Clinical Report: CNVs (Deletions of 3p24.1, 6p12.2; 12q24.22) Detected by Array CGH in Patient with Microcephaly and Early Epileptic Encephalopathy with Infantile Spasms
DOI:
https://doi.org/10.12974/2309-6179.2014.01.01.8Keywords:
Infantile spasms, microcephaly, CNVs, EOMES, TMEM14A.Abstract
Introduction: Infantile spasms (ISs) are an age-dependent epileptic seizures that are associated with mental retardation, autism, and cerebral palsy. They are part of epileptic encephalopathies such as West and Ohtahara syndromes and early myoclonic encephalopathy. There is growing evidence that ISs result from disturbances in important genetic pathways of brain development. Recent studies show that patients with ISs may have mutations in several genes including ARX, CDKL5, FOXG1, etc. as well as other candidate genes identified from pathogenic copy number variants (CNVs). Case study: The male child was born at term by normal delivery after non-complicated pregnancy. At 3 months of age infantile spasms (ISs) started alongside with deterioration of psychomotor development, affecting head control, reaching for objects and eye tracking. At time of hospitalization ISs were numerous (hundreds per day), they were combined with myoclonic seizures and episodes of motor arrest with staring. Child had axial hypotonia, lack of hand grasping and eye contact. An electodecremental event during spasms, generalized discharges of polyspykes during myoclonias and focal spikes during motor arrest were recorded. Brain MRI showed non-specific brain atrophy. Metabolic screening, including urine and serum amino acids, organic acids, lactate, pyruvate and liver function tests, was normal. Treatment with vigabatrin with doses up to 192 mg/kg/ day was ineffective and injections of synthetic analog of ACTH were started. But the child deteriorated progressively, the burst-suppresion pattern was recorded on EEG and an epileptic status developed. IV benzodiazepine and valproic acid were only partly efficacious. Refractory epileptic status was stopped by general anaesthesia. The child survived but his developmental prognosis is poor. Since the child lacked features specific for any aetiological diagnosis an array comparative genome hybridization (array CGH) was performed. It’s revealed several copy number variants (CNVs): deletion of 3p24.1 with involvement of gene EOMES that encodes the protein-regulator of neurogenesis; deletion of 6p12.2 with involvement of gene TMEM14A (inhibitor of apoptosis) and deletion of DNA of gene FBXO21, which is highly expressed in prefrontal cerebral cortex. Discussion: Epileptic encephalopathies (EE) are severe brain disorders in which the epileptic electrical discharges may contribute to progressive psychomotor dysfunction. There are single gene disorders among them (with well described phenotype) but majority of cases remained unexplained, sometimes because of the fact that clinical and EEG features of different EE are overlapping. Molecular karyotyping can help us in defining their etiology. In our patient with EE with ISs the rare combination of copy number variations (CNVs) was found. We speculate that these CNVs (including genes playing important role in brain development) may be responsible for severe epileptic encephalopathy with ISs.
References
Arnold SJ, Huang GJ, Cheung AF, et al. The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone. Genes Dev 2008; 22(18): 2479-84. http://dx.doi.org/10.1101/gad.475408
Baala L, Briault S, Etchevers HC, et al. Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis. Nat Genet. 2007; 39(4): 454-6. http://dx.doi.org/10.1038/ng1993
Bachmann-Gagescu R, Mefford HC, Cowan C. Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med 2010; 12(10): 641-7. http://dx.doi.org/10.1097/GIM.0b013e3181ef4286
Dibbens LM, Heron SE, Mulley JC. A polygenic heterogeneity model for common epilepsies with complex genetics. Genes Brain Behav 2007; 6: 593-597. http://dx.doi.org/10.1111/j.1601-183X.2007.00333.x
ISCN (2013). An International System for Human Cytogenetic Nomenclature, L.G. Shaffer, J. McGowan- Jordan, M. Schmid (eds); S. Karger, Basel, 2013.
de Kovel CG, Trucks H, Helbig I, Mefford H. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010; 133(Pt 1): 23- 32. http://dx.doi.org/10.1093/brain/awp262
Mefford HC, Mulley JC. Genetically complex epilepsies, copy number variants and syndrome constellations. Genome Med 2010; 2(10): 71. http://dx.doi.org/10.1186/gm192
Mulley John C. and Mefford H.C. Epilepsy and the New Cytogenetics Epilepsia 2011; 52(3): 423-32.
OMIM – online mendelian inheritance in man (http://www.omim.org/)
Paciorkowski A. R., Thio L. L. and Dobyns W. B. A genetic and biologic classification of infantile spasms. Pediatr Neurol 2011; 45(6): 355–367. http://dx.doi.org/10.1016/j.pediatrneurol.2011.08.010
Panayotopoulos C.P. Early myoclonic encephalopathy. Ohtahara syndrome. In A Clinical Guide to Epileptic Syndromes and their Treatment. Revised Second Edition Springer; 2010; 252-257. http://dx.doi.org/10.1007/978-1-84628-644-5
Pavone P, Striano P, Falsaperla R, et al. Infantile spasms syndrome, West syndrome and related phenotypes: What we know in 2013. Brain Dev. 2013 Nov 19. pii: S0387- 7604(13)00298-2.
[Epub ahead of print].
Spreafico R, Angelini L, Binelli S, et al. Burst suppression and impairment of neocortical ontogenesis: electroclinical and neuropathologic findings in two infants with early myoclonic encephalopathy. Epilepsia 1993; 34(5): 800-8. http://dx.doi.org/10.1111/j.1528-1157.1993.tb02093.x
Wheless J. W., Gibson P.A., Rosbeck K.L, et al. Infantile spasms (West syndrome): update and resources for pediatricians and providers to share with parents. BMC Pediatr 2012; 12: 108. http://dx.doi.org/10.1186/1471-2431-12-108
Woo IS, Jin H, Kang ES, Kim HJ, et al. TMEM14A inhibits N- (4-hydroxyphenyl) retinamide-induced apoptosis through the stabilization of mitochondrial membrane potential. Cancer Lett 2011; 309(2): 190-8. http://dx.doi.org/10.1016/j.canlet.2011.05.031