EIEE1_ARX
- Gene
- ARX
- Disease
- EIEE1
- Inheritance
- XR
- Classification
- Definitive
- Total Score
- 16.5
- Publications Reviewed
- 7
- Publication Span
- 17.66 years
- Last Updated
- 08/18/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt
Description
ARX-related early infantile epileptic encephalopathy/West syndrome is supported by X-linked familial linkage and multiple reports of ARX polyalanine repeat expansions, especially the first polyalanine tract expansion c.333_334ins(GCG)7 / pA1 expansion from 16 to 23 alanines and recurrent exon 2 polyalanine expansions associated with infantile spasms, hypsarrhythmia, developmental delay/intellectual disability, dystonia, and related epileptic encephalopathy phenotypes. Experimental support includes an Arx(GCG)10+7 knock-in mouse model recapitulating infantile spasm-like events, seizures, EEG abnormalities, behavioral impairment, and interneuron deficits, with additional gene-level ARX developmental studies supporting a role in interneuron migration and forebrain development.
Genetic evidence
Total: 11.5
| Singular Evidence | Probands | PMID:21204215 | 6 | Screened 98 unrelated patients with intellectual disability plus infantile epilepsy and/or hand dystonia; ARX polyalanine expansions were identified in four familial cases, including c.333_334ins(GCG)7 in a male with severe intellectual disability, West syndrome, spasticity, dystonia, dyskinesia, and affected relatives. |
| Singular Evidence | Probands | PMID:9307258 | 3 | Two unrelated X-linked infantile spasms/West syndrome families with multiple affected males showing infantile spasms or seizures, hypsarrhythmia, and severe/profound developmental impairment; the study mapped the disease interval to Xp11.4-Xpter before ARX was identified, so this is linkage-level rather than ARX repeat-specific proband evidence. |
| Singular Evidence | Probands | PMID:12874418 | One of eight patients with sporadic cryptogenic West syndrome carried a de novo hemizygous ARX exon 2 c.441_464dup 24-bp duplication expanding the second polyalanine tract from 12 to 20 alanines; the paper also notes prior reports of the same mutation in 57 patients from 12 families. | |
| Collective Evidence | Segregation | PMID:9307258 | 1.5 | In two X-linked infantile spasms families, markers DXS336, DXS333, DXS389, and DMD43 were completely linked with disease; combined linkage gave maximal LOD 2.357 for DXS989 and DMD49 at recombination fraction 0.0 and multipoint LOD 2.36 across Xpter-Xp11.4. This predates ARX identification and is not repeat-specific. |
| Collective Evidence | Allele | PMID:11889467 | 1 | ARX polyalanine expansion size/location was associated with phenotype: the first tract expansion from 16 to 23 alanines ((GCG)10+7) was reported in ISSX/West syndrome families, while a second tract expansion from 12 to 20 alanines occurred across X-linked MR/epilepsy/Partington phenotypes; expansions were absent from >300 control chromosomes. |
Experimental evidence
Total: 5
| Functional Alteration | Patient cells | PMID:26029707 | 1 | |
| Functional Alteration | Non-patient cells | PMID:12874418 | 0.5 | |
| Models | Non-human model organism | PMID:19587282 PMID:11889467 | 2 | PMID:19587282 generated a viable Arx(GCG)10+7 knock-in mouse model matching the human first polyalanine tract expansion, with infantile spasm-like myoclonus, persistent seizures/EEG abnormalities, cognitive and behavioral impairment, and reduced calbindin/NPY/cholinergic interneuron populations. PMID:11889467 provides gene-level mouse/zebrafish ortholog expression context, not an independent disease model. |
| Rescue | Rescue in cell culture | PMID:17460091 | 0.5 | |
| Function | Biochemical function | PMID:11889467 | 0.5 | Gene-level evidence: ARX encodes a paired-class homeodomain transcription factor with conserved homeodomain, OAR/aristaless domain, and octapeptide motif speculated to mediate transcriptional repression; the study does not directly test repeat-specific biochemical function. |
| Function | Regulatory impact | PMID:12874418 PMID:11889467 | 0.5 |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.