Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation

Abstract

Two families, originally diagnosed as having nonsyndromic X-linked mental retardation (NSXLMR), were reviewed when it was shown that they had a 24-bp duplication (428-45 1dup(24bp)) in the ARX gene [Stromme et al., 2002: Nat Genet 30:441-445]. This same duplication had also been found in three other families: one with X-linked infantile spasms and hypsarrhythmia (X-linked West syndrome, MIM 308350) and two with XLMR and dystonic movements of the hands (Partington syndrome, MIM 309510). On review, manifestations of both West and Partington syndromes were found in some individuals from both families. In addition, it was found that one individual had autism and two had autistic behavior, one of whom had epilepsy. The degree of mental retardation ranged from mild to severe. A GCG trinucleotide expansion (GCG)10+7 and a deletion of 1,517 bp in the ARX gene have also been found in association with the West syndrome, and a missense mutation (1058C>T) in a family with a newly recognized form of myoclonic epilepsy, severe mental retardation, and spastic paraplegia [Scheffer et al., 2002: Neurology, in press]. Evidently all these disorders are expressions of mutations in the same gene. It remains to be seen what proportions of patients with infantile spasms, focal dystonia, autism, epilepsy, and nonsyndromic mental retardation are accounted for by mutations in the ARX gene.

The DLX1and DLX2 genes and susceptibility to autism spectrum disorders

“…Furthermore, the Dlx genes regulate the expression of the X-linked Arx gene in basal ganglia progenitor cell populations, 41 and a subset of patients with a mutation of ARX gene have autistic features. 42,43 Both the neuropathological findings, which indicate altered organization of specific regions of the brain 44 -46 and the co-occurrence of autism with a number of neurological and cognitive disorders, including epilepsy, 8 support a role for the DLX gene complexes in interneuron development and GABAergic-mediated pathophysiological changes that are central components of autism. 47 We had only a small group of individuals (n ¼ 32) with confirmed seizures.…”

Inactivation ofArx, the Murine Ortholog of the X-Linked Lissencephaly with Ambiguous Genitalia Gene, Leads to Severe Disorganization of the Ventral Telencephalon with Impaired Neuronal Migration and Differentiation

“…Dystonia is a condition that was frequently found in different ARX-dependent disorders. Indeed, patients were described as experiencing dystonic hands movements, as well as wrist and finger contractures, accompanied by general muscle weakness (Stromme et al, 2002b;Turner et al, 2002). In other cases, stereotyped repetitive movements or tremors were reported (Turner et al, 2002).…”

“…Indeed, patients were described as experiencing dystonic hands movements, as well as wrist and finger contractures, accompanied by general muscle weakness (Stromme et al, 2002b;Turner et al, 2002). In other cases, stereotyped repetitive movements or tremors were reported (Turner et al, 2002). Together, these observations strongly suggest a functional alteration of the basal ganglia nuclei, whose function is to control and finely tune the activity of the motor cortex through both direct and indirect circuits connecting striatum, globus pallidus, substantia nigra, and other relay nuclei with the cerebral cortex.…”

Screening of the ARX gene in 682 retarded males

“…3 Variation in phenotypic expression has also been described within a family. 4 In XLMR families, ARX mutations have been suggested to be a more frequent cause of mental retardation than other XLMR genes. 5 ARX maps to Xp22 and spans 12.5 kb of genomic DNA.…”