Partington X-Linked Mental Retardation Syndrome

A number sign (#) is used with this entry because Partington syndrome (PRTS) can be caused by a 24-bp duplication, resulting in a polyalanine (polyA) repeat expansion, in the aristaless-related homeobox gene (ARX; 300382).

Description

Partington syndrome is an X-linked developmental disorder characterized by mental retardation and variable movement disturbances. Partington syndrome 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 hydranencephaly and lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1; 308350) to nonsyndromic mental retardation (300419). Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008).

Clinical Features

Partington et al. (1988) described a family (MRXS1) in which 10 males widely distributed in the pedigree and connected through females showed a syndrome of mild to moderate mental retardation and episodic dystonic movements of the hands. Some had dysarthria. X-linked recessive inheritance was supported by several facts: all affected individuals were male, and there was no male-to-male transmission; 1 woman had affected sons by different husbands and another had an obligate carrier daughter by 1 husband and an affected son by another; and the number of affected males (without the probands), unaffected males, and females in the offspring of obligate heterozygotes was satisfactorily close to the expected ratio of 1:1:2.

Claes et al. (1996) reported a family (MRX36) in which 4 males (3 brothers and a nephew) were affected with a nonspecific form of mental retardation with normal physical and neurologic findings. Two females showed an intelligence level in the low to normal range, possibly as a result of heterozygous carrier status, and a 20-month-old girl showed delayed psychomotor development. Frints et al. (2002) reexamined the 3 brothers originally reported by Claes et al. (1996). Mild facial dysmorphism was noted in 2, with mild hypertelorism, short palpebral fissures, and large mouth. Neurologic examination showed mild dystonic movements of the hands and feet in 2, and perioral dystonic movements in the third. One patient showed mild cogwheel rigidity and another showed a Parkinson-like tremor on the left side. One patient had no expressive language capabilities and the other 2 had language development of 2.5 to 3 years. Frints et al. (2002) noted that ARX gene mutations have also been described in Partington syndrome and suggested that the family reported by Claes et al. (1996) had mild clinical features of PRTS.

Frints et al. (2002) described 2 Belgian brothers with Partington syndrome. The brothers had a delayed and aberrant grasp reflex which resulted in feeding difficulties in early childhood. Dystonic hand movements became more evident during childhood. They had dysarthria with difficulties initiating speech and stuttering. The elder brother walked at 18 months of age, whereas the younger brother could sit at 1 year and walked at 19.5 months. Both brothers had mild to moderate mental retardation. Their behavior was generally friendly, quiet, and social, although the elder brother developed depressive mood and anger outbursts in his late 20s. EEG, EMG, and head MRI studies were normal in both.

Szczaluba et al. (2006) reported 18 individuals from 5 families with an X-linked mental retardation syndrome due to a hemizygous 24-bp duplication in the ARX gene. The phenotype was variable but most consistent with Partington syndrome. All patients had intellectual impairment. Twelve presented with focal hand dystonia, and 6 had EEG abnormalities with seizures. Other variable features included dysarthria (4 patients) and lower limb spasticity/foot dystonia (4 patients). One family showed enlargement of the testes, and 1 patient had a subarachnoid cyst. Affected individuals tended to have long triangular facies.

Mapping

By linkage analysis of an affected family, Partington et al. (1988) mapped the gene responsible for PRTS to the distal part of chromosome Xp (maximum lod score of 2.11 at theta = 0.00 at marker DXS41).

Claes et al. (1996) performed linkage analysis on the MRX36 family. A maximum lod score of 1.97 was obtained at markers DXS989, DXS1218, DMD49, and DMD45 when the infant girl was excluded from the analysis, but rose to 3.31 at DXS1218, defining a candidate region of less than 5 cM (Xp22.1-p21.1), when she was not included.

Frints et al. (2002) determined that 2 affected Belgian brothers shared a haplotype in the PRTS region at Xp22.1.

Molecular Genetics

In the original Australian family reported by Partington et al. (1988) and in the unrelated Belgian family reported by Frints et al. (2002), Stromme et al. (2002) found an expanded alanine repeat in the ARX gene. The polyA expansion was due to the 24-bp duplication (300382.0002). The mutation occurred against different haplotypes in the 2 families.

In one of the brothers reported by Claes et al. (1996), Bienvenu et al. (2002) identified the 24-bp in-frame duplication in the ARX gene. Frints et al. (2002) noted that the mutation had not been found in the affected infant girl or her mother, indicating that the mental retardation in the girl was caused by another factor.

Partington et al. (2004) reported 3 new families with X-linked mental retardation due to the 24-bp duplication in the ARX gene. They reviewed the clinical findings in the 46 XLMR 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.