ARX – ARX-associated infantile epileptic-dyskinetic encephalopathy

ARX encodes a paired-type homeobox transcription factor critical for GABAergic neuronal specification. X-linked recessive mutations in ARX underlie a spectrum of early epileptic encephalopathies, including infantile epileptic-dyskinetic encephalopathy. The clinical phenotype is characterized by suppression-burst epileptic spasms, dystonic movements, rapid cortical atrophy, and early mortality.

In a Chinese pedigree, a hemizygous missense variant, c.989G>A (p.Arg330His), was identified in three affected male siblings presenting with early-onset seizures, developmental regression, dystonia, visual impairment, and muscle mitochondrial complex IV deficiency; seizures were transiently responsive to pyridoxal phosphate and ultimately controlled with valproate (PMID:31324350). In two unrelated families, a novel frameshift mutation in the terminal exon (c.1384_1406del (p.Leu462fs)) segregated with Ohtahara syndrome in six male patients across two generations (PMID:20384723). Additionally, targeted sequencing of 68 Han Chinese infants with unexplained EIEE uncovered a de novo c.1600G>C (p.Ala534Pro) variant in one patient with refractory spasms (PMID:28387369). These reports span missense and truncating alleles in independent cases with consistent X-linked segregation.

Segregation of ARX variants in multiplex pedigrees, with asymptomatic carrier females and multiple affected males (affected_relatives: 6), confirms an X-linked recessive inheritance pattern.

Functional studies demonstrate that ARX acts as a potent Groucho/TLE-dependent transcriptional repressor. The homeodomain missense mutation c.98T>C (p.Leu33Pro) abolishes binding to TLE1 and relaxes repression activity (PMID:17331656), while missense mutations in nuclear localization sequences (e.g., c.1136G>T (p.Arg379Leu)) sequester ARX in importin-13 complexes, impairing nuclear import and reducing protein stability (PMID:20148114). Mouse models of polyalanine tract expansions recapitulate interneuron migration defects and motor phenotypes, further substantiating loss-of-function mechanisms.

No studies have convincingly refuted this association. The convergence of clinical, genetic, and functional data across multiple cohorts meets criteria for a Strong gene–disease relationship.

Key Take-home: ARX loss-of-function and missense mutations cause infantile epileptic-dyskinetic encephalopathy via impaired transcriptional repression and nuclear localization; ARX sequencing should be integrated into diagnostic panels for early-onset epileptic encephalopathy with dyskinesia.

References

• Brain & development • 2019 • ARX-associated infantile epileptic-dyskinetic encephalopathy with responsiveness to valproate for controlling seizures and reduced activity of muscle mitochondrial complex IV. PMID:31324350
• Epilepsia • 2010 • Frameshift mutations of the ARX gene in familial Ohtahara syndrome. PMID:20384723
• Scientific reports • 2017 • Unexplained Early Infantile Epileptic Encephalopathy in Han Chinese Children: Next-Generation Sequencing and Phenotype Enriching. PMID:28387369
• Neuroscience • 2007 • Aristaless-related homeobox gene, the gene responsible for West syndrome and related disorders, is a Groucho/transducin-like enhancer of split dependent transcriptional repressor. PMID:17331656
• PathoGenetics • 2010 • Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division. PMID:20148114

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