Cortical malformation disorders

In order to provide the best possible care to patients with a rare condition, it is essential that global knowledge about the condition is gathered. Nationwide, centers of expertise have been set up to stimulate care for rare disorders and to gather knowledge. For the formal recognition of an expertise center by the Ministry of Health, an important condition is that the expertise center gathers, analyzes and shares knowledge through publications. These can be publications in scientific journals, but also treatment guidelines for health care professionals or information brochures for patients or caregivers. We optimize care and research within ENCORE through standardized follow-up and close collaboration between doctors and researchers. That way, we can ultimately develop better treatments for rare conditions. You may therefore be asked to participate in research. Participation in research is always on a voluntary basis. The data obtained is stored and analyzed in an anonymous form. All research has been approved in advance by an ethics review committee.

Genetic testing will be performed on all Angelman Syndrome patients seen in our center of expertise to determine the genetic cause and to be able to support and advise the parents. If genetic testing has already been done elsewhere, it will not be repeated. This genetic knowledge also helps us to better understand the effect of the genetic change ("mutation") on the severity of symptoms. We can then also investigate which treatment works best for a particular mutation. In rare cases, the genetic analysis is inconclusive. In these cases, the genetic change will be further investigated in the laboratory. Cortical malformation disorders are very rare, the different subtypes even more. We cooperate internationally to pool knowledge on these very rare disorders, so we can provide you with more knowledge about prognosis and the best possible treatment.

Detailed knowledge about the course of cortical malformation disorders (which symptoms and complaints are there, and when exactly do they arise) is of great importance in order to recognize complaints early and treat them optimally. In addition, this is of great importance for drug research (trials). After all, only if we can demonstrate that a new drug improves the quality of life compared to an untreated patient, will the drug actually be approved and reimbursed. Because there are many differences between the cortical malformation disorders, it is very important to gain insights into the course, the risks and the effects of (new) treatments. For this we also work together with doctors abroad. We will examine on an individual basis whether a targeted treatment is possible. We will ask for your permission to include information about your child in our database.

In addition to permission to record these clinical data, you may be asked to provide a tube of blood for research. This blood is used to generate iPSC (induced Pluripotent Stem Cells) for research. Brain cells can be grown from these iPS cells. See the pre-clinical research page on this website for more information about iPS research.

Bar C, (2020) Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome. Epilepsia. Pubmed

Ragamin A, et al. (2020) Human RAD50 deficiency: Confirmation of a distinctive phenotype. Am J Med Genet A. 1-9. Pubmed

Severino M, (2020) Definitions and classification of malformations of cortical development: practical guidelines. Brain. 143(10); 2874-94. Pubmed

Oegema R, (2020) International consensus recommendations on the diagnostic work-up for malformations of cortical development. Nat Rev Neurol. Pubmed

Brock S, (2020) Defining the Phenotypical Spectrum Associated with Variants in TUBB2A. J Med Genet. Pubmed

Vandervore LV, (2019) TMX2 is a Crucial Regulator of Cellular Redox State, and Its Dysfunction Causes Severe Brain Developmental Abnormalities. Am J Hum Genet. Pubmed

Lee S, (2019) Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia and Global Developmental Delay. Am J Hum Genet. Pubmed

Oegema R, (2019) EML1-associated Brain Overgrowth Syndrome with Ribbon-like Heterotopia. Am J Med Genet C Semin Med Genet. Pubmed

Magini P, (2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis. Am J Hum Genet. Pubmed

Oegema R, (2019) Subcortical Heterotopic Gray Matter Brain Malformations: Classification Study of 107 Individuals. Neurology. Pubmed

Uzguiano A, (2019) Mutations in the Heterotopia Gene Eml1/EML1 Severely Disrupt the Formation of Primary Cilia. Cell Rep. Pubmed

Vandervore LV, (2019) Heterogeneous Clinical Phenotypes and Cerebral Malformations Reflected by Rotatin Cellular Dynamics. Brain. Pubmed

Dobyns WB, (2018) MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance. Am J Hum Genet. Pubmed

Vandervore LV, (2018) Mutated zinc finger protein of the cerebellum 1 leads to microcephaly, cortical malformation, callosal agenesis, cerebellar dysplasia, tethered cord and scoliosis. Eur J Med Genet. Pubmed

Smith RS, (2018) Sodium Channel SCN3A (Na1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development. Neuron. Pubmed

Reijnders MRF, (2017) RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes. Am J Hum Genet. 101(3); 466-77. Pubmed

Reijnders MRF, (2017) Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability. Nat. Commun. 8(1); 1052. Pubmed

De Mori R, (2017) Hypomorphic Recessive Variants in SUFU Impair the Sonic Hedgehog Pathway and Cause Joubert Syndrome with Cranoi-facial and Skeletal Defects. Am J Hum Genet. 101(4); 552-63. Pubmed

Oegema R, (2017) Human mutations in integrator complex subunits link transcriptome integrity to brain development. PLoS Genet. 13(5); e1006809. Pubmed

Meuwissen ME, (2016) Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med. 213(7); 1163-74. Pubmed

Mancini GM, (2016) CSTB null mutation associated with microcephaly, early developmental delay, and severe dyskinesia. Neurology. 86(9); 877-8. Pubmed

Yilmaz S, (2015) The expanding phenotypic spectrum of ARFGEF2 gene mutation: Cardiomyopathy and movement disorder. Brain Dev. 38(1); 124-7. Pubmed

Nellist M, (2015) Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia. Mol Genet Metab. 114(3); 467-73. Pubmed

Kielar M, (2014) Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human. Nat Neurosci. 17(7); 923-33. Pubmed

Poulton CJ, (2014) Severe presentation of WDR62 mutation: is there a role for modifying genetic factors? Am J Med Genet A. 164A(9); 2161-71. Pubmed

Mirzaa G, (2014) De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nat Genet. 46(5); 510-5 Pubmed

Oegema, R. et al. (2013) Novel no-stop FLNA mutation causes multi-organ involvement in males. Am J Med Genet A 161, 2376–2384. Pubmed

Oegema, R. et al. (2013) A single strand that links multiple neuropathologies in human disease. BrainPubmed

Meuwissen, M.E.C. et al. (2013) ACTA2 mutation with childhood cardiovascular, autonomic and brain anomalies and severe outcome. Am J Med Genet A 161, 1376–1380. Pubmed

Poulton, C. et al. (2013) Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations. Neurogenetics 14, 43–51. Pubmed

Kheradmand Kia, S. et al. (2012) RTTN mutations link primary cilia function to organization of the human cerebral cortex. Am J Hum Genet 91, 533–540. Pubmed

Verbeek, E. et al. (2012) COL4A2 mutation associated with familial porencephaly and small-vessel disease. Eur J Hum Genet 20, 844–851. Pubmed

Oegema, R. et al. (2012) Asymmetric polymicrogyria and periventricular nodular heterotopia due to mutation in ARX. Am J Med Genet A 158, 1472–1476. Pubmed

Poulton, C.J. et al. (2011) Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors. Am J Hum Genet 89, 265–276. Pubmed

de Wit, M.C.Y. et al. (2011) Lung disease in FLNA mutation: confirmatory report. Eur J Med Genet 54, 299–300. Pubmed

de Wit, M.C.Y. et al. (2011) Long-term follow-up of type 1 lissencephaly: survival is related to neuroimaging abnormalities. Dev Med Child Neurol 53, 417–421. Pubmed

Meuwissen, M.E.C. et al. (2011) Sporadic COL4A1 mutations with extensive prenatal porencephaly resembling hydranencephaly. Neurology 76, 844–846. Pubmed

de Wit, M.C.Y. et al. (2011) Combined cardiological and neurological abnormalities due to filamin A gene mutation. Clin Res Cardiol 100, 45–50. Pubmed

de Wit, M.C.Y. et al. (2010) Absence epilepsy and periventricular nodular heterotopia. Seizure 19, 450–452. Pubmed

Oegema, R. et al. (2010) KBG syndrome associated with periventricular nodular heterotopia. Clin. Dysmorphol. 19, 164–165. Pubmed

Verkerk, A.J.M.H. et al. (2010) Unbalanced der(5)t(5;20) translocation associated with megalencephaly, perisylvian polymicrogyria, polydactyly and hydrocephalus. Am J Med Genet A 152, 1488–1497. Pubmed

de Wit, M.-C.Y. et al. (2010) Periventricular nodular heterotopia and distal limb deficiency: a recurrent association. Am J Med Genet A 152, 954–959. Pubmed

de Wit, M.C.Y. et al. (2009) Movement disorder and neuronal migration disorder due to ARFGEF2 mutation. Neurogenetics 10, 333–336. Pubmed

de Wit, M.C.Y. et al. (2009) Filamin A mutation, a common cause for periventricular heterotopia, aneurysms and cardiac defects. J Neurol Neurosurg Psychiatry 80, 426–428. Pubmed

de Wit, M.C.Y. et al. (2008) Cortical brain malformations: effect of clinical, neuroradiological, and modern genetic classification. Arch Neurol 65, 358–366. Pubmed

de Wit, M.C.Y. et al. (2006) Microcephaly and simplified gyral pattern of the brain associated with early onset insulin-dependent diabetes mellitus. Neurogenetics 7, 259–263. Pubmed

Breedveld, G. et al. (2006) Novel mutations in three families confirm a major role of COL4A1 in hereditary porencephaly. J Med Genet 43, 490–495. Pubmed

de Wit, M.C.Y. et al. (2006) Brain abnormalities in a case of malonyl-CoA decarboxylase deficiency. Mol. Genet. Metab. 87, 102–106. Pubmed

Brooks, A.S. et al. (2005) Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems. Am J Hum Genet 77, 120–126. Pubmed

Mancini, G.M.S. et al. (2004) Hereditary porencephaly: clinical and MRI findings in two Dutch families. Eur J Paediatr Neurol 8, 45–54. Pubmed

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