Curation EIEE1 ARX

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.

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.

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.

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.

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.

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.

The phenotypes exhibited in the mutant mice match those of patients with infantile spasms. The mice also develop partial seizures early in life that evolve into different seizure types and persist into adulthood as in humans.

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.

The repeat may modulate epigenetic silencing (X inactivation) in symptomatic individuals.