Mental Retardation, X-Linked, With Or Without Seizures, Arx-Related

A number sign (#) is used with this entry because this form of nonspecific X-linked mental retardation is caused by mutation in the ARX gene (300382) on chromosome Xp21.

Description

ARX-related mental retardation is a form of nonsyndromic X-linked mental retardation. It is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1; 308350) to Partington syndrome (309510) (Kato et al., 2004; Wallerstein et al., 2008).

Clinical Features

Hamel et al. (1999) described a two 4-generation families (MRX43 and MRX52) segregating X-linked mental retardation. Affected members in family MRX43 had moderate to profound nonprogressive mental retardation recognized in early childhood. Only 1 patient was able to read and write. Characteristic features included obesity, large head, periorbital fullness, wide palpebral fissures, full lower lip, and normal behavior. Two brothers were treated for epilepsy, one only in adolescence and the other into adulthood. Affected members in family MRX52 had moderate to profound nonprogressive mental retardation noted in childhood. Only 1 patient was able to accomplish basic academic tasks. Behavior was unremarkable, and characteristic features included downslanting palpebral fissures, and midface hypoplasia.

Laperuta et al. (2007) reported an Italian family in which 5 men had X-linked mental retardation (MRX87). 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. Genetic analysis identified a 24-bp duplication in the ARX gene (300382.0002). Carrier women were unaffected.

Mapping

In a family in which 7 males had X-linked mental retardation, Hane et al. (1996) found linkage to a locus, termed MRX29, on Xp22.3-p21.3. A maximal 2-point lod score of 3.31 was demonstrated for tight linkage to marker DXS1202 with crossovers between the 3-prime portion of the DMD (300377) gene (DXS1234) proximally and locus DXS989 distally. The localization of MRX29 overlapped with at least 6 other MRX entities linked to the distal short arm of the X chromosome, such as Partington syndrome and Coffin-Lowry syndrome (303600).

Hamel et al. (1999) performed linkage analysis in the MRX43 family and obtained a maximum lod score of 2.23 (theta = 0.0) with marker DXS985. Using haplotype construction, they identified DXS987 and DMD as the closest flanking markers, defining the region of linkage to Xp22.31-p21.2, spanning approximately 25 cM. Hamel et al. (1999) also performed linkage analysis in family MRX52 and obtained a maximum lod score of 3.14 (theta = 0.0) with marker DXS559. Using haplotype construction, they identified ALAS2 and DXS3 as the closest flanking markers, defining the region of linkage to Xp11.21-q22.3, spanning approximately 19 cM.

Jemaa et al. (1999) reported a large Tunisian family with X-linked nonspecific mental retardation. By linkage analysis, they identified a disease locus, termed MRX54, located in a critical region spanning approximately 2.7 cM between DXS989 and DXS1218 in Xp22.1-p21.3, with a maximum lod score of 3.56.

Molecular Genetics

In the MRX43 family reported by Hamel et al. (1999) and in the MRX76 family reported by Kleefstra et al. (2002), Bienvenu et al. (2002) identified the same 24-bp in-frame duplication (300382.0002) in the ARX gene.

In the MRX54 family reported by Jemaa et al. (1999), Bienvenu et al. (2002) identified a missense mutation in the ARX gene (300382.0013).

Stepp et al. (2005) identified the 24-bp duplication in the ARX gene in affected individuals from 4 of 11 unrelated families with X-linked mental retardation. The MRX29, MRX32, MRX33, and MRX38 families had previously been reported by Hane et al. (1996), Hane et al. (1999), Holinski-Feder et al. (1996), and Schutz et al. (1996), respectively. The findings suggested that the 24-bp duplication is the most common mutation in nonsyndromic XLMR families linked to Xp22.1.

De Brouwer (2019) stated that a missense mutation (R2085H; 300382.0025) in the ARX gene was identified in affected members of the MRX52 family reported by Hamel et al. (1999).