• Clinical and Experimental Pediatrics
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• 제60권1호
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• pp.1-9
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• 2017

Malformations of cortical development are rare congenital anomalies of the cerebral cortex, wherein patients present with intractable epilepsy and various degrees of developmental delay. Cases show a spectrum of anomalous cortical formations with diverse anatomic and morphological abnormalities, a variety of genetic causes, and different clinical presentations. Brain magnetic resonance imaging has been of great help in determining the exact morphologies of cortical malformations. The hypothetical mechanisms of malformation include interruptions during the formation of cerebral cortex in the form of viral infection, genetic causes, and vascular events. Recent remarkable developments in genetic analysis methods have improved our understanding of these pathological mechanisms. The present review will discuss normal cortical development, the current proposed malformation classifications, and the diagnostic approach for malformations of cortical development.

• Journal of Korean Neurosurgical Society
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• 제62권3호
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• pp.265-271
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• 2019

The expansion and folding of the cerebral cortex occur during brain development and are critical factors that influence cognitive ability and sensorimotor skills. The disruption of cortical growth and folding may cause neurological disorders, resulting in severe intellectual disability and intractable epilepsy in humans. Therefore, understanding the mechanism that regulates cortical growth and folding will be crucial in deciphering the key steps of brain development and finding new therapeutic targets for the congenital anomalies of the cerebral cortex. This review will start with a brief introduction describing the anatomy of the brain cortex, followed by a description of our understanding of the proliferation, differentiation, and migration of neural progenitors and important genes and molecules that are involved in these processes. Finally, various types of disorders that develop due to malformation of the cerebral cortex will be discussed.

• Journal of Korean Neurosurgical Society
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• 제62권3호
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• pp.272-287
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• 2019

The mechanistic target of rapamycin (mTOR) pathway coordinates the metabolic activity of eukaryotic cells through environmental signals, including nutrients, energy, growth factors, and oxygen. In the nervous system, the mTOR pathway regulates fundamental biological processes associated with neural development and neurodegeneration. Intriguingly, genes that constitute the mTOR pathway have been found to be germline and somatic mutation from patients with various epileptic disorders. Hyperactivation of the mTOR pathway due to said mutations has garnered increasing attention as culprits of these conditions : somatic mutations, in particular, in epileptic foci have recently been identified as a major genetic cause of intractable focal epilepsy, such as focal cortical dysplasia. Meanwhile, epilepsy models with aberrant activation of the mTOR pathway have helped elucidate the role of the mTOR pathway in epileptogenesis, and evidence from epilepsy models of human mutations recapitulating the features of epileptic patients has indicated that mTOR inhibitors may be of use in treating epilepsy associated with mutations in mTOR pathway genes. Here, we review recent advances in the molecular and genetic understanding of mTOR signaling in epileptic disorders. In particular, we focus on the development of and limitations to therapies targeting the mTOR pathway to treat epileptic seizures. We also discuss future perspectives on mTOR inhibition therapies and special diagnostic methods for intractable epilepsies caused by brain somatic mutations.

• Clinical and Experimental Pediatrics
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• 제49권2호
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• pp.187-191
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• 2006

목 적 : MCD는 항경련제에 반응하지 않는 난치성 간질의 중요한 원인으로 수술적 치료의 대상으로 고려되어지지만, 병변의 범위나 분포에 따라 제한적이고 치료효과에 있어서도 차이가 보고되고 있다. 케톤생성 식이요법은 최근까지 대부분의 연구들에서 뛰어난 간질 억제효과를 보고하고 있으나, MCD 병변을 보이는 난치성 간질을 대상으로 시행한 케톤생성 식이요법의 치료 효과에 대한 보고는 국내외적으로 지금까지 없는 상태로, 본 연구에서는 이 환자군들에 대해 간질 수술보다 덜 침습적인 치료법인 케톤생성 식이요법의 간질 억제효과를 알아보고자 하였다. 방 법 : 1998년 이후 난치성 간질로 케톤생성 식이요법을 시행하였던 소아 환아들 중 뇌 MRI상 MCD 소견을 보이는 30명을 대상으로 후향적 의무기록 고찰과 분석을 시행하였으며, 케톤 생성 식이요법 시행 후 경련의 감소효과를 분석하였다. 결 과 : 전체 대상 30명 환아들의 남녀비는 1 : 1.1이었고, 경련을 처음 시작한 연령은 평균 $2.0{\pm}2.9$세, 케톤생성 식이요법을 시작한 평균 연령은 $5.4{\pm}4.6$세, 케톤생성 식이요법을 시작할 때까지의 경련 지속기간은 평균 $3.5{\pm}3.3$년, 환아들의 추적 관찰기간은 평균 $29.0{\pm}21.0$개월이었다. MCD의 종류는 대뇌 피질 이형성증(cortical dysplasia)이 24명(80.0%)으로 가장 많았고, MCD의 분포는 일측 대뇌 반구에만 있는 경우가 23명(76.7%), 양측 대뇌 반구 모두에 병변이 있는 경우가 7명(23.3%)이었다. 케톤생성 식이요법에 의한 경련의 감소 정도는 전체 30명의 환아 중 9명(30.0%)에서 경련이 완전히 소실되었으며, 50% 이상 경련이 감소된 경우는 14명(46.7%)이었는데, 경련을 처음 시작한 연령이나 케톤생성 식이요법을 시작할 때까지의 경련 지속기간은 경련의 감소효과와 통계학적 유의성이 없었고, 케톤생성 식이요법을 시작한 나이가 어릴수록, 케톤생성 식이요법의 기간이 길수록 경련의 감소효과가 높은 경향을 나타내었으나 통계적 유의성은 없었으며, MCD의 분포에 따른 특별한 연관관계는 없었다. 결 론 : 케톤생성 식이요법이 MCD 소견을 동반하고 있어 수술적 치료가 고려되어지는 난치성 소아 간질 환아에서도 간질 수술의 여러 가지 제한적인 측면과 침습성을 고려해 볼 때 효과적인 치료 결과를 기대할 수 있을 것으로 판단되며, 아직까지 국내외적으로 MCD를 동반한 난치성 소아 간질 환아에 대한 케톤생성 식이요법의 효과에 대한 자료가 미미한 상태이므로 전향적인 대규모의 비교 연구 및 분석이 필요할 것으로 사료된다.

• 대한영상의학회지
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• 제81권5호
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• pp.1246-1249
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• 2020

튜불린병증, 즉 튜불린 유전자의 변이는 복합 뇌피질 발달 기형의 원인으로 알려져 있다. 그중에서 TUBB3 유전자가 기형의 원인인 사례는 매우 드물어 이를 보고하고자 한다. 21개월 남아가 발달지연을 주소로 내원하였다. 환아는 혼자 걷지 못하였고 구사 가능한 단어가 5개 이내였다. 신체검사상 우측 내사시와 양하지 근력저하가 관찰되었다. 뇌 자기공명영상에서 뇌간의 이형성, 기저핵의 이형성 및 과형성 소견이 보였고 우측 시상의 크기가 좌측보다 작았으며 붕괴된 소뇌이랑의 소견이 보였다. DNA 염기서열 분석 결과 TUBB3 유전자의 과오돌연변이가 확인되었다.

• Molecules and Cells
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• 제41권10호
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• pp.881-888
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• 2018

During the cortical development, cells in the brain acquire somatic mutations that can be implicated in various neurodevelopmental disorders. There is increasing evidence that brain somatic mutations lead to sporadic form of epileptic disorders with previously unknown etiology. In particular, malformation of cortical developments (MCD), ganglioglioma (GG) associated with intractable epilepsy and non-lesional focal epilepsy (NLFE) are known to be attributable to brain somatic mutations in mTOR pathway genes and others. In order to identify such somatic mutations presenting as low-level in epileptic brain tissues, the mutated cells should be enriched and sequenced with high-depth coverage. Nevertheless, there are a lot of technical limitations to accurately detect low-level of somatic mutations. Also, it is important to validate whether identified somatic mutations are truly causative for epileptic seizures or not. Furthermore, it will be necessary to understand the molecular mechanism of how brain somatic mutations disturb neuronal circuitry since epilepsy is a typical example of neural network disorder. In this review, we overview current genetic techniques and experimental tools in neuroscience that can address the existence and significance of brain somatic mutations in epileptic disorders as well as their effect on neuronal circuitry.

• Toxicological Research
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• 제17권
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• pp.11-16
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• 2001

The development of the central nervous system is a continuous process during the embryonic and fetal periods. For a better understanding of congenital anomalies of central nervous system, three major events of normal development, i.e., neurulation (3 to 4 weeks), brain vesicle formation (4 to 7 weeks) and mantle formation (over 8 weeks) should be kept in mind. The first category of anomalies is neural tube defect. Neural tube defects encompass all the anomalies arise in completion of neurulation. The second category of central nervous system anomalies is disorders of brain vesicle formation. This is anomaly that applies for "the face predicts the brain". Holoprosencephaly covers a spectrum of anomalies of intracranial and midfacial development which result from incomplete development and septation of midline structures within the forebrain or prosencephalon. The last category of central nervous system malformation is disorders involving the process of mantle formation. In the human, neurons are generated in two bursts, the first from 8 to 10 weeks and next from 12 to 14 weeks. By 16 weeks, most of the neurons have been generated and have started their migration into the cortex. Mechanism of migration disorders are multifactorial. Abnormal migration into the cortex, abnormal neurons, faulty neural growth within the cortex, unstable pial-glial border, degeneration of neurons, neural death by exogenous factors are some of the proposed mechanism. Agyria-pachygyria are characterized by a four-layerd cortex. Polymicrogyria is gyri that are too numerous and too small, and is morphologically heterogeneous. Cortical dysplasia is characterized by the presence Q[ abnormal neurons and glia arranged abnormally in focal areas of the cerebral cortex. Neuroglial malformative lesions associated with medically intractable epilepsy are hamartia or hamartoma, focal cortical dysplasia and microdysgenesis.ysgenesis.

• Journal of Genetic Medicine
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• 제16권2호
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• pp.71-75
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• 2019

Periventricular nodular heterotopia (PNH) is a malformation of cortical development in which normal neurons inappropriately cluster in periventricular areas. Patients with Mowat-Wilson syndrome (MWS) typically present with facial gestalt, complex neurologic problems (e.g., severe developmental delay with marked speech impairment and epilepsy), and multiple anomalies (e.g., Hirschsprung disease, urogenital anomalies, congenital heart defects, eye anomalies, and agenesis of the corpus callosum [CC]). MWS is mostly caused by haploinsufficiency of the gene encoding zinc-finger E-box-binding homeobox 2 (ZEB2) due to premature stops or large deletions. We present a case report of a 9-year-old girl with PNH, drug-responsive epilepsy, severe intellectual disability, and facial dysmorphisms only in whom we performed whole-exome sequencing and found a de novo heterozygous missense mutation (c.3134A>C; p.His1045Pro) of ZEB2 (NM_014795.3; NP_055610.1). This mild case of MWS caused by a rare novel missense mutation of ZEB2 represents the first report of MWS with isolated PNH.

• Journal of Korean Neurosurgical Society
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• 제29권8호
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• pp.1126-1135
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• 2000

Objectives : The goal of surgical management of cerebral arteriovenous malformation(AVM) is elimination of the lesion without development of new neurological deficits. To improve the management results of cerebral AVMs in the future, this article discusses about surgical complications of the AVM and their management. Material and Methods : During the past 18 years, 116 patients with cerebral AVMs were managed by surgery. Among these cases, 7 cases died, 7 cases developed new neurological deficits, 11 cases residual AVM and 5 cases intracerebral hematoma(ICH) after surgery. The author analyzes the causes of those complications and investigates the methods to minimized those complications based on the review of the literatures. Results : One stage removal of AVM and ICH in the poor neurological state were performed in 5 of 7 death cases. Subtotal removal of ICH followed by delayed AVM surgery after recovery is regard as one method to improve the outcome of patient with large ICH. Postoperative new neurological deficits developed owing to normal perfusion pressure breakthrough(NPPB) in 3, judgement error in 2, preoperative embolization in 1 and cortical injury in 1 case(s). Proper management of NPPB, accurate anatomical knowledge and physiological monitoring during operation, and well trained skill for embolization are regard as methods to minimize those complications. Residual AVMs after surgery were noticed in 11 cases, in which unintended 6 cases due to inaccurate dissection of peripheral margin of AVM, and intended 3 cases due to massive brain swelling during operation, 1 cases due to diffuse type and 1 case due to multiple type of AVM. Accurate dissection of peripheral margin of AVM and mild hypotension during operation may help to avoid this complication. Postoperative hemorrhage occurred in 3 cases due to rupture of the residual AVM and in 2 cases due to oozing from the AVM bed. Complete resection of AVM, complete control of bleeding points at AVM bed and mild hypotension during early postoperative period are the methods to avoid this complication. Conclusion : A precise but flexible therapeutic strategy and refined skill for endovascular, radiosurgical and microsurgical techniques are required to successful treatment of cerebral AVM. Adequate timing of AVM resection, accurate anatomical knowledge, proper management of NPPB and accurate dissection of peripheral margin of AVM are the key points for avoiding complications of the AVM surgery.

• 대한유전성대사질환학회지
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• 제17권2호
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• pp.48-54
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• 2017

목적: Fukuyama 선천성 근이영양증은 희귀한 열성 유전질환으로 영아 시기에 발병하는 근긴장 저하, 뇌 기형 및 dystroglycanopathy 특징들을 보인다. 선천성 근육병의 넓은 스펙트럼에 여러 질환들이 존재하여 Fukuyama 선천성 근이영양증 진단을 어렵게 하지만, 유전형과 표현형 상관관계를 파악하면 진단을 도울 수 있다. 이 연구에서는 분자유전학 분석을 통해 선정한 FKTN 유전자와 Fukuyama 선천성 근이영증의 표현형의 연관성에 대해 알아보았다. 방법: 이 연구는 후향적으로 9명의 대상자들로 진행하였다. 영아 시기에 발병하는 근긴장 저하의 증상 및 뇌 자기공명영상에서 기형 소견을 보인 환자들을 대상으로 선정하였다. 그리고 FKTN 유전자를 이용한 염기서열 검사를 통해 유전자를 분석하였다. 결과: 9명의 대상자들 중 남성이 4명(44.4%), 여성이 5명(55.5%) 였다. 첫 증상이 발병한 나이의 중간값은 3.1개월였다. 6명(66.7%) 에서 첫 증상이 발달지연으로 나타났다. 모든 환자들은 영아 시기에 근긴장 저하 및 전반적 발달 지연 소견을 보였다. 또한, 모든 환자들은 뇌 자기공명영상에서 뇌 피질 기형 소견을 보였다. 9명의 환자들 중 6명이 근육생검 검사를 실시하였고 그 중 4명(4/6; 66.7%)이 특이 소견을 보였다. Fukuyama 선천성 근이영양증을 일으키는 FKTN 유전자 돌연변이는 3명에서 발견되었다. 결론: 이 연구에서 FKTN 유전자 변이를 보인 3명의 대상자들은 모두 뇌 자기공명영상에서 큰뇌이랑증 및 소뇌 형성장애 소견들을 보였다. 이것을 통해 근육병 증상을 보이면서 뇌 자기공명영상에서 특징적인 소견들을 보일 시 Fukuyama 선천성 근이영양증을 진단할 가능성을 높일 수 있다는 것을 확인하였다.