Lissencephaly, X-Linked, 2

A number sign (#) is used with this entry because X-linked lissencephaly with ambiguous genitalia (LISX2, XLAG), as well as hydranencephaly and abnormal genitalia, can be caused by mutation in the ARX gene (300382).

See also Proud syndrome (300004), an allelic disorder with an overlapping phenotype. Early infantile epileptic encephalopathy-1 (EIEE1; 308350) and 2 other forms of X-linked mental retardation (see 309510 and 300419) are allelic disorders without brain malformations.

Description

X-linked lissencephaly-2 (LISX2) is a developmental disorder characterized by structural brain anomalies, early-onset intractable seizures, severe psychomotor retardation, and ambiguous genitalia. Males are severely affected and often die within the first days or months of life, whereas females may be unaffected or have a milder phenotype (Bonneau et al., 2002). LISX2 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 to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008).

For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).

Clinical Features

Dobyns et al. (1999) recognized 5 children from 4 unrelated families with an almost identical disorder comprising lissencephaly with a posterior-to-anterior gradient and only moderate increase in thickness of the cortex, absent corpus callosum, neonatal-onset epilepsy, hypothalamic dysfunction including deficient temperature regulation, and ambiguous genitalia in genotypic males. All also had mild nonspecific dysmorphic facial changes, such as prominent forehead, low forehead, micrognathia, pinched nasal alae, and wide nasal bridge. Their observation of 5 affected males in one of the families was consistent with an X-linked pattern of inheritance. However, the disorder differed in many respects from the X-linked form of isolated lissencephaly sequence that is associated with mutations in the XLIS, or doublecortin, gene (DCX; 300121). Therefore, Dobyns et al. (1999) proposed that this disorder comprises a novel X-linked malformation syndrome, which they referred to as X-linked lissencephaly with ambiguous genitalia.

Ogata et al. (2000) reported an additional infant with this condition. The infant had lissencephaly, agenesis of the corpus callosum, intractable epilepsy of neonatal onset, hypothalamic dysfunction including temperature instability, ambiguous genitalia, and a 46,XY karyotype. The infant died at 6 weeks of age and an autopsy showed ventricular septal defect, patent ductus arteriosus (see 607411), mild left lung hypoplasia, megacolon, and small dysgenetic testes, in addition to the brain anomalies. The nonconsanguineous parents had 2 previous pregnancies, both recorded as males, in whom fetal ultrasound studies showed a hydrocephalic appearance. The first resulted in a neonate at 32 weeks of gestation who died of respiratory failure shortly after birth. The second was terminated at 18 weeks of gestation. Although no autopsy was performed on the earlier-born fetuses and information on them was limited, they supported X-linked inheritance of this condition.

Bonneau et al. (2002) reported 3 affected boys from 3 unrelated families. The children were all born of nonconsanguineous parents and exhibited tonic-clonic seizures within the first hours of life with variable hypotonia, in addition to having micropenis and undescended testes. Two were described as having craniofacial abnormalities, such as prominent forehead and micrognathia. Brain MRI of all 3 infants showed absence of the corpus callosum, lissencephaly consisting of frontal pachygyria and posterior agyria, abnormally thick cortex, enlarged ventricles, and poorly delineated basal ganglia. Neuropathologic examination showed abnormal lamination of the neocortex with areas of disorganization, gliosis, and numerous pyramidal neurons. Examination of 5 female members of the families, including 2 mothers, revealed absence or partial absence of the corpus callosum, even without clinical symptoms. These findings suggested a semidominant X-linked mode of inheritance. Bonneau et al. (2002) concluded that XLAG is a distinct entity, possibly resulting from a disturbance of key neuronal developmental events.

Kitamura et al. (2002) summarized the clinical features of XLAG. All affected individuals with this disorder had been genotypic males, and had severe congenital or postnatal microcephaly, lissencephaly, agenesis of the corpus callosum, neonatal-onset intractable epilepsy, poor temperature regulation, chronic diarrhea, and ambiguous or underdeveloped genitalia. XLAG differs considerably from classic lissencephaly (see 300067), as the resultant cortical thickness is only 6-7 mm in XLAG, rather than 15-20 mm seen in classic lissencephaly associated with mutation in PAFAH1B1 (601545) or DCX (300121). In addition, the cerebral white matter of individuals with XLAG appears immature compared to that associated with classic lissencephaly.

Carrier Females

Marsh et al. (2009) reviewed 25 heterozygous female carriers of known ARX mutations and found that 8 (35%) had significant developmental abnormalities. Twenty-three of the 25 were relatives of a male with an ARX mutation, including 14 mothers and 9 other female relatives. Six of the females had been reported by Bonneau et al. (2002) and 4 had been reported by Proud et al. (1992), ascertained based on the identification of a male relative with XLAG or Proud syndrome (300004), respectively. Clinical features of the affected females were variable, but included agenesis of the corpus callosum, delayed motor development, attention-deficit hyperactivity disorder, learning disabilities, and seizures. None had infantile spasms. Only 3 (33%) of the 9 female relatives other than mothers had completely normal development. Marsh et al. (2009) noted an ascertainment bias: the first reports of human ARX mutations described asymptomatic mothers as healthy carriers of the mutations, which fits well with their having lived to adulthood and having high reproductive fitness. In contrast, other female relatives tended to be more severely affected. The data of Marsh et al. (2009) did not show clear evidence for skewing of X inactivation in either symptomatic or asymptomatic females, but the number of females tested was too low to draw firm conclusions. Marsh et al. (2009) also found that about half of female mice with targeted disruption of the Arx gene developed seizures, further indicating that some female carriers may be affected.

Molecular Genetics

Kitamura et al. (2002) identified loss-of-function mutations in the ARX gene (300382) in individuals affected with XLAG and in some female relatives. Kitamura et al. (2002) suggested that this may have been the first incidence in which phenotypic analysis of the knockout mice was used to identify a gene associated with an X-linked human brain malformation.

In 20 patients with brain and genital malformations, Kato et al. (2004) identified 13 novel and 2 recurrent mutations in the ARX gene. Most of the patients had XLAG, but 2 had hydranencephaly and abnormal genitalia (see, e.g., 300382.0016) and 3 males from 1 family had Proud syndrome (300382.0015). Two of the families had been reported by Bonneau et al. (2002), and were found to have the same mutation (E78X; 300382.0020).

Genotype/Phenotype Correlations

In a review of 29 males with ARX mutations, Kato et al. (2004) found that those with premature termination or nonsense mutations had brain malformation syndromes, including XLAG and Proud syndrome, whereas those with expansion of the polyalanine tract (300382.0001 and 300382.0002) had epileptic encephalopathy (308350) or mental retardation (309510; 300419) without brain malformations. Missense mutations were equally divided between the 2 groups, but the more severe phenotypes correlated with mutations in highly conserved regions.

Animal Model

Kitamura et al. (2002) demonstrated that male embryonic mice with mutations in the Arx gene developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing gamma-aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex as well as abnormal testicular differentiation. These characteristics recapitulated some of the clinical features of XLAG in humans.