Mental Retardation, X-Linked, With Cerebellar Hypoplasia And Distinctive Facial Appearance

A number sign (#) is used with this entry because of evidence that X-linked mental retardation with cerebellar hypoplasia and distinctive facial appearance is caused by mutation in the oligophrenin-1 gene (OPHN1; 300127) on chromosome Xq12.

Clinical Features

Billuart et al. (1998) reported a large family in which 4 males had X-linked mental retardation. Des Portes et al. (2004) performed clinical and 3-dimensional brain MRI evaluations on the affected males of the family studied by Billuart et al. (1998) and an unrelated female patient with an X;12 balanced translocation described by Bienvenu et al. (1997) (see 300127). Clinical features shared by affected individuals were neonatal hypotonia with motor delay but no obvious ataxia, marked strabismus, early-onset complex partial seizures, and moderate to severe mental retardation. Brain MRIs in 2 brothers and the unrelated female patient revealed a complex cerebellar dysgenesis including incomplete sulcation of the anterior and posterior vermis with the most prominent defect in lobules VI and VII. Nonspecific cerebral corticosubcortical atrophy was also observed.

Philip et al. (2003) reported 2 families in which 4 males and 1 male, respectively, had X-linked mental retardation associated with subtle facial dysmorphism and cerebellar anomalies, including hypoplasia of the vermis, expansion of the cisterna magna, and retrocerebellar cysts.

Bergmann et al. (2003) reported a family of German descent in which 5 brothers had moderate to severe mental retardation associated with enlargement of the lateral ventricles and cerebellar hypoplasia. Other features included seizures, ataxia, strabismus, and hypogenitalism with cryptorchidism, hypoplastic scrotum, and microphallus. Genetic analysis revealed a deletion in the OPHN1 gene (300127.0004).

Chabrol et al. (2005) reported a family with X-linked mental retardation associated with a mutation in the OPHN1 gene (300127.0005). The 2 affected males had mild facial dysmorphism with long face, prominent forehead, deep-set eyes, marked infraorbital creases, strabismus, short or upturned philtrum, and large ears. Neuroradiographic findings included hypoplasia of the cerebellar vermis, cystic dilatation of the cisterna magna, ventricular dilatation, and global reduction of cerebral volume, particularly in the frontal lobes. Two obligate female carriers showed subtle facial changes. In a review of the 2 families reported by Philip et al. (2003), Chabrol et al. (2005) noted that affected males had similar facial features.

Al-Owain et al. (2011) reported a Saudi family in which 4 boys and 1 girl had a syndromic form of X-linked mental retardation. The 19-year-old proband showed generalized hypotonia and delayed psychomotor development in infancy. He had moderate mental retardation (IQ of 40) and autistic features with minimal social interaction, poor eye contact, and poor speech. At age 8 years, he developed partial complex seizures that were well-controlled. Physical examination showed dysmorphic facial features with long semi-triangular face, deep-set eyes, strabismus, broad high nasal root, peaked prominent nose, and prominent chin. Cerebellar signs included mild ataxia and intention tremor on finger-nose pointing. Brain MRI showed a cerebellar hypoplasia and ventriculomegaly. The 3 other brothers were similarly affected, although 2 did not have ataxia and the severity of the seizure disorder was variable. The 10-year-old girl had mild cognitive delay, moderate speech impairment, attention-deficit hyperactivity disorder, seizures, and similar dysmorphic features as her affected brothers. Brain MRI showed mild cerebellar hypoplasia. X-inactivation studies showed normal random X inactivation in the girl.

Mapping

In a large family segregating X-linked mental retardation, Billuart et al. (1998) found linkage of the disorder to Xp11.4-q12 with a maximum lod score of 3.01 at a marker from the androgen receptor gene (AR; 313700) and with flanking markers OTC (300461) and DXS981.

Molecular Genetics

In a family with X-linked mental retardation, Billuart et al. (1998) identified a 1-bp deletion in the OPHN1 gene (300127.0001). All 4 affected males had the mutation and 7 unaffected females carried the mutation.

Philip et al. (2003) identified 2 different mutations in the OPHN1 gene (300127.0002 and 300127.0003) in affected members of 2 unrelated families with syndromic X-linked mental retardation.

Zanni et al. (2005) identified 4 different novel mutations in the OPHN1 gene in 2 (12%) of 17 unrelated males with mental retardation and known cerebellar anomalies and in 2 (1%) of 196 unrelated males with X-linked mental retardation without previous brain imaging studies. Retrospective imaging studies, when possible, detected cerebellar hypoplasia in the latter patients, indicating that OPHN1 mutations are associated with a syndromic form of X-linked mental retardation with cerebellar hypoplasia.

In affected members of a Saudi family with syndromic X-linked mental retardation, Al-Owain et al. (2011) identified an intragenic 68-kb deletion spanning exons 7 to 15 in the OPHN1 gene (300127.0006).

Animal Model

The pathophysiologic hypothesis of mental retardation caused by the deficiency of OPHN1 relies on the well-known functions of Rho GTPases on neuronal morphology (i.e., dendritic spine structure). Khelfaoui et al. (2007) generated Ophn1-null mice and observed behavior defects in spatial memory together with impairment in social behavior, lateralization, and hyperactivity. In cultured mouse cells, inactivation of Ophn1 function increased the density and proportion of immature dendritic spines. Conditional loss of Ophn1 function in the mouse model confirmed the immaturity defect and showed that Ophn1 is required at all stages of development. Khelfaoui et al. (2007) conclude that depending on the context, OPHN1 controls the maturation of dendritic spines either by maintaining the density of mature spines or by limiting the extension of new filopodia.