Neuronal Cortical Migration Disorder Associated with Epilepsy in Sudanese Male Twins A case report and literature Review. Haydar El Hadi Babikir 1 , Mohmmed Salah Magzoub 2 , Anas O. Hamdoun 3 Epilepsy is the most common neurological disorder affecting young people. The aetiologies are multiple and most cases are sporadic. However, genetics malformations have important role. Disturbances of neuroblast migration and consequently abnormal development of the human cortex are recognized as significant causes of mental retardation, symptomatic epilepsy, and congenital neurologic deficits with abnormal neurological development in children. These malformations may be restricted to the brain or may be one component of a generalized malformation syndrome. This review will discuss two male twins with cortical malformation and epileptic seizures failure to thrive, microcephaly and global developmental delay. The classical facies of Miller-Dieker syndrome are not present. The family history suggested a hereditary disorder of XL type. Key words: epilepsy, child, cortical migratory disorders, Miller-Dieker syndrome, genetic inheritance twins Sudan. 1- Professor of Child Health, Head, department of Graduate Medical studies, Faculty of Medicine, University of Gezira, Sudan. 2- Associate Professor of Neurophysiology, Head department of Physiology. Faculty of Medicine, Ribat National University . 3- Associate Professor of radiology, Institute of Nuclear Medicine, Molecular Biology and Oncology-University of Gezira. Address correspondence: Dr. Haydar E. Babikir MD, Faculty of Medicine, University of Gezira, Sudan. B.O. Box 20. e. mail: haydarbabikir@yahoo.com INTRODUCTION: The development of the cerebral cortex progresses through defined stages including neural proliferation, neuroblast migration and neuronal differentiation. Beginning with the seventh gestational week, neuronal and glial precursors are generated in the germinal matrix that lines the lateral and third ventricles. These young neurons then migrate along the radial glial fibers that extend from the ventricle to the brain surface. There is a direct correspondence between the site of cell proliferation within the germinal zone and location within the cerebral cortex. 1 (Barkovich AJ) Disruption in the normal process of neuronal migration results in spectrum of brain malformations. 2 Lissencephaly; a brain with absent or poor sulcation. Lissencephaly is either complete (agyria) or incomplete (agyria-pachgyria). Collections of normal neurons in abnormal location secondary to arrest of migrating neurons are called gray matter heterotopias. A large number of human cortical malformations have been identified and classified; focal cortical dysplasia, polymicrogyria, periventricular nodular heterotopia, subcortical band heterotopia, lissencephaly and schizencephaly as examples of migratory cortical dysplasias (MCDs). 3 CASE REPORT: Two male twins ten month-old of a consanguint parents presented to me with focally initiated tonic clonic seizures that become generalized. The fits associated with arching of the back brief dystonic posturing of the limbs and followed by high pitch cry. These events were unprovoked and recurred many times a day. No history of birth asphyxia, ischaemia, exposure to drugs or radiation. They are failing to thrive with developmental delay and microcephaly. (Fig. 1&2) Their sister was quite healthy when she died of acute infectious diseases. The family pedigree suggested an XL inherited disorder (Fig 3). Axial T1 & T2 brain MRI showed severe diffuse pachgyria with brain atrophy (dilated CSF spaces), without midline shift or SLO and normal brain stem and basal ganglia (Fig. 4 & 5). EEG record showed sleep changes of stage II. There were bursts of very high amplitude of regular and irregular primitive spike-sharp and slow waves. (Figs. 6, 7 & 8) These are prominent on the right hemisphere. The seizures were reasonably controlled with carabmazepine. Fig 1 & 2. Both twins have microcephaly, no MDS facies. DISCUSSION: The development of the cerebral cortex progresses through defined stages including neural proliferation, neuroblast migration and neuronal differentiation. Disruptions in each of these developmental stages can lead to characteristic cerebral cortical malformations. 4 Genetic microcephaly and lissencephaly are a significant cause of neurological morbidity in children worldwide, responsible for many cases of mental retardation, cerebral palsy, and epilepsy. 5 However, the clinical manifestations of migratory disorders are generally nonspecific with considerable overlap of symptoms and signs amongst the various disorders. Generally, these infants present with failure to thrive, microcephaly, marked developmental delay and a severe seizure disorder. Ocular abnormalities are common, including hypoplasia of the optic nerve and micro-ophthalmia. It can occur as an isolated finding, but it is associated with Miller- Dieker syndrome (MDS) in about 15% of cases. 6 These children have characteristic facies, including a prominent forehead, bitemporal hallowing, antevereted nostrils, a prominent upper lip and micrognathia. About 90% of children with MDS have visible or submicroscopic chromosomal deletions of 17p13.3. The gene LIS-1 (lissencephaly 1) that maps to chromosome region 17p13.3 is deleted in patients with MDS. More recently identified genes include STIL, causing primary autosomal recessive microcephaly (microcephaly vera) and TUBA1A, causing lissencephaly. Numerous other disease genes are likely still to be identified. 7&8 Fig.3. Family pedigree suggestive of an XL pattern of inheritance Mutations of the DCX gene (Xp22.3) cause X-linked lissencephaly in male and double cortex syndrome (DCS) or subcorticalbandheterotopia(SBH) in females. SBH is characterized by bilateral bands of grey matter interposed in the white matter between the cortex and the lateral ventricles. The main clinical manifestation in patients with SBH is epilepsy, which may be partial or generalized and is intractable in approximately 65% of the patients. 7 Major advances in recent years in the technology of neuroimaging and in molecular genetics make these disorders, continuously being redefined with greater precision in living subjects and detected the aetiology of epilepsy in children with early or late epilepsy. Casara, G. et al reported a case of late onset focal epilepsy in a mentally and neurologically normal girl in which the MRI showed a focal heterotopias. In some cases,disorders of migration may be grouped into syndromes that are more easily diagnosed during life. 9 Fig.4. T1 & T2 MRI axial view showing severe diffuse pachgyria with brain atrophy Recent advances in molecular genetics have led to the identification of several genes involved in the formation of the cerebral cortex and thus accurate molecular diagnosis and improved genetic counseling has become available for many patients and their families. Mutations in genes involved in the fine tuning of proliferation and neurogenesis, neuronal migration and differentiation and connectivity, are responsible for neuro-developmental disorders, such as cortical migratory disorders, which are usually associated with severe mental retardation and epilepsy. Figs (5 & 6) Abnormal EEG showing a generalized active seizure discharges probably of right hemispheric initiation. Many of the genes that control neuronal migration have strong genetic or biochemical links to the cytoskeleton, suggesting that the field of neuronal migration might be closing in on the underlying cytoskeleton events. 10 The cytoskeleton components in cellular processes, reinforced by the association of mutations in the LIS1 and DCX genes, which both encode proteins involved in microtubule (MT) homeostasis, with cerebral cortex developmental disorders had been studied. The recent discovery of patients with lissencephaly and bilateral asymmetrical polymicrogyria (PMG) carrying mutations in the alpha- and beta-tubulin-encoding genes TUBA1A and TUBB2B further supports this view, and also raises interesting questions about the specific roles played by certain tubulin isotypes during the development of the cortex. 11 Fig.7. Figs (2, 3 & 4) Abnormal EEG showing a generalized active seizure discharges probably of right hemispheric initiation. CONCLUSION: Lissencephaly and double cortex appear to be caused by defects of ongoing process of migration with strong interactions with microtubules suggesting a microtubule based disorder. This case of early onset infantile epilepsy in mentally and neurologically abnormal twins in which the MRI showed cortical migratory disorder indicates that MRI is the most sensitive imaging modality for identifying CNS malformations. The identification of causative genes involved in the formation of the cerebral cortex now allows for a rational approach with which to interpret the underlying basic mechanism for many of these disorders. In the future more cases of epilepsy previously classified as «cryptogenetic» will be demonstrated as secondary to developmental abnormalities. REFERENCES: 1- Barckovich AJ. Congenital malformations of the brain. In Pediatric Neuroimmaging, pp77147-, New York, Raven Press, 1990. 2- Barckovich AJ. Gressens P, Evrard P. Formation, maturation, and disorders of brain neocortex. AJNR. 13:4231992 ,446-. 3- Andrade, D. M. Genetic basis in epilepsies caused by malformations of cortical development and in those with structurally normal brain. Hum Genet. 2009. 126;1:17393-. 4- Flores-Sarnat, L. Hemimegalencephaly: part 1. Genetic, clinical, and imaging aspects. J Child Neurol. 2002. 17;5:37384-; discussion 384. 5- Mochida, G. H. Genetics and biology of microcephaly and lissencephaly. Semin Pediatr Neurol. 2009. 16;3: 1206-. 6- Miller SP, Shevell MI, Patenaude Y, et al: Septo-optic dysplasia plus: A spectrum of malformations of cortical development. Neurology 2000;54:17011703-. 7- Parisi, P. Miano, S. Mei, D. Paolino, M. C. Castaldo, R. Villa, M. P. Diffuse subcortical band heterotopia, periodic limb movements during sleep and a novel «de novo» mutation in the DCX gene. Brain Dev.2009. 8- Berry-Kravis, E.; Israel, J. X-linked pachygyria and agenesis of the corpus callosum: evidence for an X chromosome lissencephaly locus. Ann Neurol. 1994.36:2. 33229-. 9- Leventer, R. J.; Mills, P. L.; Dobyns, W. B. X-linked malformations of cortical development. Am J Med Genet. 2000. 97;3: 20213-. 10- Joseph G. Gleeson, Christopher A. Walsh. Neuronal migration disorders: fromgenetic diseases to developmental mechanisms. Trends Neurosci. 2000;23. 352359-. 11- Jaglin, X. H. Chelly , J. Tubulin-related cortical dysgeneses: microtubule dysfunction underlying neuronal migration defects. Trends Genet.2009. 25;12:55566-. pdf Machine A pdf writer that produces quality PDF files with ease! Produce quality PDF files in seconds and preserve the integrity of your original documents. Compatible across nearly all Windows platforms, simply open the document you want to convert, click “print”, select the “Broadgun pdfMachine printer” and that’s it! Get yours now!