathy.
Downstream
Multisystem Neurological Decline White-matter disruption contributes to the dementia-dominant cognitive phenotype.
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis."
Establishes the corticomedullary-junction DWI hyperintensity as the characteristic imaging finding.
PMID:27797808 SUPPORT Human Clinical
"All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging."
Links the leukoencephalopathy to the dementia-dominant clinical subgroup.
Peripheral and Autonomic Nerve Involvement
Inclusions are present in peripheral and autonomic neurons, and nerve conduction studies are frequently abnormal in both sporadic and familial NIID, alongside elevated cerebrospinal fluid protein. Clinically this arm produces sensory disturbance, muscle weakness, miosis, and bladder dysfunction.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology.
Downstream
Multisystem Neurological Decline Peripheral and autonomic involvement contributes weakness, sensory loss, miosis, and bladder dysfunction to the clinical syndrome.
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases."
Documents frequent nerve-conduction abnormality and raised CSF protein as evidence of peripheral nerve involvement.
PMID:42428984 SUPPORT Human Clinical
"eosinophilic intranuclear inclusion bodies in the nuclei of neurons in the central, peripheral, and autonomic nervous systems"
Confirms that the inclusion pathology extends to peripheral and autonomic neurons.
Multisystem Neurological Decline
The clinical endpoint is a slowly progressive, highly heterogeneous multisystem neurological syndrome. Two clinicopathologically defined presentations recur: a dementia-dominant group (sporadic, later onset, with miosis, ataxia, and episodes of unconsciousness) and a limb-weakness-dominant group (familial, onset before 40, with sensory disturbance, miosis, and bladder dysfunction). Episodic features — headache, fever, altered consciousness, and seizures — punctuate the course and are a frequent source of misdiagnosis.
Show evidence (3 references)
PMID:27797808 SUPPORT Human Clinical
"In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness."
Defines the dementia-dominant sporadic presentation and its component features.
PMID:27797808 SUPPORT Human Clinical
"It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia."
Defines the early-onset familial limb-weakness presentation.
PMID:42428984 SUPPORT Human Clinical
"The clinical presentation of this disease is diverse, manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction, making it prone to misdiagnosis in clinical practice."
Summarizes the heterogeneous multisystem clinical output and its diagnostic consequence.
✶

Histopathology

1
Eosinophilic hyaline intranuclear inclusions
The diagnostic lesion is an eosinophilic hyaline intranuclear inclusion that is ubiquitin- and SUMO1-immunoreactive. It is found in neurons and glia and, critically for antemortem diagnosis, in skin adipocytes, fibroblasts, and sweat gland cells, where roughly 10% of adipocytes carry inclusions and where they are ultrastructurally identical to the neuronal inclusions. Inclusions are absent from normal controls and from patients with other neurological diseases.
Show evidence (3 references)
PMID:21411744 SUPPORT Human Clinical
"Approximately 10% of adipocytes showed intranuclear inclusions."
Quantifies the inclusion burden in skin adipocytes, the basis of the skin-biopsy test.
PMID:21411744 SUPPORT Human Clinical
"No intranuclear inclusions were identified in the skin samples from normal control subjects and patients with other neurologic diseases."
Establishes the specificity of the skin inclusion finding against controls and other neurological disease.
PMID:27797808 SUPPORT Human Clinical
"based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion"
States the histopathological diagnostic criterion used to define adult-onset NIID cases.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Neuronal Intranuclear Inclusion Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Genitourinary 1
Bladder Dysfunction FREQUENT Neurogenic bladder HP:0000011 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurogenic bladder (HP:0000011). HP:0000011 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"followed by sensory disturbance, miosis, bladder dysfunction, and dementia"
Lists bladder dysfunction among the leading features of familial early-onset NIID.
PMID:31178126 SUPPORT Human Clinical
"The main clinical manifestations in these affected familial individuals included bladder dysfunction (56.4%)"
Quantifies bladder dysfunction at 56.4% in the 40-patient familial expansion-carrier cohort, mapping to the FREQUENT band (79-30%); the sporadic subset of the same study is concordant at 60%.
Musculoskeletal 1
Muscle Weakness FREQUENT HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324), qualified as course progressive. HP:0001324 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (3 references)
PMID:27797808 SUPPORT Human Clinical
"It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia."
Establishes muscle weakness as the universal presenting feature of early-onset familial NIID.
PMID:27797808 SUPPORT Human Clinical
"Muscle weakness and sensory disturbance were also observed."
Confirms muscle weakness also occurs in the sporadic group.
PMID:31178126 SUPPORT Human Clinical
"bladder dysfunction (56.4%), tremor (47.5%), muscle weakness (46.2%)"
Quantifies muscle weakness at 46.2% across the 40-patient familial expansion-carrier cohort, mapping to the FREQUENT band (79-30%); the 100% figure in the other series is specific to the early-onset limb-weakness subgroup.
Nervous System 11
Dementia HP:0000726 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dementia (HP:0000726), qualified as course progressive. HP:0000726 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness."
Quantifies dementia as the initial symptom in 94.7% of sporadic adult-onset NIID cases.
PMID:27797808 SUPPORT Human Clinical
"Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores."
Provides instrumented evidence of cognitive decline in both sporadic and familial NIID.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352). HP:0002352 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis."
Establishes the imaging phenotype and its diagnostic value.
PMID:27797808 SUPPORT Human Clinical
"We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy."
Positions NIID within the adult leukoencephalopathy differential.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27797808 SUPPORT Human Clinical
"followed by miosis, ataxia and unconsciousness"
Lists ataxia among the most frequent features of the sporadic dementia-dominant group.
Somatic Sensory Disturbance FREQUENT Somatic sensory dysfunction HP:0003474 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Somatic sensory dysfunction (HP:0003474). HP:0003474 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia"
Ranks sensory disturbance immediately after weakness in early-onset familial NIID.
PMID:31178126 SUPPORT Human Clinical
"abnormal behavior (37.5%), sensory disturbance (35.1%), dementia (35.0%)"
Quantifies sensory disturbance at 35.1% in the familial expansion-carrier cohort, mapping to the FREQUENT band (79-30%).
Peripheral Neuropathy HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases."
Documents frequent electrophysiological neuropathy in NIID.
PMID:27797808 SUPPORT Human Clinical
"We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy."
Places NIID in the adult neuropathy differential diagnosis.
Autonomic Dysfunction Abnormal autonomic nervous system physiology HP:0012332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal autonomic nervous system physiology (HP:0012332). HP:0012332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42428984 SUPPORT Human Clinical
"manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction"
Lists autonomic dysfunction as part of the recognized NIID presentation.
Episodic Encephalopathy HP:0001298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Encephalopathy (HP:0001298), qualified as temporality recurrent. HP:0001298 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:42428984 SUPPORT Human Clinical
"The clinical presentation of this disease is diverse, manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction, making it prone to misdiagnosis in clinical practice."
Documents altered consciousness with headache and fever as part of the NIID presentation and its diagnostic consequence.
PMID:27797808 SUPPORT Human Clinical
"followed by miosis, ataxia and unconsciousness"
Lists unconsciousness among the leading features of sporadic adult-onset NIID.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42428984 SUPPORT Human Clinical
"manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction"
Lists seizures within the recognized NIID clinical spectrum.
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42428984 SUPPORT Human Clinical
"manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction"
Lists headache within the recognized NIID clinical spectrum.
Tremor FREQUENT HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31178126 SUPPORT Human Clinical
"The main clinical manifestations in these affected familial individuals included bladder dysfunction (56.4%), tremor (47.5%), muscle weakness (46.2%), abnormal behavior (37.5%), sensory disturbance (35.1%), dementia (35.0%), rigidity (30.0%), bradykinesia (30.0%), ataxia (17.5%), disturbance of..."
Directly quantifies tremor at 47.5% in the familial expansion-carrier cohort, which maps to the FREQUENT band (79-30%).
PMID:31178126 SUPPORT Human Clinical
"Tremor was frequently seen in the early stages of almost all of the affected members."
Documents tremor as an early feature within the muscle-weakness-dominant subgroup.
Parkinsonism HP:0001300 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Parkinsonism (HP:0001300). HP:0001300 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31178126 SUPPORT Human Clinical
"Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD."
Supports parkinsonism as part of the NOTCH2NLC expansion spectrum; marked PARTIAL because these families were ascertained as parkinsonism/AD rather than as classical NIID.
Other 1
Miosis HP:0000616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Miosis (HP:0000616). HP:0000616 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness"
Lists miosis among the leading features of sporadic adult-onset NIID.
PMID:27797808 SUPPORT Human Clinical
"muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia"
Confirms miosis also occurs in the early-onset familial presentation.
🧬

Genetic Associations

1
NOTCH2NLC (Causative non-coding GGC (CGG) repeat expansion in the 5' region/5' UTR)
Gene: NOTCH2NLC hgnc:53924 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NOTCH2NLC (hgnc:53924). hgnc:53924 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (6 references)
PMID:31332381 SUPPORT Human Clinical
"Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases."
Establishes the expansion across multiple unrelated families and a large sporadic case series.
PMID:31178126 SUPPORT Human Clinical
"Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects."
Independent confirmation of the causal expansion in additional familial and sporadic NIID cases.
PMID:31332380 SUPPORT Human Clinical
"we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively"
Places the NIID expansion within a family of non-coding CGG repeat disorders sharing a repeat motif across different host genes.
+ 3 more references
Variants (1)
NOTCH2NLC 5' region GGC repeat expansion Pathogenic
Gene: NOTCH2NLC hgnc:53924 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in NOTCH2NLC (hgnc:53924). hgnc:53924 is a gene from the HUGO Gene Nomenclature Committee. trinucleotide repeat expansion
Expansion of the non-coding GGC (CGG) trinucleotide repeat in the 5' region/5' UTR of NOTCH2NLC, above the normal repeat-length range. The expanded repeat is embedded in the uN2C upstream open reading frame and is translated into the polyglycine protein uN2CpolyG. Reported allele sizes in affected individuals span 66-517 repeats, against a control distribution of 5-38 (usually under 40) repeats in 211 healthy subjects. Repeat length shows no clear association with severity or age at onset, though it tracks loosely with presenting subgroup in the discovery cohort (muscle-weakness-dominant 118-517, dementia-dominant 91-268, parkinsonism-dominant 66-102) — which is why the genotype-phenotype relationship is curated below as an open knowledge gap rather than as a rule.
💊

Medical Actions

2
Symptomatic and Supportive 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. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists for NIID. Management is symptomatic and supportive, directed at the individual patient's dominant problems (cognitive decline, weakness, neuropathic symptoms, seizures, autonomic and bladder dysfunction), and is best delivered as coordinated multidisciplinary care alongside early diagnosis.
Show evidence (1 reference)
PMID:42428984 SUPPORT Human Clinical
"emphasizing the importance of early diagnosis and comprehensive treatment in managing this rare neurological disorder"
Supports early diagnosis plus comprehensive (supportive, multidisciplinary) management as the current standard; no disease-modifying option is described.
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. Ontology label: Genetic Counseling NCIT:C15240
Because familial NIID is autosomal dominant and caused by a defined repeat expansion, genetic counseling and NOTCH2NLC repeat-length testing are relevant for probands and at-risk relatives.
Show evidence (1 reference)
PMID:31332381 SUPPORT Human Clinical
"By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members."
Establishes a defined, testable germline lesion segregating in families, which is the basis for counseling and cascade testing.
🔬

Biochemical Markers

1
Cerebrospinal fluid protein
Show evidence (1 reference)
PMID:27797808 SUPPORT Human Clinical
"Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases."
Documents frequently elevated CSF protein as a laboratory finding in NIID.
🔬

Diagnosis

3
Skin Biopsy
Skin biopsy demonstrating eosinophilic, ubiquitin/p62- and SUMO1-positive intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells is the established, minimally invasive antemortem diagnostic procedure for NIID. Its adoption converted NIID from a post-mortem to an antemortem diagnosis and is directly responsible for the rise in adult-onset NIID case ascertainment. In current practice it is paired with NOTCH2NLC repeat-length genetic testing.
skin biopsy with immunohistochemistry for intranuclear inclusions NCIT:C51692 NCI Thesaurus (NCIT)
Results: Eosinophilic ubiquitin/p62- and SUMO1-positive intranuclear inclusions in dermal adipocytes, fibroblasts, and sweat gland cells
Unlike the corticomedullary-junction DWI sign, the skin-biopsy finding was positive in all familial expansion carriers examined in PMID:31178126, so it does not lose sensitivity in the early-onset familial group.
Show evidence (5 references)
PMID:21411744 SUPPORT Human Clinical
"Skin biopsy is an effective and less invasive antemortem diagnostic tool for NIID."
States the conclusion establishing skin biopsy as the antemortem diagnostic procedure.
PMID:21411744 SUPPORT Human Clinical
"No intranuclear inclusions were identified in the skin samples from normal control subjects and patients with other neurologic diseases."
Establishes the specificity of the skin inclusion finding against controls and other neurological disease.
PMID:27797808 SUPPORT Human Clinical
"since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID"
Documents the effect of skin biopsy on NIID case ascertainment.
+ 2 more references
Diffusion-Weighted Brain MRI
High signal intensity along the corticomedullary junction on diffusion-weighted brain MRI is the strongest antemortem imaging clue to NIID and, together with skin biopsy, underpins the published diagnostic flow chart for adult-onset disease. It was present in all dementia-dominant cases in the largest adult-onset series. Sensitivity is presentation-dependent rather than universal: in an independent familial cohort only about 37.5% of expansion carriers showed the classic corticomedullary DWI lesion, so a negative MRI does not exclude NIID — particularly in the early-onset limb-weakness group.
diffusion-weighted brain MRI NCIT:C111116 NCI Thesaurus (NCIT)
Results: Symmetrical high signal at the corticomedullary junction on DWI, with white matter hyperintensity on FLAIR/T2
Show evidence (4 references)
PMID:27797808 SUPPORT Human Clinical
"Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis."
Establishes the corticomedullary-junction DWI sign as the key antemortem imaging clue in both sporadic and familial NIID.
PMID:27797808 SUPPORT Human Clinical
"All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging."
Quantifies complete penetrance of the imaging finding within the dementia-dominant group.
PMID:27797808 SUPPORT Human Clinical
"Based on these clinicopathological features, we proposed a diagnosis flow chart of adult-onset NIID."
Documents that these imaging and pathological features were assembled into a formal diagnostic algorithm.
+ 1 more reference
NOTCH2NLC GGC Repeat-Length Genetic Testing
Sizing the non-coding GGC repeat in the 5' region of NOTCH2NLC is the molecular confirmatory test. Because the repeat is GC-rich and can be very long, it is assayed by repeat-primed PCR combined with GC-rich PCR, or by long-read sequencing; short-read exome sequencing does not resolve it. Affected individuals in the discovery cohorts carried more than 66 repeats, against a control range of roughly 5-38 (usually under 40) repeats.
NOTCH2NLC GGC repeat-length testing NCIT:C15709 NCI Thesaurus (NCIT)
Markers: NOTCH2NLC 5' GGC repeat length
Results: Expanded 5' NOTCH2NLC GGC repeat (>66 repeats reported in affected individuals; controls usually <40)
Show evidence (4 references)
PMID:31178126 SUPPORT Human Clinical
"we designed primer sets for both repeat-primed PCR (RP-PCR) and GC-rich PCR (GC-PCR) assays to detect both normal and expanded GGC repeats"
Describes the assay pair used to size the expansion, which is the basis of the clinical genetic test.
PMID:31178126 SUPPORT Human Clinical
"Among the 211 healthy control subjects that we examined, the GGC repeat sizes range from 5 to 38, with modes at 11 and 16 repeats"
Provides the control repeat-length distribution against which an expanded allele is called.
PMID:31178126 SUPPORT Human Clinical
"All affected individuals from both familial and sporadic case subjects carried an expanded GGC repeat larger than 66."
Provides the affected repeat-length threshold observed across familial and sporadic cases.
+ 1 more reference
📈

Progression

2
Onset
Age: Mean 59.7 years overall; familial early-onset cases before age 40
Age at onset is bimodal with respect to presentation: sporadic adult cases in the largest series had onset between 51 and 76 years and presented with dementia, whereas familial cases with onset before 40 years presented with limb weakness. Familial cases with onset after 40 resemble the sporadic dementia-dominant group.
Show evidence (2 references)
PMID:31332381 SUPPORT Human Clinical
"The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases."
Provides the mean age at onset across the reported NIID case literature.
PMID:27797808 SUPPORT Human Clinical
"In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%)"
Documents the sporadic adult-onset age range and its dementia-dominant presentation.
Progressive course
NIID is slowly progressive. Cognitive decline is measurable on MMSE and the Frontal Assessment Battery in both sporadic and familial disease. No quantitative survival data are curated here.
Show evidence (2 references)
PMID:27797808 SUPPORT Human Clinical
"Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs."
Establishes the slowly progressive natural history.
PMID:27797808 SUPPORT Human Clinical
"Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores."
Documents instrumented cognitive decline over the disease course.
📊

Prevalence

1
Worldwide (reported NIID case literature, pre-2019)
Cases In Literature Unknown
Approximately 140 NIID cases had been reported at the time the causal expansion was identified, mostly sporadic. No population-based prevalence estimate is cited here; the true frequency is unknown and probably underestimated because antemortem diagnosis only became practical after skin biopsy and MRI criteria were established.
Show evidence (2 references)
PMID:31332381 SUPPORT Human Clinical
"The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases."
Provides the reported case count in the literature at the time of gene discovery.
PMID:27797808 SUPPORT Human Clinical
"Our study suggested that the prevalence rate of adult-onset NIID may be higher than previously thought, and that NIID may be underdiagnosed."
Supports the statement that NIID is underdiagnosed and its true prevalence higher than the reported case count implies.
{ }

Source YAML

click to show 
name: Neuronal Intranuclear Inclusion Disease
creation_date: "2026-07-11T12:00:00Z"
category: Mendelian
parents:
- Trinucleotide Repeat Disorder
- Neurodegenerative Disease
synonyms:
- NIID
- neuronal intranuclear hyaline inclusion disease
- Intranuclear inclusion body disease
- NIID-related disorders
- NIIDRD
description: >-
  Neuronal intranuclear inclusion disease (NIID) is a slowly progressive, multisystem
  neurodegenerative disorder defined pathologically by eosinophilic, ubiquitin- and
  SUMO1-positive intranuclear inclusions in neurons and glia throughout the central,
  peripheral, and autonomic nervous systems and also in visceral and somatic cells
  (adipocytes, dermal fibroblasts, sweat gland cells). It is caused by a non-coding GGC
  repeat expansion in the 5' region of the human-specific gene NOTCH2NLC. The expanded
  repeat sits inside a small upstream open reading frame and is translated into a toxic
  polyglycine protein, uN2CpolyG, which accumulates in the inclusions — placing NIID in
  the "polyG diseases" alongside FXTAS (FMRpolyG) rather than in the translated
  CAG/polyglutamine family. Clinical expression is strikingly heterogeneous: adult
  sporadic disease is usually dementia-dominant with miosis, ataxia, and episodes of
  unconsciousness, whereas early-onset familial disease is usually limb-weakness-dominant
  with sensory disturbance and bladder dysfunction. The radiologic hallmark — high
  signal at the corticomedullary junction on diffusion-weighted MRI — together with skin
  biopsy has converted NIID from a post-mortem diagnosis into an antemortem one, and the
  disease is now thought to be substantially underdiagnosed.
disease_term:
  preferred_term: Neuronal Intranuclear Inclusion Disease
  term:
    id: MONDO:0011327
    label: neuronal intranuclear inclusion disease
mappings:
  ncit_mappings:
  - term:
      id: NCIT:C122655
      label: Neuronal Intranuclear Inclusion Disease
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO:0011327
    mapping_justification: >-
      MONDO:0011327 lists NCIT:C122655 as a cross-reference and the two terms denote the
      same disease entity. The NCIT definition is dated in one respect — it describes NIID
      as "usually affects children", which predates the recognition (PMID:27797808) that
      adult-onset disease dominates the ascertained population once skin biopsy is used —
      but the entity is the same, so the mapping is exact rather than close.
notes: >-
  Scope and boundary notes. (1) NIID is a polyGLYCINE disease driven by a NON-coding
  GGC/CGG repeat translated from an upstream ORF; it deliberately does NOT declare
  conformance to the `polyglutamine_expansion_proteotoxicity` module, which is explicitly
  scoped to translated CAG/polyQ disorders. (2) The same NOTCH2NLC repeat expansion also
  causes oculopharyngodistal myopathy type 3 (see the `Oculopharyngodistal Myopathy`
  entry, which cross-references NIID); the determinants of the NIID-versus-OPDM3
  phenotypic split are unresolved and are captured as a knowledge gap below. (3) A
  conformance edge to `peripheral_axonal_degeneration` is a plausible follow-up for the
  peripheral-nerve arm, but the currently cited evidence (frequent nerve-conduction
  abnormality) does not by itself establish the distal axonal-degeneration/demyelination
  chain, so it is not asserted here. (4) There is no disease-modifying therapy; the
  triggering case report (PMID:42428984) discusses potential therapeutic implications
  only and is cited for clinical/diagnostic description, never as sole support for a
  mechanistic claim.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Familial NIID segregates as an autosomal dominant trait: linkage analysis in large
    multiplex families mapped the locus to chromosome 1p, and the NOTCH2NLC GGC repeat
    expansion was found in all affected members of those families.
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members."
    explanation: Co-segregation of the expansion with affected status in a large multiplex family supports dominant transmission of familial NIID.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1"
    explanation: >-
      Supports a single Mendelian locus for familial NIID at 1p13.3-q23.1 (the NOTCH2NLC
      region). Note that linkage mapping alone does not establish the mode of inheritance;
      dominance rests on the co-segregation evidence in the item above and on the
      pedigrees in this same study.
- name: Sporadic
  inheritance_term:
    preferred_term: Sporadic
    term:
      id: HP:0003745
      label: Sporadic
  description: >-
    Most reported NIID cases are sporadic rather than familial, although the same GGC
    repeat expansion is found in sporadic cases; sporadic and familial cases differ
    systematically in age at onset and in dominant clinical presentation.
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases."
    explanation: Documents that the reported NIID case series is composed mostly of sporadic cases.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported."
    explanation: Confirms that NIID occurs in both familial and sporadic forms.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_un2cpolyg_proteotoxicity_model
  hypothesis_label: Canonical uORF-Translated Polyglycine (uN2CpolyG) Proteotoxicity Model
  status: CANONICAL
  description: >-
    The dominant model holds that the pathogenic species in NIID is a protein, not the
    RNA. The expanded GGC repeat lies within a small upstream open reading frame (uN2C)
    in the NOTCH2NLC 5' UTR; translation through the expanded repeat produces a
    polyglycine-containing protein, uN2CpolyG, which misfolds, accumulates in the
    nucleus, and forms the eosinophilic ubiquitin-positive intranuclear inclusions that
    define the disease. Expression of uN2CpolyG alone is sufficient to cause inclusion
    formation, neuronal loss, locomotor impairment, and premature death in mice, which is
    the key causal (rather than merely correlative) evidence for this arm. The model is
    directly parallel to FMRpolyG in FXTAS and defines a class of polyG diseases.
  evidence:
  - reference: PMID:33887199
    reference_title: "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG."
    explanation: Establishes the uORF-translation route from the expanded GGC repeat to the polyglycine protein that is the proposed pathogenic species.
  - reference: PMID:33887199
    reference_title: "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals."
    explanation: Mouse expression of the polyglycine protein alone reproduces neurodegeneration, supporting a causal rather than epiphenomenal role.
- hypothesis_group_id: repeat_rna_gain_of_function_model
  hypothesis_label: Expanded-Repeat RNA Gain-of-Function Model
  status: ALTERNATIVE
  description: >-
    A non-exclusive alternative arm proposes that the expanded GGC/CGG repeat is also
    pathogenic at the RNA level, as it is in other non-coding repeat expansion disorders
    (FXTAS, myotonic dystrophy): expanded-repeat sense and antisense transcripts
    accumulate and may sequester RNA-binding proteins. Patient-derived fibroblasts show
    abnormal antisense transcripts that are absent from unaffected individuals, and the
    disease gene was found by explicitly reasoning from the clinical and neuroimaging
    similarity to FMR1 CGG-repeat FXTAS. A necessary precondition for this arm is
    satisfied: the expanded repeat is not hypermethylated even above 200 repeats and
    NOTCH2NLC expression is unchanged in carriers, so — unlike full-mutation FMR1 — the
    locus is not silenced and repeat-containing transcript continues to be made. That is
    permissive, not demonstrative: it shows the substrate exists without showing it is
    toxic. The relative contribution of RNA toxicity versus uN2CpolyG proteotoxicity in
    human NIID brain is not resolved.
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals."
    explanation: Patient-specific abnormal antisense transcripts are the primary evidence offered for an RNA-level arm of NIID pathogenesis.
  - reference: PMID:31332380
    reference_title: "Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1"
    explanation: The clinical/radiologic parallel to FXTAS, itself a canonical non-coding repeat RNA gain-of-function disorder, motivates the RNA-toxicity arm.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "the expanded GGC repeat does not alter the expression of NOTCH2NLC and that the GGC repeat RNA could potentially play a role in the molecular pathogenesis of NIID"
    explanation: INDIRECT — unchanged expression of the unmethylated expanded allele establishes that repeat-containing RNA is still produced (a precondition for RNA toxicity) but does not demonstrate that the RNA is itself pathogenic; the authors state it only as a possibility.
pathophysiology:
- name: NOTCH2NLC 5' UTR GGC Repeat Expansion
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The initiating lesion is an expanded non-coding GGC (CGG) trinucleotide repeat in the
    5' region of NOTCH2NLC, a human-specific gene that arose by segmental duplication of
    NOTCH2. The expansion was identified independently by two long-read-sequencing
    studies and by a targeted repeat search, in familial and sporadic NIID alike. Because
    the repeat is non-coding, the mechanism is not loss of NOTCH2NLC function but a
    gain-of-function acting through the expanded repeat itself.
  gene:
    preferred_term: NOTCH2NLC
    modifier: ABNORMAL
    term:
      id: hgnc:53924
      label: NOTCH2NLC
  downstream:
  - target: uORF Translation of the Polyglycine Protein uN2CpolyG
    causal_link_type: DIRECT
    description: >-
      The expanded repeat lies within an upstream open reading frame and is translated
      through, generating the polyglycine protein.
    hypothesis_groups:
    - canonical_un2cpolyg_proteotoxicity_model
  - target: Expanded-Repeat Transcript Accumulation
    causal_link_type: DIRECT
    description: >-
      Transcription across the expanded repeat yields abnormal sense and antisense
      repeat-containing transcripts.
    hypothesis_groups:
    - repeat_rna_gain_of_function_model
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease."
    explanation: Establishes the NOTCH2NLC GGC repeat expansion as the causal lesion of NIID.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC."
    explanation: Independent replication of the causal repeat expansion in a separate NIID cohort.
  - reference: PMID:31332380
    reference_title: "Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID"
    explanation: Third independent identification of the non-coding repeat expansion as the NIID mutation.
- name: uORF Translation of the Polyglycine Protein uN2CpolyG
  biological_scale: MOLECULAR
  role: mediator
  description: >-
    The expanded GGC repeat is embedded in a small upstream open reading frame (uN2C) in
    the NOTCH2NLC 5' UTR. Translation of that uORF reads through the expanded repeat and
    produces uN2CpolyG, a protein carrying a long polyglycine tract. This is the same
    class of event as RAN/uORF translation of FMRpolyG from the FMR1 CGG premutation in
    FXTAS, and it is what makes NIID a polyglycine rather than a polyglutamine disease.
  biological_processes:
  - preferred_term: translation
    term:
      id: GO:0006412
      label: translation
    modifier: ABNORMAL
  downstream:
  - target: Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation
    causal_link_type: DIRECT
    description: >-
      uN2CpolyG accumulates in the nucleus and is a constituent of the intranuclear
      inclusions.
    hypothesis_groups:
    - canonical_un2cpolyg_proteotoxicity_model
  evidence:
  - reference: PMID:33887199
    reference_title: "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that these repeats are embedded in a small upstream open reading frame (uORF) (uN2C), resulting in their translation into a polyglycine-containing protein, uN2CpolyG."
    explanation: Directly demonstrates uORF translation of the expanded repeat into the polyglycine protein.
  - reference: PMID:33887199
    reference_title: "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NIID is caused by an expansion of GGC repeats in the 5' UTR of the NOTCH2NLC (N2C) gene."
    explanation: Confirms the 5' UTR location of the expansion that places it within the upstream ORF.
- name: Expanded-Repeat Transcript Accumulation
  biological_scale: MOLECULAR
  role: mediator
  description: >-
    Transcription across the expanded repeat produces abnormal repeat-containing
    transcripts, including antisense transcripts detectable in patient fibroblasts but
    not in cells from unaffected individuals. By analogy with FXTAS and other non-coding
    repeat expansion disorders, such transcripts are candidate mediators of an RNA
    gain-of-function arm; their contribution in human NIID brain remains unquantified.
  biological_processes:
  - preferred_term: gene expression
    term:
      id: GO:0010467
      label: gene expression
    modifier: ABNORMAL
  downstream:
  - target: Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Postulated RNA-mediated route to nuclear inclusion pathology, by analogy with
      RNA-binding-protein sequestration in other non-coding repeat expansion disorders.
    hypothesis_groups:
    - repeat_rna_gain_of_function_model
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals."
    explanation: Demonstrates patient-specific abnormal antisense transcripts arising from the expanded locus.
- name: Eosinophilic Ubiquitin-Positive Intranuclear Inclusion Formation
  biological_scale: CELLULAR
  role: effector
  conforms_to: "loss_of_proteostasis#Misfolded-Protein Aggregation"
  description: >-
    The defining pathological lesion is an eosinophilic, hyaline, ubiquitin- and
    SUMO1-positive intranuclear inclusion. NIID is a systemic inclusion-body disease:
    inclusions occur in neurons and glia of the central, peripheral, and autonomic
    nervous systems, in visceral organs, and in somatic cells of the skin — adipocytes,
    fibroblasts, and sweat gland cells — where they are ultrastructurally identical to
    those in neurons. This node conforms to the conserved misfolded-protein aggregation
    step of the proteostasis module, substituting uN2CpolyG as the aggregating species
    and the widely distributed neuronal, glial, and somatic cells as the affected
    populations.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: glial cell
    term:
      id: CL:0000125
      label: glial cell
  - preferred_term: dermal fibroblast
    term:
      id: CL:0002551
      label: fibroblast of dermis
  - preferred_term: adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  - preferred_term: sweat gland epithelial cell
    term:
      id: CL:1000448
      label: epithelial cell of sweat gland
  biological_processes:
  - preferred_term: inclusion body assembly
    term:
      id: GO:0070841
      label: inclusion body assembly
    modifier: INCREASED
  downstream:
  - target: Progressive Neuronal Dysfunction and Loss
    causal_link_type: DIRECT
    description: >-
      Nuclear accumulation of the polyglycine protein is proteotoxic to long-lived
      postmitotic neurons.
    hypothesis_groups:
    - canonical_un2cpolyg_proteotoxicity_model
  evidence:
  - reference: PMID:21411744
    reference_title: "Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In NIID skin biopsy samples, intranuclear inclusions were observed in adipocytes, fibroblasts, and sweat gland cells."
    explanation: Establishes the somatic (skin) cell types carrying the inclusions.
  - reference: PMID:21411744
    reference_title: "Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These inclusions were stained with both anti-ubiquitin and anti-SUMO1 antibodies."
    explanation: Documents the ubiquitin/SUMO1 immunoprofile of the inclusions.
  - reference: PMID:21411744
    reference_title: "Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopy revealed that the features of the intranuclear inclusions in adipocytes, fibroblasts, and sweat gland cells were identical to those of neuronal cells."
    explanation: Shows the somatic and neuronal inclusions are the same lesion, supporting a single systemic aggregation process.
  - reference: PMID:33887199
    reference_title: "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This protein accumulates in intranuclear inclusions in cell and mouse models and in tissue samples of individuals with NIID."
    explanation: Identifies uN2CpolyG as a component of the inclusions in patient tissue, linking the aggregating species to the lesion.
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuronal intranuclear inclusion disease (NIID) is a chronic progressive neurodegenerative disorder characterized by the formation of eosinophilic intranuclear inclusion bodies in the nuclei of neurons in the central, peripheral, and autonomic nervous systems, as well as visceral organs."
    explanation: Confirms the multisystem anatomical distribution of the inclusions.
- name: Progressive Neuronal Dysfunction and Loss
  biological_scale: CELLULAR
  role: effector
  description: >-
    Proteotoxic nuclear accumulation of uN2CpolyG produces progressive neuronal
    dysfunction and neuronal loss. The strongest causal evidence is from mouse models
    expressing uN2CpolyG, which develop neuronal cell loss, locomotor impairment, and
    premature death; the corresponding human evidence is the slowly progressive
    neurodegenerative course.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  downstream:
  - target: Corticomedullary-Junction Leukoencephalopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neuronal and glial injury is accompanied by the characteristic white-matter
      abnormality at the corticomedullary junction.
  - target: Peripheral and Autonomic Nerve Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inclusion-bearing peripheral and autonomic neurons develop conduction abnormality
      and clinical neuropathy.
  - target: Multisystem Neurological Decline
    causal_link_type: DIRECT
    description: >-
      Cumulative neuronal loss produces the progressive clinical syndrome.
  evidence:
  - reference: PMID:33887199
    reference_title: "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals."
    explanation: Mouse model evidence that the polyglycine protein causes neuronal loss and progressive neurological impairment.
  - reference: PMID:33887199
    reference_title: "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These results suggest that translation of expanded GGC repeats into a novel and pathogenic polyglycine-containing protein underlies the presence of intranuclear inclusions and neurodegeneration in NIID."
    explanation: States the authors' causal chain from polyglycine translation to inclusions and neurodegeneration.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs."
    explanation: Establishes the slowly progressive neurodegenerative course in humans.
- name: Corticomedullary-Junction Leukoencephalopathy
  biological_scale: TISSUE
  role: effector
  description: >-
    NIID produces a distinctive leukoencephalopathy whose radiologic signature is high
    signal intensity along the corticomedullary junction on diffusion-weighted MRI. In a
    57-case adult-onset series this finding was present in both sporadic and familial
    cases and in all dementia-dominant cases, and it is the single strongest imaging clue
    to the diagnosis. NIID therefore belongs in the differential diagnosis of adult
    leukoencephalopathy.
  downstream:
  - target: Multisystem Neurological Decline
    causal_link_type: DIRECT
    description: >-
      White-matter disruption contributes to the dementia-dominant cognitive phenotype.
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis."
    explanation: Establishes the corticomedullary-junction DWI hyperintensity as the characteristic imaging finding.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging."
    explanation: Links the leukoencephalopathy to the dementia-dominant clinical subgroup.
- name: Peripheral and Autonomic Nerve Involvement
  biological_scale: TISSUE
  role: effector
  description: >-
    Inclusions are present in peripheral and autonomic neurons, and nerve conduction
    studies are frequently abnormal in both sporadic and familial NIID, alongside
    elevated cerebrospinal fluid protein. Clinically this arm produces sensory
    disturbance, muscle weakness, miosis, and bladder dysfunction.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  downstream:
  - target: Multisystem Neurological Decline
    causal_link_type: DIRECT
    description: >-
      Peripheral and autonomic involvement contributes weakness, sensory loss, miosis,
      and bladder dysfunction to the clinical syndrome.
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases."
    explanation: Documents frequent nerve-conduction abnormality and raised CSF protein as evidence of peripheral nerve involvement.
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eosinophilic intranuclear inclusion bodies in the nuclei of neurons in the central, peripheral, and autonomic nervous systems"
    explanation: Confirms that the inclusion pathology extends to peripheral and autonomic neurons.
- name: Multisystem Neurological Decline
  biological_scale: ORGANISM
  role: outcome
  description: >-
    The clinical endpoint is a slowly progressive, highly heterogeneous multisystem
    neurological syndrome. Two clinicopathologically defined presentations recur: a
    dementia-dominant group (sporadic, later onset, with miosis, ataxia, and episodes of
    unconsciousness) and a limb-weakness-dominant group (familial, onset before 40, with
    sensory disturbance, miosis, and bladder dysfunction). Episodic features — headache,
    fever, altered consciousness, and seizures — punctuate the course and are a frequent
    source of misdiagnosis.
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness."
    explanation: Defines the dementia-dominant sporadic presentation and its component features.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia."
    explanation: Defines the early-onset familial limb-weakness presentation.
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation of this disease is diverse, manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction, making it prone to misdiagnosis in clinical practice."
    explanation: Summarizes the heterogeneous multisystem clinical output and its diagnostic consequence.
phenotypes:
- name: Dementia
  category: Neurological
  diagnostic: true
  description: >-
    Progressive cognitive decline is the dominant presenting feature of adult sporadic
    NIID, present as the initial symptom in 94.7% of the sporadic cases in the largest
    adult-onset series, with measurable decline on MMSE and Frontal Assessment Battery.
  phenotype_term:
    preferred_term: Dementia
    clinical_course: PROGRESSIVE
    term:
      id: HP:0000726
      label: Dementia
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness."
    explanation: Quantifies dementia as the initial symptom in 94.7% of sporadic adult-onset NIID cases.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores."
    explanation: Provides instrumented evidence of cognitive decline in both sporadic and familial NIID.
- name: Leukoencephalopathy
  category: Neurological
  diagnostic: true
  description: >-
    Diffuse white matter disease with the characteristic diffusion-weighted MRI high
    signal at the corticomedullary junction. This is the key antemortem imaging clue and
    places NIID in the differential diagnosis of adult leukoencephalopathy.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis."
    explanation: Establishes the imaging phenotype and its diagnostic value.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy."
    explanation: Positions NIID within the adult leukoencephalopathy differential.
- name: Miosis
  category: Ophthalmologic
  description: >-
    Pupillary constriction is a characteristic autonomic sign of NIID, reported in both
    the sporadic dementia-dominant and the familial limb-weakness presentations.
  phenotype_term:
    preferred_term: Miosis
    term:
      id: HP:0000616
      label: Miosis
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness"
    explanation: Lists miosis among the leading features of sporadic adult-onset NIID.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia"
    explanation: Confirms miosis also occurs in the early-onset familial presentation.
- name: Ataxia
  category: Neurological
  description: >-
    Ataxia is a common feature of sporadic adult-onset NIID, ranking behind dementia and
    miosis among the leading clinical signs.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by miosis, ataxia and unconsciousness"
    explanation: Lists ataxia among the most frequent features of the sporadic dementia-dominant group.
- name: Muscle Weakness
  category: Neuromuscular
  frequency: FREQUENT
  description: >-
    Limb weakness is the defining and universal feature of the early-onset familial
    presentation, present in 100% of familial cases with onset before age 40, and is also
    observed in sporadic cases.
  phenotype_term:
    preferred_term: Muscle weakness
    clinical_course: PROGRESSIVE
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia."
    explanation: Establishes muscle weakness as the universal presenting feature of early-onset familial NIID.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle weakness and sensory disturbance were also observed."
    explanation: Confirms muscle weakness also occurs in the sporadic group.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bladder dysfunction (56.4%), tremor (47.5%), muscle weakness (46.2%)"
    explanation: Quantifies muscle weakness at 46.2% across the 40-patient familial expansion-carrier cohort, mapping to the FREQUENT band (79-30%); the 100% figure in the other series is specific to the early-onset limb-weakness subgroup.
- name: Somatic Sensory Disturbance
  category: Neurological
  frequency: FREQUENT
  description: >-
    Sensory disturbance accompanies the peripheral nerve involvement of NIID, is the
    second most frequent feature of the early-onset familial limb-weakness group, and is
    reported in 35.1% of familial NOTCH2NLC expansion carriers overall.
  phenotype_term:
    preferred_term: Somatic sensory dysfunction
    term:
      id: HP:0003474
      label: Somatic sensory dysfunction
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia"
    explanation: Ranks sensory disturbance immediately after weakness in early-onset familial NIID.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal behavior (37.5%), sensory disturbance (35.1%), dementia (35.0%)"
    explanation: Quantifies sensory disturbance at 35.1% in the familial expansion-carrier cohort, mapping to the FREQUENT band (79-30%).
- name: Peripheral Neuropathy
  category: Neurological
  description: >-
    Clinical and electrophysiological peripheral neuropathy is frequent in NIID; nerve
    conduction studies are abnormal in both sporadic and familial cases, and NIID should
    be considered in the differential diagnosis of adult neuropathy.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases."
    explanation: Documents frequent electrophysiological neuropathy in NIID.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy."
    explanation: Places NIID in the adult neuropathy differential diagnosis.
- name: Bladder Dysfunction
  category: Genitourinary
  frequency: FREQUENT
  description: >-
    Bladder dysfunction is a recognized autonomic feature of NIID, prominent in the
    early-onset familial limb-weakness group, and is the single most common clinical
    manifestation (56.4%) across familial NOTCH2NLC expansion carriers.
  phenotype_term:
    preferred_term: Neurogenic bladder
    term:
      id: HP:0000011
      label: Neurogenic bladder
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by sensory disturbance, miosis, bladder dysfunction, and dementia"
    explanation: Lists bladder dysfunction among the leading features of familial early-onset NIID.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical manifestations in these affected familial individuals included bladder dysfunction (56.4%)"
    explanation: Quantifies bladder dysfunction at 56.4% in the 40-patient familial expansion-carrier cohort, mapping to the FREQUENT band (79-30%); the sporadic subset of the same study is concordant at 60%.
- name: Autonomic Dysfunction
  category: Autonomic
  description: >-
    Autonomic involvement — reflecting inclusion pathology in the autonomic nervous
    system — is part of the recognized NIID clinical spectrum and includes pupillary and
    bladder abnormality.
  phenotype_term:
    preferred_term: Abnormal autonomic nervous system physiology
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
  evidence:
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction"
    explanation: Lists autonomic dysfunction as part of the recognized NIID presentation.
- name: Episodic Encephalopathy
  category: Neurological
  description: >-
    Episodes of altered consciousness or encephalopathy — often with headache and fever —
    punctuate the NIID course and are a leading cause of misdiagnosis; unconsciousness is
    among the leading features of the sporadic dementia-dominant group.
  phenotype_term:
    preferred_term: Encephalopathy
    temporality: RECURRENT
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation of this disease is diverse, manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction, making it prone to misdiagnosis in clinical practice."
    explanation: Documents altered consciousness with headache and fever as part of the NIID presentation and its diagnostic consequence.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by miosis, ataxia and unconsciousness"
    explanation: Lists unconsciousness among the leading features of sporadic adult-onset NIID.
- name: Seizure
  category: Neurological
  description: >-
    Seizures occur in NIID, often in the context of the episodic encephalopathic
    presentations.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction"
    explanation: Lists seizures within the recognized NIID clinical spectrum.
- name: Headache
  category: Neurological
  description: >-
    Headache, frequently accompanying the episodic encephalopathic attacks, is part of
    the NIID clinical spectrum.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting as headaches, fever, altered consciousness, dementia, seizures, sensory and motor disturbances, and autonomic dysfunction"
    explanation: Lists headache within the recognized NIID clinical spectrum.
- name: Tremor
  category: Neurological
  frequency: FREQUENT
  description: >-
    Tremor is one of the most common clinical features of NOTCH2NLC expansion carriers,
    reported in 47.5% of 40 affected familial individuals — second only to bladder
    dysfunction — and is frequently an early sign in the muscle-weakness-dominant subgroup.
    Its prominence is one of the clinical parallels between NIID and FXTAS, the other
    non-coding CGG/GGC repeat disorder.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main clinical manifestations in these affected familial individuals included bladder dysfunction (56.4%), tremor (47.5%), muscle weakness (46.2%), abnormal behavior (37.5%), sensory disturbance (35.1%), dementia (35.0%), rigidity (30.0%), bradykinesia (30.0%), ataxia (17.5%), disturbance of consciousness (17.5%), miosis (17.2%), stroke-like episodes (10.0%), and encephalitic episodes (5.0%)"
    explanation: Directly quantifies tremor at 47.5% in the familial expansion-carrier cohort, which maps to the FREQUENT band (79-30%).
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tremor was frequently seen in the early stages of almost all of the affected members."
    explanation: Documents tremor as an early feature within the muscle-weakness-dominant subgroup.
- name: Parkinsonism
  category: Neurological
  description: >-
    NOTCH2NLC GGC repeat expansions have been identified in families presenting with
    parkinsonism (and with Alzheimer disease), prompting the proposal of a broader
    category of NIID-related disorders. Parkinsonism is therefore part of the NOTCH2NLC
    expansion phenotypic spectrum rather than of classical NIID alone.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD."
    explanation: Supports parkinsonism as part of the NOTCH2NLC expansion spectrum; marked PARTIAL because these families were ascertained as parkinsonism/AD rather than as classical NIID.
biochemical:
- name: Cerebrospinal fluid protein
  notes: >-
    Cerebrospinal fluid protein is frequently elevated in NIID, in both sporadic and
    familial cases, consistent with the peripheral nerve and root involvement. No
    disorder-specific reference interval is curated here.
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases."
    explanation: Documents frequently elevated CSF protein as a laboratory finding in NIID.
genetic:
- name: NOTCH2NLC
  gene_term:
    preferred_term: NOTCH2NLC
    term:
      id: hgnc:53924
      label: NOTCH2NLC
  association: Causative non-coding GGC (CGG) repeat expansion in the 5' region/5' UTR
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    NOTCH2NLC is a human-specific gene generated by segmental duplication of NOTCH2. The
    NIID mutation is an expanded non-coding GGC/CGG repeat in its 5' region, discovered
    independently by long-read sequencing in two NIID cohorts and by a targeted repeat
    search. Because the repeat is non-coding and lies within an upstream ORF,
    pathogenicity is a gain of function (polyglycine protein production and possible RNA
    toxicity), not NOTCH2NLC haploinsufficiency. Two observations reinforce that reading
    and bear on the two curated mechanistic arms: unlike the FMR1 CGG repeat, NOTCH2NLC
    alleles exceeding 200 repeats are NOT hypermethylated, and NOTCH2NLC expression in
    carrier blood is unchanged — so the locus is neither silenced nor transcriptionally
    upregulated, and the expanded repeat continues to be transcribed and thus available
    both for uORF translation and for RNA-level effects. The same expanded repeat also
    causes oculopharyngodistal myopathy type 3, and has been found in families ascertained
    for parkinsonism and Alzheimer disease.
  variants:
  - name: NOTCH2NLC 5' region GGC repeat expansion
    description: >-
      Expansion of the non-coding GGC (CGG) trinucleotide repeat in the 5' region/5' UTR
      of NOTCH2NLC, above the normal repeat-length range. The expanded repeat is embedded
      in the uN2C upstream open reading frame and is translated into the polyglycine
      protein uN2CpolyG. Reported allele sizes in affected individuals span 66-517
      repeats, against a control distribution of 5-38 (usually under 40) repeats in 211
      healthy subjects. Repeat length shows no clear association with severity or age at
      onset, though it tracks loosely with presenting subgroup in the discovery cohort
      (muscle-weakness-dominant 118-517, dementia-dominant 91-268, parkinsonism-dominant
      66-102) — which is why the genotype-phenotype relationship is curated below as an
      open knowledge gap rather than as a rule.
    gene:
      preferred_term: NOTCH2NLC
      term:
        id: hgnc:53924
        label: NOTCH2NLC
    type: trinucleotide repeat expansion
    clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases."
    explanation: Establishes the expansion across multiple unrelated families and a large sporadic case series.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects."
    explanation: Independent confirmation of the causal expansion in additional familial and sporadic NIID cases.
  - reference: PMID:31332380
    reference_title: "Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively"
    explanation: Places the NIID expansion within a family of non-coding CGG repeat disorders sharing a repeat motif across different host genes.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a wide range (66-517) of repeat numbers were observed in affected individuals, while control subjects have fewer than 40 repeats"
    explanation: Provides the affected and control repeat-length ranges quoted in the variant description.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is no apparent association between GGC repeat size and the severity or the onset age in NIID"
    explanation: Establishes that repeat length alone is not prognostic, which is the substance of the curated genotype-phenotype knowledge gap.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "many expanded alleles associated with NIID-affected individuals exceeded 200 repeats but were not methylated"
    explanation: Supports the statement that, unlike FMR1, the expanded NOTCH2NLC repeat is not hypermethylated and the locus is therefore not transcriptionally silenced.
prevalence:
- population: Worldwide (reported NIID case literature, pre-2019)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Approximately 140 NIID cases had been reported at the time the causal expansion was
    identified, mostly sporadic. No population-based prevalence estimate is cited here;
    the true frequency is unknown and probably underestimated because antemortem
    diagnosis only became practical after skin biopsy and MRI criteria were established.
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases."
    explanation: Provides the reported case count in the literature at the time of gene discovery.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study suggested that the prevalence rate of adult-onset NIID may be higher than previously thought, and that NIID may be underdiagnosed."
    explanation: Supports the statement that NIID is underdiagnosed and its true prevalence higher than the reported case count implies.
progression:
- phase: Onset
  age_range: Mean 59.7 years overall; familial early-onset cases before age 40
  notes: >-
    Age at onset is bimodal with respect to presentation: sporadic adult cases in the
    largest series had onset between 51 and 76 years and presented with dementia, whereas
    familial cases with onset before 40 years presented with limb weakness. Familial
    cases with onset after 40 resemble the sporadic dementia-dominant group.
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases."
    explanation: Provides the mean age at onset across the reported NIID case literature.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%)"
    explanation: Documents the sporadic adult-onset age range and its dementia-dominant presentation.
- phase: Progressive course
  notes: >-
    NIID is slowly progressive. Cognitive decline is measurable on MMSE and the Frontal
    Assessment Battery in both sporadic and familial disease. No quantitative survival
    data are curated here.
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs."
    explanation: Establishes the slowly progressive natural history.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores."
    explanation: Documents instrumented cognitive decline over the disease course.
histopathology:
- name: Eosinophilic hyaline intranuclear inclusions
  description: >-
    The diagnostic lesion is an eosinophilic hyaline intranuclear inclusion that is
    ubiquitin- and SUMO1-immunoreactive. It is found in neurons and glia and, critically
    for antemortem diagnosis, in skin adipocytes, fibroblasts, and sweat gland cells,
    where roughly 10% of adipocytes carry inclusions and where they are
    ultrastructurally identical to the neuronal inclusions. Inclusions are absent from
    normal controls and from patients with other neurological diseases.
  evidence:
  - reference: PMID:21411744
    reference_title: "Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 10% of adipocytes showed intranuclear inclusions."
    explanation: Quantifies the inclusion burden in skin adipocytes, the basis of the skin-biopsy test.
  - reference: PMID:21411744
    reference_title: "Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No intranuclear inclusions were identified in the skin samples from normal control subjects and patients with other neurologic diseases."
    explanation: Establishes the specificity of the skin inclusion finding against controls and other neurological disease.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion"
    explanation: States the histopathological diagnostic criterion used to define adult-onset NIID cases.
diagnosis:
- name: Skin Biopsy
  diagnosis_term:
    preferred_term: skin biopsy with immunohistochemistry for intranuclear inclusions
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  description: >-
    Skin biopsy demonstrating eosinophilic, ubiquitin/p62- and SUMO1-positive intranuclear
    inclusions in adipocytes, fibroblasts, and sweat gland cells is the established,
    minimally invasive antemortem diagnostic procedure for NIID. Its adoption converted
    NIID from a post-mortem to an antemortem diagnosis and is directly responsible for the
    rise in adult-onset NIID case ascertainment. In current practice it is paired with
    NOTCH2NLC repeat-length genetic testing.
  results: Eosinophilic ubiquitin/p62- and SUMO1-positive intranuclear inclusions in dermal adipocytes, fibroblasts, and sweat gland cells
  notes: >-
    Unlike the corticomedullary-junction DWI sign, the skin-biopsy finding was positive in
    all familial expansion carriers examined in PMID:31178126, so it does not lose
    sensitivity in the early-onset familial group.
  evidence:
  - reference: PMID:21411744
    reference_title: "Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin biopsy is an effective and less invasive antemortem diagnostic tool for NIID."
    explanation: States the conclusion establishing skin biopsy as the antemortem diagnostic procedure.
  - reference: PMID:21411744
    reference_title: "Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No intranuclear inclusions were identified in the skin samples from normal control subjects and patients with other neurologic diseases."
    explanation: Establishes the specificity of the skin inclusion finding against controls and other neurological disease.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID"
    explanation: Documents the effect of skin biopsy on NIID case ascertainment.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, all skin biopsies revealed eosinophilic, p62-positive, and ubiquitin-positive intranuclear inclusions in dermal cells"
    explanation: Independent series in which every expansion carrier biopsied showed the diagnostic dermal inclusion, supporting the sensitivity claim in the notes.
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This article reports a case of NIID diagnosed through skin biopsy and genetic testing, along with a review of relevant literature."
    explanation: Confirms current practice pairs skin biopsy with genetic testing for diagnosis.
- name: Diffusion-Weighted Brain MRI
  diagnosis_term:
    preferred_term: diffusion-weighted brain MRI
    term:
      id: NCIT:C111116
      label: Diffusion Weighted Imaging
  description: >-
    High signal intensity along the corticomedullary junction on diffusion-weighted brain
    MRI is the strongest antemortem imaging clue to NIID and, together with skin biopsy,
    underpins the published diagnostic flow chart for adult-onset disease. It was present
    in all dementia-dominant cases in the largest adult-onset series. Sensitivity is
    presentation-dependent rather than universal: in an independent familial cohort only
    about 37.5% of expansion carriers showed the classic corticomedullary DWI lesion, so a
    negative MRI does not exclude NIID — particularly in the early-onset limb-weakness
    group.
  results: Symmetrical high signal at the corticomedullary junction on DWI, with white matter hyperintensity on FLAIR/T2
  evidence:
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis."
    explanation: Establishes the corticomedullary-junction DWI sign as the key antemortem imaging clue in both sporadic and familial NIID.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging."
    explanation: Quantifies complete penetrance of the imaging finding within the dementia-dominant group.
  - reference: PMID:27797808
    reference_title: "Clinicopathological features of adult-onset neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on these clinicopathological features, we proposed a diagnosis flow chart of adult-onset NIID."
    explanation: Documents that these imaging and pathological features were assembled into a formal diagnostic algorithm.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only about 37.5% of affected familial individuals presented with the classical NIID radiological findings of symmetrical hyperintense linear lesions in the corticomedullary junction in DWI"
    explanation: PARTIAL because it confirms the sign occurs but bounds its sensitivity in familial cases, showing a negative DWI cannot exclude the diagnosis.
- name: NOTCH2NLC GGC Repeat-Length Genetic Testing
  diagnosis_term:
    preferred_term: NOTCH2NLC GGC repeat-length testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Sizing the non-coding GGC repeat in the 5' region of NOTCH2NLC is the molecular
    confirmatory test. Because the repeat is GC-rich and can be very long, it is assayed by
    repeat-primed PCR combined with GC-rich PCR, or by long-read sequencing; short-read
    exome sequencing does not resolve it. Affected individuals in the discovery cohorts
    carried more than 66 repeats, against a control range of roughly 5-38 (usually under
    40) repeats.
  results: Expanded 5' NOTCH2NLC GGC repeat (>66 repeats reported in affected individuals; controls usually <40)
  markers: NOTCH2NLC 5' GGC repeat length
  evidence:
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we designed primer sets for both repeat-primed PCR (RP-PCR) and GC-rich PCR (GC-PCR) assays to detect both normal and expanded GGC repeats"
    explanation: Describes the assay pair used to size the expansion, which is the basis of the clinical genetic test.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 211 healthy control subjects that we examined, the GGC repeat sizes range from 5 to 38, with modes at 11 and 16 repeats"
    explanation: Provides the control repeat-length distribution against which an expanded allele is called.
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals from both familial and sporadic case subjects carried an expanded GGC repeat larger than 66."
    explanation: Provides the affected repeat-length threshold observed across familial and sporadic cases.
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This article reports a case of NIID diagnosed through skin biopsy and genetic testing, along with a review of relevant literature."
    explanation: Confirms that genetic testing is used alongside skin biopsy in current diagnostic practice.
treatments:
- name: Symptomatic and Supportive Care
  description: >-
    No disease-modifying therapy exists for NIID. Management is symptomatic and
    supportive, directed at the individual patient's dominant problems (cognitive
    decline, weakness, neuropathic symptoms, seizures, autonomic and bladder
    dysfunction), and is best delivered as coordinated multidisciplinary care alongside
    early diagnosis.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:42428984
    reference_title: "Neuronal Intranuclear Inclusion Disease: A Case Report With Insights Into Clinical Features and Potential Therapeutic Implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "emphasizing the importance of early diagnosis and comprehensive treatment in managing this rare neurological disorder"
    explanation: Supports early diagnosis plus comprehensive (supportive, multidisciplinary) management as the current standard; no disease-modifying option is described.
- name: Genetic Counseling
  description: >-
    Because familial NIID is autosomal dominant and caused by a defined repeat expansion,
    genetic counseling and NOTCH2NLC repeat-length testing are relevant for probands and
    at-risk relatives.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members."
    explanation: Establishes a defined, testable germline lesion segregating in families, which is the basis for counseling and cascade testing.
discussions:
- discussion_id: gap_niid_notch2nlc_genotype_phenotype
  prompt: >-
    Why does the same non-coding NOTCH2NLC GGC repeat expansion produce phenotypes as
    different as dementia-dominant adult NIID, early-onset limb-weakness familial NIID,
    oculopharyngodistal myopathy type 3, parkinsonism, and Alzheimer-disease-like
    presentations — and what (repeat length, repeat interruption/impurity, methylation,
    somatic instability, modifier loci) determines which a given carrier develops?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#NOTCH2NLC 5' UTR GGC Repeat Expansion
  - pathophysiology#Multisystem Neurological Decline
  rationale: >-
    A single lesion class producing a spectrum this wide means allele identity alone
    cannot be prognostic. The gap is clinically consequential: it blocks counseling of
    expansion-positive relatives, and it determines whether NIID, OPDM3, and
    NOTCH2NLC-associated parkinsonism should be curated as one entity or several. The
    proposal of an umbrella NIID-related disorders category is an explicit
    acknowledgement that the boundary is unresolved.
  proposed_experiments:
  - experiment_id: exp_niid_pooled_genotype_phenotype
    name: Pooled NOTCH2NLC expansion genotype-phenotype correlation
    description: >-
      Relate repeat length, repeat purity/interruption, and methylation status to
      presenting syndrome (NIID dementia-dominant vs NIID limb-weakness vs OPDM3 vs
      parkinsonism) across a pooled multi-ancestry cohort of expansion carriers.
  - experiment_id: exp_niid_tissue_resolved_polyg_burden
    name: Tissue-resolved somatic instability and uN2CpolyG burden
    description: >-
      Measure somatic repeat instability and uN2CpolyG protein burden in brain versus
      skeletal muscle from carriers with divergent phenotypes, testing whether
      tissue-specific expansion or translation efficiency explains the NIID/OPDM3 split.
  evidence:
  - reference: PMID:31178126
    reference_title: "Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC."
    explanation: The authors' proposal of an umbrella category is direct evidence that the entity boundaries and genotype-phenotype relationship are unresolved.
  - reference: PMID:31332380
    reference_title: "Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases."
    explanation: Frames the same repeat motif as generating a broad clinical spectrum, which is the substance of this gap.
- discussion_id: interp_niid_rna_versus_protein_toxicity
  prompt: >-
    In human NIID brain, how much of the pathology is driven by the uN2CpolyG polyglycine
    protein versus by the expanded-repeat RNA itself?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#uORF Translation of the Polyglycine Protein uN2CpolyG
  - pathophysiology#Expanded-Repeat Transcript Accumulation
  rationale: >-
    The two mechanistic arms curated here are not mutually exclusive and rest on
    asymmetric evidence: the protein arm has a sufficiency experiment (uN2CpolyG
    expression alone causes neuronal loss in mice), whereas the RNA arm rests on
    patient-specific abnormal antisense transcripts in fibroblasts plus analogy to FXTAS.
    Resolving the balance matters therapeutically, because repeat-RNA-directed strategies
    (for example antisense oligonucleotides) and polyG-directed strategies target
    different steps.
  evidence:
  - reference: PMID:33887199
    reference_title: "Translation of GGC repeat expansions into a toxic polyglycine protein in NIID defines a novel class of human genetic disorders: The polyG diseases."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, expression of uN2CpolyG in mice leads to locomotor alterations, neuronal cell loss, and premature death of the animals."
    explanation: The sufficiency result that makes the protein arm the stronger of the two.
  - reference: PMID:31332381
    reference_title: "Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals."
    explanation: The observation supporting an RNA arm; INDIRECT because it is correlative, in fibroblasts rather than brain, and does not establish toxicity.
datasets: []