ARX – West syndrome

The X-linked ARX gene encodes a paired-type homeobox transcription factor essential for GABAergic interneuron development in the forebrain. Hemizygous loss-of-function or missense mutations in ARX cause a spectrum of neurodevelopmental disorders, prominently including early-onset epileptic spasms known clinically as West syndrome. Affected males present with infantile spasms, hypsarrhythmia and developmental delay, reflecting ARX’s critical role in neuronal proliferation, migration and differentiation.

Genetic studies have identified over 100 unrelated families harboring more than 44 distinct ARX mutations, including non-conservative homeodomain missense changes and polyalanine tract expansions (59% of alleles) in patients with West syndrome. For example, the de novo c.1072A>T (p.Arg358Trp) homeodomain variant was identified in a male with infantile spasms and corpus callosum agenesis (1 proband) (PMID:21416597). Recurrent expansions such as c.426_449dup (p.Gly143_Ala150dup) have been reported across multiple kindreds (PMID:20506206).

Inheritance is X-linked recessive, with maternal transmission and skewed X-inactivation observed in carrier females. In one family, an unaffected mother displayed 85:15 non-random X chromosome inactivation, correlating with asymptomatic carrier status (PMID:21416597). Segregation analysis across multiple pedigrees has demonstrated at least 19 affected male relatives inheriting ARX mutations.

Functional assays in vitro reveal that ARX mutations disrupt DNA binding and transcriptional repression. Missense changes in the homeodomain abolish binding to target gene promoters (e.g., LMO1, SHOX2) and reduce repression activity (PMID:22194193). Polyalanine expansions increase aggregation propensity and alter subcellular localization, causing partial loss of function (PMID:17331656).

In vivo mouse models recapitulate ARX-related phenotypes. Homeodomain knock-in mutants (e.g., P353R) exhibit early epileptic phenotypes and interneuron deficits mirroring human West syndrome, while polyalanine expansion knock-ins demonstrate seizure susceptibility and learning impairment, confirming ARX haploinsufficiency as the pathogenic mechanism (PMID:19605412).

No studies have definitively refuted the ARX–West syndrome association. Variable expressivity in female carriers and overlaps with related ARX-linked phenotypes underscore the need for genotype–phenotype correlation but do not dispute causality.

In summary, robust genetic and experimental evidence supports a strong association between ARX mutations and X-linked infantile spasms. Molecular confirmation of ARX variants informs diagnosis, genetic counseling and potential therapeutic targeting of interneuron development pathways.

Key Take-home: ARX loss-of-function mutations are a strong, clinically actionable cause of X-linked West syndrome.

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
• Human mutation • 2010 • ARX spectrum disorders: making inroads into the molecular pathology PMID:20506206
• American journal of medical genetics. Part A • 2011 • Corpus callosum agenesis, severe mental retardation, epilepsy, and dyskinetic quadriparesis due to a novel mutation in the homeodomain of ARX PMID:21416597
• Human molecular genetics • 2012 • ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression PMID:22194193

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