ARX – Developmental and Epileptic Encephalopathy

Mutations in the X-linked ARX gene, encoding a paired-type homeobox transcription factor, cause a spectrum of early-onset developmental and epileptic encephalopathies (DEE) characterized by intractable seizures, developmental delay, and variable brain malformations. DEE attributable to ARX includes West syndrome, Ohtahara syndrome, and infantile spasms, often presenting in male infants with X-linked recessive inheritance and de novo protein-truncating variants.

Genetic analyses have identified multiple loss-of-function and missense ARX mutations in affected males. A recurrent null variant, c.81C>G (p.Tyr27Ter), was found in two male cousins—one with Ohtahara syndrome and one with West syndrome—segregating in an X-linked family (PMID:19738637). A novel early truncating variant, c.34G>T (p.Glu12Ter), was detected in two unrelated boys with infantile spasms; both showed reinitiation of translation producing an N-terminally truncated protein with reduced expression and impaired transcriptional repression (PMID:26306640). Additionally, targeted panel screening of cryptogenic infantile EE identified one ARX point mutation among 26 patients (PMID:25951140).

Segregation analysis supports X-linked recessive transmission, with two affected relatives in the c.81C>G family. Female carriers may exhibit milder neuropsychiatric phenotypes, underscoring variable expressivity and reduced penetrance in heterozygotes.

Functional studies demonstrate a loss-of-function mechanism. Premature truncating mutations abolish the octapeptide corepressor domain, reducing interaction with Groucho/TLE cofactors and diminishing transcriptional repression activity in luciferase assays (PMID:17331656). Truncating variants show markedly decreased protein levels and impaired nuclear localization, correlating with seizure phenotypes.

A partly humanized mouse model carrying the common c.428_451dup24 polyalanine expansion recapitulates fine motor defects, interneuron migration defects, and hyperactivity, mirroring patient phenotypes and validating the pathogenic role of ARX haploinsufficiency in DEE (PMID:29659809).

Integration of genetic and functional data establishes a strong causal relationship between ARX loss-of-function mutations and DEE. These findings support early genetic testing for ARX in male infants with cryptogenic epileptic encephalopathy to inform diagnosis, prognosis, and emerging targeted therapeutic approaches.

Key Take-home: X-linked ARX truncating mutations cause DEE via haploinsufficiency of transcriptional repression, guiding genetic diagnosis and potential functional rescue strategies.

References

• 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
• European journal of human genetics : EJHG • 2010 • Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X). PMID:19738637
• European journal of human genetics : EJHG • 2016 • Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX. PMID:26306640
• Human molecular genetics • 2018 • A new mouse model of ARX dup24 recapitulates the patients' behavioral and fine motor alterations. PMID:29659809

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