Lissencephaly 4

A number sign (#) is used with this entry because lissencephaly-4 (LIS4) is caused by homozygous mutation in the NDE1 gene (609449) on chromosome 16p13.

Mutation in the NDE1 gene has also been reported in microhydranencephaly (MHAC; 605013).

Description

Lissencephaly-4 is an autosomal recessive neurodevelopmental disorder characterized by lissencephaly, severe brain atrophy, extreme microcephaly (head circumference of more than 10 standard deviations (SD) below the mean), and profound mental retardation. It has also been referred to as 'microlissencephaly' (summary by Bakircioglu et al., 2011 and Alkuraya et al., 2011).

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

Clinical Features

Bakircioglu et al. (2011) reported 6 offspring from 3 consanguineous families with lissencephaly, extreme congenital microcephaly, and profound mental retardation. Two families were of Pakistani origin, and the third was of Turkish origin. The head circumferences of all patients were at least 10 SD below the mean, with onset at 18 weeks' gestation. Mental retardation was evident within the first few months of life; none of the children recognized their parents, and they showed little response to the outside world, even to painful stimuli. Seizures began by 3 months and evolved from occasional rhythmic jerks into complex partial and tonic-clonic seizures. The children gradually adopted a fetal position over the first 3 years of life, with a paucity of movements, but were not hypotonic or spastic. All but 1 died in the first 5 years of life of chest infections and aspiration. Brain imaging, available from 1 individual from each family, showed severe microcephaly, simplified gyral pattern of the cerebral cortex, small cerebellum, normal gross brain architecture, and normal cortical ribbon. Postmortem examination of 1 patient showed severe hypoplasia of the frontal lobes with abnormal gyral pattern. The temporal and occipital lobes were almost smooth, and the only major sulcus visible was the Sylvian fissure, consistent with lissencephaly. Cortical layering was abnormal, with several layers jumbled together and disorganized and a large loss of neurons. The disorder was described as a 'microlissencephaly.'

Alkuraya et al. (2011) reported 2 unrelated consanguineous families from Saudi Arabia with lissencephaly and severe microcephaly (more than 11 SD below the mean). In the first family, 2 affected sisters showed marked hypertonia and lack of development but no seizures. Brain MRI of 1 girl showed severe microcephaly with a proportionate reduction in the size of most other brain structures, including the cerebellum and brain stem, associated with agenesis of the corpus callosum. The gyral folding of the cerebral cortex was extremely simplified; there were almost no detectable sulci other than the Sylvian fissure. Brain MRI of the second girl showed showed microcephaly, severe simplification of the gyral pattern, agenesis of the corpus callosum, and colpocephaly. In the second family, a brother and sister were similarly affected with extreme microcephaly. Clinical details on the girl were not available. At birth, CT scan of the boy showed small brain size. Seizures developed at age 2 months. Brain MRI at 11 months showed marked decrease in the size of both cerebral hemispheres, a large midline fluid-filled structure, dilatation of the right lateral ventricle, small cerebellum, and agenesis of the corpus callosum. All 4 patients reported by Alkuraya et al. (2011) showed overall poor growth.

Inheritance

Lissencephaly-4 is inherited in an autosomal recessive pattern (Bakircioglu et al., 2011).

Molecular Genetics

By linkage analysis followed by candidate gene sequencing, Bakircioglu et al. (2011) identified 2 different truncating mutations in the NDE1 gene (609449.0001 and 609449.0002, respectively) in affected members of 3 consanguineous families with lissencephaly-4. The disorder showed dual pathogenesis of profound early prenatal failure of neuron production and later prenatal deficiency of cortical lamination. The findings suggested that loss of NDE1 at the centrosomes of apical neuroepithelial cells plays a critical role in these processes, highlighting the importance of the centrosome in neurogenesis.

Alkuraya et al. (2011) independently identified 2 truncating mutations in the NDE1 gene in affected members from 2 Saudi Arabian families with LIS4. Patient-derived lymphoblast cells showed spindle-structure defects, including tripolar spindles, misaligned mitotic chromosomes, nuclear fragmentation, and abnormal microtubule organizations, supporting an essential role for NDE1 in normal mitotic spindle function, neuronal proliferation, and human cerebral cortical neurogenesis.

Animal Model

Feng and Walsh (2004) found that Nde1-null mice were viable, but they showed a small-brain phenotype. At 6 to 8 weeks of age, the brains of Nde1-null mice were one-third smaller than their wildtype or heterozygous counterparts. The size reduction predominantly affected the cerebral cortex, while other brain structures, including the hippocampus, midbrain, and cerebellum, appeared normal or were only slightly reduced in size. Cortical lamination was mostly preserved, but the mutant cortex had fewer neurons and thin superficial cortical layers II to IV. Bromodeoxyuridine birthdating revealed retarded and modestly disorganized neuronal migration. More dramatic defects were found in mitotic progression, mitotic orientation, and chromosome localization in cortical progenitors. The small cerebral cortex of Nde1-null mice appeared to reflect both reduced progenitor cell division and altered neuronal cell fates. In vitro analysis demonstrated that Nde1 was essential for centrosome duplication and mitotic spindle assembly. Feng and Walsh (2004) concluded that mitotic spindle function and orientation are essential for normal cortical development.