Epilepsy in Numerical Chromosomal Abnormalities

Numerical chromosomal abnormalities cause a broad spectrum of clinical symptoms for children, including congenital malformations, developmental delay, and epilepsy. The combinations and significance of such symptoms are associated with specific chromosome regions. Prognosis of developmental delay and epilepsy also depends on the chromosomal regions affected. Many distinctive chromosomal deletion syndromes have been clinically recognized.

Miller–Dieker syndrome, due to the subtelomeric deletion of the short arm of chromosome 17, is one of the most characteristic chromosomal aberrations. Because patients with 17p monosomy show typical lissencephaly and distinctive facial features, they are easily recognized by the combinatory findings of clinical manifestations. Patients with 17p monosomy show variable deletion sizes. Accumulated genetic information regarding the size of 17p deletions and patients' clinical information led to the establishment of genotype–phenotype relationships and narrowed the causative chromosomal regions for each clinical finding.[1] The genes responsible for each clinical finding have been identified; LIS1 and YWHAE are the causative genes for lissencephaly and distinctive facial features, respectively.[2]

Such genotype–phenotype correlation studies have been accelerated by the development of genetic technologies. Microarray-based comparative genomic hybridization (aCGH) is one of such technologies. aCGH can accurately identify small chromosomal deletions at the molecular level.[3] Therefore, the resolution of genotype–phenotype correlation studies has been improved, and causative genes for clinical findings are more easily identified.

In this special issue, we provide reviews focused on various chromosome regions that are related to epilepsy, including 1p36 deletion syndrome, 2q24 deletions, Wolf–Hirschhorn syndrome (4p-), 9q34 deletions, Angelman syndrome (15q11.2), 16p11.2 deletion/duplication syndrome, ring(20) syndrome, and Xq28 duplication syndrome (MECP2). The 1p36 deletion syndrome is the most common among the subtelomeric deletion syndromes.[4] On the other hand, the Xq28 duplication syndrome is the most common among the chromosomal duplication syndromes.[5] The 16p11.2 deletion/duplication syndrome is newly established based on aCGH studies.[6] The 16p11.2 deletion of ∼600 kb is common among patients with neuropsychiatric disorders. However, clinical features are often nonspecific. Chromosomal deletions of the 2q24.3 region have also been identified using aCGH.[7] Sodium channel genes including SCN1A are located in this region as a clustering. Small deletions in this region have been identified in patients with intractable epilepsy. Chromosomal deletions of the 9q34.11 region are symbolic, because the causative gene for Ohtahara syndrome, STXBP1, was first identified in this region.[8] Both the 15q11.2 deletion and ring(20) syndrome are well-known chromosome aberrations. Recent progress related to these particular deletions has been reviewed.

As an invited editor of this special issue, I encouraged specialists from around the world to contribute reviews. However, all of the authors who agreed my proposals were from Japan. I am grateful to all of the contributing authors for their excellent reviews and timely submissions. The review process was kindly supported by the deputy editor, Professor Okumura, Aichi Medical University, Japan. I hope that the reviews provide a better understanding of chromosomal aberrations related to childhood epilepsy for the readers of this journal.

• References

• 1 Cardoso C, Leventer RJ, Ward HL , et al. Refinement of a 400-kb critical region allows genotypic differentiation between isolated lissencephaly, Miller-Dieker syndrome, and other phenotypes secondary to deletions of 17p13.3. Am J Hum Genet 2003; 72 (4) 918-930
• 2 Shimojima K, Sugiura C, Takahashi H , et al. Genomic copy number variations at 17p13.3 and epileptogenesis. Epilepsy Res 2010; 89 (2-3) 303-309
• 3 Emanuel BS, Saitta SC. From microscopes to microarrays: dissecting recurrent chromosomal rearrangements. Nat Rev Genet 2007; 8 (11) 869-883
• 4 Shimada S, Okamoto N, Hirasawa K , et al. Clinical manifestations of Xq28 functional disomy involving MECP2 in one female and two male patients. Am J Med Genet A 2013; 161A (7) 1779-1785
• 5 Shimada S, Okamoto N, Ito M , et al. MECP2 duplication syndrome in both genders. Brain Dev 2013; 35 (5) 411-419
• 6 Shimojima K, Inoue T, Fujii Y, Ohno K, Yamamoto T. A familial 593-kb microdeletion of 16p11.2 associated with mental retardation and hemivertebrae. Eur J Med Genet 2009; 52 (6) 433-435
• 7 Takatsuki S, Nakamura R, Haga Y , et al. Severe pulmonary emphysema in a girl with interstitial deletion of 2q24.2q24.3 including ITGB6. Am J Med Genet A 2010; 152A (4) 1020-1025
• 8 Saitsu H, Kato M, Mizuguchi T , et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet 2008; 40 (6) 782-788