Mental Retardation, X-Linked 1

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-1 (MRX1) is caused by hemizygous or heterozygous mutation in the IQSEC2 gene (300522) on chromosome Xp11.

Clinical Features

Suthers et al. (1988) reported a large family in which multiple males spanning several generations had nonsyndromic X-linked mental retardation. Two developed psychiatric problems and 1 had infrequent seizures. Carrier females were 'less academically able compared to their non-carrier sibs' (Shoubridge et al., 2010).

Shoubridge et al. (2010) provided follow-up of a family with X-linked mental retardation reported by Gedeon et al. (1994) as MRX18. Affected males had moderate to severe intellectual disability, and some had seizures. Carrier females had varying levels of intellectual disability. Some affected individuals had brachycephaly, large ears, and a fixed flexion deformity of the elbows. Three males had autistic features, and most had delayed language skills.

Tran Mau-Them et al. (2014) reported 3 unrelated males with severe intellectual disability, neonatal hypotonia, and delayed psychomotor development with lack of speech or poor speech. Other features included strabismus, hypermetropia, and stereotypic and autistic behavior. Two had postnatal microcephaly and 2 developed seizures. Facial dysmorphism was nonspecific.

De Vries et al. (2002) reported a family in which 6 males and 3 females over 3 generations had nonspecific mental retardation. The inheritance pattern was X-linked semidominant. The retardation in males was severe to moderate and nonprogressive, whereas in females it varied from severe to mild. There were no other abnormalities. This family was designated as MRX78. Kalscheuer et al. (2016) reported follow-up of the family reported by de Vries et al. (2002). There were 6 affected males and 7 affected females. Three males were severely affected with mental retardation and lack of speech, whereas the other males had moderate to severe mental retardation. Two males had epilepsy, and 1 had a single seizure. Many of the males had behavioral problems, including aggression and autistic features. The females were much less severely affected, and tended to have learning difficulties or mild intellectual disability.

Pathogenesis

Chelly (1999) reviewed molecular and cellular mechanisms underlying X-linked mental retardation. He gave a general conceptualization of nonspecific mental retardation as disorders resulting from a dysfunctioning of genes required for processes such as remodeling, establishment, and stabilization of connections between neuronal cells. Such processes are crucial for the development of intellectual and cognitive functions. Chelly (1999) suggested that since these functions begin to evolve mainly in postnatal stages through contact with various stimuli and environments, the potential therapeutic approach would be the development of drugs that target cellular signaling pathways shown to be implicated in MRX.

Mapping

Suthers et al. (1987, 1988) obtained positive lod scores with Xp markers in a family with a nondysmorphic form of X-linked mental retardation. A 2-point lod score of 2.08 was obtained at marker DXS14, and they concluded that the regional localization of the disease gene was Xp11.3-Xq21.1. Affected males had moderate intellectual handicap, were not dysmorphic, had head circumferences and testicular volumes within the normal range, and had no muscular weakness. Obligate carriers were not overtly mentally retarded. Lod scores with DXYS1 were negative at values of theta 0.30 and less.

Arveiler et al. (1987, 1988) presented data on families with nonspecific mental retardation suggesting the existence of at least 2 X-linked mental retardation loci: one in Xp22 and the other in the Xq11-q12 region. From a study of the contiguous gene syndromes resulting from various deletions in the distal portion of Xp, Ballabio et al. (1989) suggested that there is a gene for X-linked mental retardation at Xp22.3 (MRX2; 300428).

By linkage analysis in a family with X-linked nonsyndromic mental retardation, de Vries et al. (2002) identified a 15.16-cM candidate region on chromosome Xp11.4-p11.23 (maximum 2-point lod score of 4.69 at theta = 0.0 with markers DXS8054 and DXS1003).

Molecular Genetics

In affected members of 4 unrelated families with X-linked nonsyndromic mental retardation (MRX1; 309530), Shoubridge et al. (2010) identified 4 different hemizygous mutations in the IQSEC2 gene (300522.0001-300522.0004). Two of the families had been reported by Suthers et al. (1988) and Gedeon et al. (1994). Some carrier females had learning disabilities. The authors suggested that a defect in the GTP-binding activity of mutant IQSEC2 may influence the regulation of actin cytoskeleton organization and neuronal development in the brain.

In 3 unrelated males with severe MRX1, Tran Mau-Them et al. (2014) identified 3 different mutations in the IQSEC2 gene (300522.0005-300522.0007). Two of the mutations were intragenic duplications, resulting in premature termination, and the third was a nonsense mutation. Tran Mau-Them et al. (2014) suggested that the severe phenotype resulted from the truncating mutations.

In affected members of the family with MRX78 originally reported by de Vries et al. (2002), Kalscheuer et al. (2016) identified a missense mutation in the IQSEC2 gene (A789V; 300522.0008). The mutation, which was found by X-chromosome exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the mutant protein had decreased catalytic activity compared to wildtype.

Population Genetics

Herbst (1980) reviewed 24 pedigrees ascertained in British Columbia; cytogenetic studies were not done. Based on this study, Herbst and Miller (1980) calculated an incidence of X-linked mental retardation of 1.83 per 1,000 live male births and a carrier frequency of 2.44 per 1,000 live female births. Assuming a mutation rate for X-linked loci of 3 to 9 x 10(-5) and a fitness of zero for affected males, they estimated that 7 to 19 genes cause nonspecific mental retardation. Included in their pedigrees were some having marXq28 ('fragile X'); based on literature review, they estimated that one-half of X-linked mental retardation is associated with marXq28, leaving a substantial proportion of cases which could be labeled 'nonspecific.'

History

Penrose (1938) observed a 25% excess of males over females among individuals institutionalized with mental retardation.

The Human Gene Mapping Nomenclature Committee (Mulley et al., 1992) proposed to designate each newly reported apparently unique X-linked mental retardation (MRX) family with gene symbols (e.g., MRX1, MRX2) if a minimal lod score of 2.0 was demonstrated between the MR locus and 1 or more X chromosome markers.

Neri et al. (1994) listed 18 X-linked pedigrees, published since 1960, having mental retardation in the apparent absence of other abnormalities.

Reviews

Opitz and Sutherland (1984) reported on a conference in which fragile X mental retardation and X-linked mental retardation of numerous other types were discussed. The report contains a rather comprehensive discussion by Opitz of the nosology of X-linked mental retardation.

Raymond (2006) reviewed the diagnosis and classification of X-linked mental retardation and discussed the phenotypes associated with genes causing syndromic and nonsyndromic mental retardation.