ARX spectrum disorders

Author: J. Gecz
Submitted: Saturday 25th of September 2010 07:48:15 AM
Submitted by: egf
Educational levels: expert, qc3



Mutations of the Aristaless related homeobox, ARX, gene are amongst the most frequent causes of familial X-linked intellectual disability, rivalling fragile X syndrome. So far there have been close to 100 families and isolated cases with ARX mutations reported in at least nine clinical phenotypes. Among these are non-syndromic mental retardation, West syndrome or X-linked infantile spasms syndrome (ISSX), Partington syndrome (PRTS), X-linked myoclonic epilepsy with severe intellectual disability (XMESID), X-linked lisencephaly with ambigious genitalia (XLAG), Proud syndrome, Ohtahara syndrome, hydranencephaly with abnormal genitalia, etc.. While the type of the mutation and associated phenotype vary considerably, it is becoming clear that the most frequent mutations are polyalanine track 1 and 2 expansions. Polyalanine tract mutations represent about 60% of all ARX mutations. In addition to the most frequent, recurrent 304ins(GCG)7 (9 families) and 429-452dup (dup24; 40 families) mutations, novel expansions/duplications of either polyalanine tract have been identified. In general there is a good correlation between the length of the polyalanine tract (1 or 2) and the severity of the patient phenotype. The increasing lengths of the polyalanine tracts led to more severe cellular phenotypes, presented as nuclear and cytoplasmic ARX protein aggregation. While it appears that the overall number of alanines (irrespective of tract 1 or 2) is the major predictor of the severity of the phenotype, the homogeneity of the tract also matters. This observation is based on one familial case of polyalanine tract 2 duplication of 33bp, which resulted in a non-homogeneous polyalanine tract 2 expansion (from AGA12 to AGA10GA12; i.e. a G interruption of otherwise 22 long polyalanine tract). The analysis of more than 40 families with the dup24 mutation showed that none of the carrier females was apparently affected. This, together with our experimental data shows, that these polyalanine tract expansion mutations of ARX most likely represent partial loss of function mutations, situation different to the ~8 other, autosomal polyalanine tract associated disorders. Interestingly and contrary to the polyalanine tract expansion mutations, the majority of the ARX protein truncation mutations and homeodomain mutations, which are predicted to lead to a complete loss of function of the protein, often show carrier female phenotype and as such can be seen as gain of function mutations, however, they are just X-chromosome linked. ARX mutations are frequent as a group (~8-9% of X-linked, Fragile X negative families). ARX screening should be considered in individuals with non-syndromic intellectual disability and/or infantile spasms, XLAG and in particular when an X-linked inheritance is suspected. References 1. Strømme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, Lütcherath V, et al. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. J. Nat Genet, 30(4):441-5, 2002. 2. Bienvenu T, Poirier K, Friocourt G, Bahi N, Beaumont D, Fauchereau F, Ben Jeema L, et al. ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum Mol Genet, 11(8):981-91, 2002. 3. Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A, Kusaka M, et al. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet, 32(3):359-69, 2002.


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J. Gecz. ARX spectrum disorders. EUROGENE portal. September 2010. online:

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