title: ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia.
abstract: Mutations in the ARX gene cause both nonsyndromic and several forms of syndromic mental retardation (MR). Two polyalanine (polyA) expansions of ARX are recurrent mutations. The most common one, the c.428_451dup, is associated with a wide spectrum of phenotypes, ranging from the most severe West syndrome to Partington syndrome (MR and hand dystonia), and even nonsyndromic X-linked mental retardation (NS-XLMR). Studies of patients not selected for specific clinical signs showed that the c.428_451dup is relatively frequent in families harboring X-linked MR (7.5%), but less common in familial cases compatible with X-linked NR (1%), and very rare in sporadic cases (0.1%). The c.333_334ins(GCG)7 expansion is less frequent and mainly associated with West syndrome. We screened for both ARX polyA expansions in 98 unrelated patients selected for the presence of NR associated with different types of epilepsy and/or with hand dystonia. We also studied two families with an initial diagnosis of NS-XLMR, one of which was identified as showing linkage to the ARX locus. The c.428_451dup was identified in three patients and the c.333_334ins(GCG)7 in one; all of the patients were from families with two affected brothers. We also found the c.428_451dup in the family linked to ARX, and clinical re-evaluation showed subtle, previously undetected signs. Our study illustrates that ARX polyA expansions are primarily associated with syndromic MR and shows a higher yield (18% in our cohort) when these mutations are screened in familial cases of MR with epilepsy and/or dystonia.
authors.affiliation: Hôpitaux Universitaires de Strasbourg, France. mireille.cossee@cch.aphp.fr
authors.forename: Mireille
authors.initials: M
authors.lastname: Cossée
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: Christophe
authors.initials: C
authors.lastname: Philippe
authors.forename: Heifa
authors.initials: H
authors.lastname: Hichri
authors.forename: Anne
authors.initials: A
authors.lastname: de Saint-Martin
authors.forename: Vincent
authors.initials: V
authors.lastname: Laugel
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lemaitre
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.forename: Bruno
authors.initials: B
authors.lastname: Delobel
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Demeer
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.forename: Valérie
authors.initials: V
authors.lastname: Biancalana
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pinoit
authors.forename: Sophie
authors.initials: S
authors.lastname: Julia
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Didier
authors.initials: D
authors.lastname: Devys
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D042622:DNA Repeat Expansion / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D010375:Pedigree; D010455:Peptides / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C469264:ARX protein, human; D018398:Homeodomain Proteins; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine