Alternative titles; symbols
SNOMEDCT: 717977003; ORPHA: 89844; DO: 0060902;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q22.1 | Lissencephaly 2 (Norman-Roberts type) | 257320 | Autosomal recessive | 3 | RELN | 600514 |
A number sign (#) is used with this entry because of evidence that lissencephaly-2 (LIS2) is caused by homozygous mutation in the gene encoding reelin (RELN; 600514) on chromosome 7q22.
Lissencephaly ('smooth brain') is a severe disorder of brain development in which neuronal migration is impaired, leading to a thickened cerebral cortex in which the normally folded contour is simplified and smooth. Lissencephaly-2 (LIS2) is associated with severe abnormalities of the cerebellum and hippocampus (summary by Hong et al., 2000).
For a general phenotypic description and a discussion of genetic heterogeneity of lissencephaly, see LIS1 (607432).
Dobyns et al. (1984) suggested the designation Norman-Roberts syndrome for this disorder, which was first reported by Norman et al. (1976).
Dobyns et al. (1984) discussed the differences between Miller-Dieker syndrome (247200), Norman-Roberts syndrome, and classic (formerly type I) lissencephaly. They stated that type I lissencephaly is characterized by microcephaly and a thickened cortex with 4 rather than 6 layers. Patients with Norman-Roberts syndrome show a low sloping forehead and a prominent nasal bridge, features not seen in the Miller-Dieker syndrome. Furthermore, chromosomes are normal, whereas in Miller-Dieker syndrome an abnormality of 17p13 has been found. Dobyns et al. (1984) published photographs demonstrating the craniofacial features of the Norman-Roberts syndrome.
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 classic lissencephaly, 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 family, previously reported by Hourihane et al. (1993), was British with 3 affected sibs. At birth the sibs 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. The second family was Saudi Arabian with 3 affected sibs. The sibs 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.
Valence et al. (2016) reported a Moroccan girl (patient 1), born to consanguineous parents, who presented with neonatal seizures. She had severe developmental delay, and at age 7 years she had feeding difficulties, poor spontaneous movements, axial hypotonia, limb spasticity, nystagmus, and strabismus. A brain MRI showed profound cerebellar hypoplasia without foliation, pontine hypoplasia, and pachygyria with a simplified gyral pattern. She was found to have mutation in the RELN gene.
The transmission pattern of LIS2 in the families reported by Dobyns et al. (1984) and Hong et al. (2000) was consistent with autosomal recessive inheritance.
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.
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.
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).
In a Moroccan girl (patient 1), born to consanguineous parents, with lissencephaly-2, Valence et al. (2016) identified a homozygous splice site mutation in the RELN gene (c.8844-2A-G; 600514.0007). Valence et al. (2016) noted that the severity of the patient's neocortical defect, involvement of the cerebellar hemispheres with absent folia, and level of disability were strongly suggestive of a defect in the reelin pathway.
Caksen, H., Tuncer, O., Kirimi, E., Fryns, J. P., Uner, A., Unal, O., Cinal, A., Odabas, D. Report of two Turkish infants with Normal-Roberts syndrome. Genet. Counsel. 15: 9-17, 2004. [PubMed: 15083694]
Dobyns, W. B., Stratton, R. F., Greenberg, F. Syndromes with lissencephaly. I: Miller-Dieker and Norman-Roberts syndromes and isolated lissencephaly. Am. J. Med. Genet. 18: 509-526, 1984. [PubMed: 6476009] [Full Text: https://doi.org/10.1002/ajmg.1320180320]
Hong, S. E., Shugart, Y. Y., Huang, D. T., Al Shahwan, S., Grant, P. E., Hourihane, J. O., Martin, N. D. T., Walsh, C. A. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature Genet. 26: 93-96, 2000. Note: Erratum: Nature Genet. 27: 225 only, 2001. [PubMed: 10973257] [Full Text: https://doi.org/10.1038/79246]
Hourihane, J. O., Bennett, C. P., Chaudhuri, R., Robb, S. A., Martin, N. D. T. A sibship with a neuronal migration defect, cerebellar hypoplasia and congenital lymphedema. Neuropediatrics 24: 43-46, 1993. [PubMed: 7682675] [Full Text: https://doi.org/10.1055/s-2008-1071511]
Iannetti, P., Schwartz, C. E., Dietz-Band, J., Light, E., Timmerman, J., Chessa, L. Norman-Roberts syndrome: clinical and molecular studies. Am. J. Med. Genet. 47: 95-99, 1993. [PubMed: 8368261] [Full Text: https://doi.org/10.1002/ajmg.1320470120]
Norman, M. G., Roberts, M., Sirois, J., Tremblay, L. J. M. Lissencephaly. Canad. J. Neurol. Sci. 3: 39-46, 1976. [PubMed: 175907] [Full Text: https://doi.org/10.1017/s0317167100025981]
Valence, S., Garel, C., Barth, M., Toutain, A., Paris, C., Amsallem, D., Barthez, M. A., Mayer, M., Rodriguez, D., Burglen, L. RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes. Clin. Genet. 90: 545-549, 2016. [PubMed: 27000652] [Full Text: https://doi.org/10.1111/cge.12779]
Zaki, M., Shehab, M., El-Aleem, A. A., Abdel-Salam, G., Koeller, H. B., Ilkin, Y., Ross, M. E., Dobyns, W. B., Gleeson, J. G. Identification of a novel recessive RELN mutation using a homozygous balanced reciprocal translocation. Am. J. Med. Genet. 143A: 939-944, 2007. [PubMed: 17431900] [Full Text: https://doi.org/10.1002/ajmg.a.31667]