Lissencephaly 2

A number sign (#) is used with this entry because of evidence that lissencephaly-2 can be caused by homozygous mutation in the gene encoding reelin (RELN; 600514) on chromosome 7q22.

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

Clinical Features

Dobyns et al. (1984) suggested the designation Norman-Roberts syndrome for a disorder which, like the Miller-Dieker syndrome (247200), is associated with type I lissencephaly but has distinctive associated features. (Type I lissencephaly is characterized by microcephaly and a thickened cortex with 4 rather than 6 layers.) This disorder, first reported by Norman et al. (1976), shows a low sloping forehead and a prominent nasal bridge, features not seen in the Miller-Dieker syndrome. Furthermore, chromosomes are normal whereas in the latter syndrome an abnormality of 17p13 has been found. Dobyns et al. (1984) published photographs demonstrating the craniofacial features of the Norman-Roberts syndrome. Multiple affected sibs and parental consanguinity have been observed.

Iannetti et al. (1993) described a 7-year-old boy with microcephaly, bitemporal hollowing, low sloping forehead, slightly prominent occiput, widely set eyes, broad and prominent nasal bridge, and severe postnatal growth deficiency. Neurologic features included hypertonia, hyperreflexia, seizures, and profound mental retardation. Brain MRI showed changes consistent with lissencephaly type I, grade 2. Molecular studies did not demonstrate deletion in the Miller-Dieker/isolated lissencephaly critical region on 17p.

Hong et al. (2000) studied an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem in 2 consanguineous pedigrees. The first consisted of British parents related as half first cousins (Hourihane et al., 1993). At birth the 3 affected children showed normal head size, congenital lymphedema, and hypotonia. Brain magnetic resonance imaging showed moderate lissencephaly and profound cerebellar hypoplasia. Cognitive development was delayed, with little or no language and no ability to sit or stand unsupported. There was also myopia, nystagmus, and generalized seizures that could be controlled with medication. A second pedigree from Saudi Arabia consisted of first-cousin parents, with 3 affected offspring. The affected children showed severe delay in neurologic and cognitive development, hypotonia, and epilepsy.

Caksen et al. (2004) described 2 Turkish infants with Norman-Roberts syndrome. Both patients had typical craniofacial abnormalities and abnormal magnetic resonance imaging findings, but no deletion in 17p13.3, typical of Miller-Dieker syndrome.

Cytogenetics

Zaki et al. (2007) reported 2 sibs from a consanguineous Egyptian marriage who had cortical lissencephaly with cerebellar hypoplasia, severe epilepsy, and mental retardation. Karyotype analysis identified a homozygous, apparently balanced reciprocal translocation, t(7;12)(q22;p13), in both children. Further analysis confirmed a disruption of the RELN gene at 7q22.1 and undetectable levels of the protein in the children. The unaffected parents were related as double first cousins and were heterozygous for the translocation.

Mapping

In 2 consanguineous pedigrees segregating an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem, Hong et al. (2000) found linkage of the disorder close to the RELN gene on chromosome 7q22.

Molecular Genetics

In affected members of 2 consanguineous pedigrees segregating an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem, Hong et al. (2000) identified homozygous mutations in the RELN gene (600514.0001-600514.0002).