Developmental and Epileptic Encephalopathy 1
In a Norwegian family described by Stromme et al. (1999), Stromme et al. (2002) found that 7 males with developmental and epileptic encephalopathy (DEE1; 308350), who were clinically diagnosed with infantile spasms/West syndrome, had a 24-bp duplication of nucleotides 429-451 in exon 2. This resulted in a polyalanine expansion from a tract of 12 alanines (amino acids 144-155) to a tract of 20 alanines.
Partington Syndrome
Stromme et al. (2002) found the same 24-bp duplication in the ARX gene in 2 families with X-linked mental retardation and in 2 families with Partington syndrome (PRTS; 309510). The 2 families in which Partington syndrome was caused by the 24-bp duplication in exon 2 were an Australian family described by Partington et al. (1988) and a Belgian family described by Frints et al. (2002).
Turner et al. (2002) reviewed the 2 families reported by Stromme et al. (2002) with X-linked mental retardation and the 24-bp duplication. They concluded that the variable expression of the mutation in individuals from both families included manifestations of both West and Partington syndromes. In addition, 1 individual had autism and 2 had autistic behavior, 1 of whom also had epilepsy.
Stromme et al. (2003) described bilateral cyst-like cavities in both the cerebral and the cerebellar hemispheres. The patient was a 72-year-old man who lived in a home for the mentally handicapped. He was a member of a family in which X-linked mental retardation was due to a 24-bp duplication in exon 2 the ARX gene.
In the MRX36 (see 309510) family reported by Claes et al. (1996) with nonspecific X-linked mental retardation, Bienvenu et al. (2002) identified the 24-bp duplication in exon 2 of the ARX gene. Frints et al. (2002) suggested that the patients reported by Claes et al. (1996) had mild clinical features of PRTS.
Polyalanine expansions in 1 of the 2 polyalanine tracts in exon 2 of the ARX gene represent the most frequently occurring mutation in the ARX gene, and interfamilial as well as intrafamilial variability are observed. Van Esch et al. (2004) reported a family in which 4 males with mental retardation had the ARX 24-bp duplication. The proband also had agenesis of the corpus callosum, transsphenoidal encephalocele, and a hypothalamic variant of partial anterior hypopituitarism. The patient had been reported by Grubben et al. (1990) as being born with a median cleft lip and palate and a transsphenoidal encephalocele. One of his affected uncles had dysarthria and dystonic movements of the hands, consistent with Partington syndrome. None of the patients had seizures. Van Esch et al. (2004) noted that congenital basal encephaloceles are very rare and are classified into 4 types, of which the transsphenoidal type is the least frequent (Suwanwela and Suwanwela, 1972). The reported endocrine defects associated with basal encephalocele involve mostly anterior pituitary hormones. The pattern of ARX expression in the brain during embryonic development suggested a causal role for the mutated protein in the origin of the encephalocele in the proband.
Partington et al. (2004) reported 3 families with X-linked mental retardation due to the 24-bp duplication in the ARX gene. They reviewed the clinical findings in the 46 MRX patients from 9 families that had been reported with this mutation and noted that mental retardation ranged from mild to severe. Infantile spasms (West syndrome; 308350) occurred in 12.5% and less severe forms of seizures in 37.5%. Characteristic dystonic movements of the hands were seen in 63% and dysarthria in 54%. Partington et al. (2004) suggested that focal dystonia in association with mental retardation may be diagnostic of this mutation.
Poirier et al. (2005) reported 2 brothers with mental retardation who had the 24-bp duplication in the ARX gene and whose healthy sister was heterozygous for the duplication. Their unaffected mother did not apparently carry the mutation, as determined by denaturing high-performance liquid chromatography (DHPLC) and by fragment size analysis, but semiquantitative fluorescent PCR revealed her to be a somatic mosaic, with 4% of her lymphocytes and 24% of her fibroblasts harboring the duplication. Because all 3 of her children received the affected X chromosome, Poirier et al. (2005) suggested that the level of mosaicism might be higher in the mother's germ cells.
Stepp et al. (2005) identified the 24-bp duplication in affected individuals from 4 of 11 unrelated families designated as MRX29, MRX32, MRX33, and MRX38 with X-linked mental retardation (300419). The findings suggested that the 24-bp duplication is the most common mutation in nonsyndromic XLMR families linked to Xp22.1.
Laperuta et al. (2007) identified the 24-bp duplication of the ARX gene in 5 affected men from an Italian family designated MRX87 with X-linked mental retardation (300419). There was marked intrafamilial variation with cognitive deficits ranging from moderate to severe. There were no dysmorphic features, but 3 patients had flat feet, 2 had urinary incontinence, and 1 had a congenital hindbrain herniation of the cerebellar tonsils. The oldest patient, age 67 years, had other neurologic signs, including pyramidal hypotonia, extensor plantar responses, hypoacusis, and signs of dementia. Carrier women were unaffected.
Intellectual Developmental Disorder, X-linked 29
In the MRX43 family reported by Hamel et al. (1999) with X-linked mental retardation (XLID29; 300419), Bienvenu et al. (2002) identified the 24-bp duplication in exon 2 of the ARX gene.
In the MRX76 family reported by Kleefstra et al. (2002), Bienvenu et al. (2002) also identified the same 24-bp duplication.
