Lissencephaly

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Continuing Education Activity

Lissencephaly is a spectrum of severe and rare brain malformations. It is caused by non-genetic and genetic factors. Treatment of children with lissencephaly is supportive and aims to reduce symptoms severity. This activity reviews the etiology, epidemiology, evaluation, and treatment options and highlights the role of the professional team in the care of patients with this condition.

Objectives:

  • Identify the etiology of lissencephaly.
  • Describe the evaluation of lissencephaly.
  • Outline the management options available for lissencephaly.
  • Summarize interprofessional team strategies for improving care coordination and improving outcomes in patients with lissencephaly.

Introduction

Lissencephaly includes a range of severe brain malformations, including agyria (absent gyri), pachygyria (broad gyri), and subcortical band heterotopia.[1] In lissencephaly (which literally means smooth brain), the surface of the brain appears smooth.[2] It may occur as an isolated lissencephaly or in association with certain syndromes (Miller-Dieker syndrome).[3]

Lissencephaly is caused by a defect in neuronal migration during embryonic development between 12 and 24 weeks of gestation that results in the absence of normal development of brain gyri and sulci.[4] Children with lissencephaly present with significant developmental delays and mental disability, but these vary from child to child depending on the degree of brain malformation and intractable epilepsy.[5]

Etiology

Lissencephaly can be caused by non-genetic and genetic factors. Non-genetic factors include viral infections of the mother or the fetus, especially during the first trimester and insufficient supply of oxygenated blood to the brain during fetal development.[6] There are several genetic causes also.[2][7]

Some of the known genetic causes are listed below:

  • LIS1

LIS1 (PAFAH1B1) is the most studied. This gene is located on chromosome 17p13.3.[8] LIS1 regulates the motor protein dynein, which is linked to neuronal nuclei movement along microtubules.[9] The mutation or deletion in the LIS1 gene is associated with both isolated Lissencephaly syndrome and Miller-Dieker syndrome.[8]

  • DCX

DCX is located on the X chromosome.[10] DCX encodes for the doublecortin protein, which encodes a neuronal microtubule-associated protein, which is known to be essential for neuronal migration. DCX mutation causes defects in neuronal migration and reduced folding in the cerebral cortex.[11][12] Males with DCX mutation are more likely to be severely affected, while females with the same mutation have a milder version of the syndrome.[13]

  • ARX

The ARX gene encodes for the aristaless related homeobox protein, which is a transcription factor with an important role in the forebrain and other tissue.[14] Children with ARX mutation present with other symptoms such as the absence of portions of the brain (corpus callosum agenesis), abnormal genitalia, and severe epilepsy.[15][16]

  • RELN

RELN gene encodes reelin, an extracellular matrix glycoprotein. The mutation of this gene is involved in lissencephaly associated with cerebellar hypoplasia and hippocampal abnormalities.[17]

  • Other genes:

Several genes have established a relationship with lissencephaly. Those genes are VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5.[18]

Cytomegalovirus (CMV) has been associated with developing lissencephaly by reducing blood supply to the fetal brain. The severity of CMV infection depends on the gestational age. Early infection is more likely to cause lissencephaly because neuronal migration takes place early in the pregnancy.[19]

Epidemiology

Lissencephaly is a relatively rare disorder of the brain and the incidence of which is not known. A study of lissencephaly in the Netherlands estimated the prevalence of around 1.2/100,000 births.[20][21] The diagnosis and the prevalence of lissencephaly will increase with improving imaging technology.

Genetic studies of 17 genes associated with lissencephaly revealed that LIS1 mutation or deletion accounts for 40% of the patients, and 23% was associated with DCX mutation, followed by TUBA1A (5%), and DYNC1H1 (3%).[22]

Pathophysiology

The genetic and non-genetic causes lead to an absent migration of the newly formed neurons to the surface of the brain. This results in an absent infolding of the cerebral cortex in addition to the reduced number of cellular layers in the cortex.

History and Physical

Lissencephaly has different levels of severity and symptoms.[23]

Symptoms may include seizures, feeding difficulty, muscle spasm, mental disability, severe psychomotor impairment, failure to thrive, developmental delays, and sometimes hands, finger, or toe anomalies. However, some children may develop normally with a mild learning disability.[24][25]

Epilepsy develops in the first year of life in 9 out of 10 lissencephaly cases.

Evaluation

Lissencephaly is usually diagnosed at birth through clinical evaluation and head imaging (ultrasound, computed tomogram (CT), or magnetic resonance imaging (MRI)). It is characterized by the absence or reduction of the sulci and gyri of the cerebral surface and a thickened cortex. To confirm the diagnosis, DNA studies like chromosomal analysis or/and specific gene mutational analysis are needed to find a mutation.[26][27] Another test that can aid in the diagnosis is the electroencephalogram (EEG).[28]

Treatment / Management

Management for children with lissencephaly is symptomatic and supportive. Treatment aims to improve the intake of nutrients in patients with feeding difficulties and the use of anticonvulsant drugs to prevent or control seizures. Genetic counseling is usually offered to families of affected children, coupled with genetic studies.[25]

Differential Diagnosis

There are more than 20 types of lissencephaly, most of them are listed under 2 main categories: Classic lissencephaly (Type 1) and Cobblestone lissencephaly (Type 2). Each category shares similar clinical presentations but different genetic mutations.[20][29]

Examination of the brain in type I lissencephaly shows a cerebral cortex with four layers instead of six layers as in normal patients, while in type 2 lissencephaly the cerebral cortex is disorganized, and appears pebbled or nodular due to complete displacement of the cerebral cortex with clusters of cortical neurons separated by glio-mesenchymal tissue. The patients also had abnormalities of muscle and eyes.[20]

  • Classic lissencephaly (type 1):
  1. LIS1: Isolated lissencephaly and Miller-Dieker syndrome (lissencephaly associated with facial dysmorphism).[30]
  2. LISX1: DCX gene mutation. Compared to lissencephaly caused by LIS1 mutations, DCX shows a six-layered cortex instead of four.
  3. Isolated lissencephaly without other known genetic defects
  • Cobblestone lissencephaly (type 2):
  1. Walker-Warburg syndrome
  2. Fukuyama syndrome
  3. Muscle-eye-brain disease
  • Other types cannot be placed in one of the two aforementioned groups:
  1. LIS2: Norman-Roberts syndrome, similar to type I lissencephaly or Miller-Dieker syndrome, but without deletion of the chromosome 17.
  2. LIS3
  3. LISX2
  4. Microlissencephaly: It is a combination of the absence of normal cerebral cortex folding and an abnormally small head. Children with usual lissencephaly have a normal head size at birth. In children with reduced head size at birth, microlissencephaly is typically diagnosed.

It is also important to differentiate between lissencephaly and polymicrogyria, which is a different developmental malformation of the brain.

Prognosis

The prognosis varies depending on the severity of the syndrome. Many children may remain in an early developmental level. Life expectancy is short, and many will die before the age of 10 years. The most common cause of death among lissencephaly patients is aspiration and respiratory disease.

Lissencephaly may affect some areas of the brain more severely than others. The gradient of severity is dependent on the lissencephaly type and gene mutations.[31]

Complications

Every case is different, but the most common complications in patients with lissencephaly are breathing problems, feeding difficulty, and seizures.[32]

Deterrence and Patient Education

It is very important to teach the patient's family how to care for patients with feeding problems, learning disabilities, and seizures. It is also important to do genetic counseling when there is a risk for lissencephaly.

Enhancing Healthcare Team Outcomes

An interprofessional approach to lissencephaly is recommended. Lissencephaly is a spectrum of disorders characterized by severe mental insult. Patients with lissencephaly are at an increased risk of having learning disabilities, developmental delays, seizures, and muscle spasms. An interprofessional team consisting of a geneticist, primary clinicians, physiatrist, and neurologist is recommended to decrease the morbidity and mortality of this disease. The primary clinicians should refer these patients to the appropriate specialist as soon as the diagnosis is made.[24]


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References


[1]

Di Donato N, Chiari S, Mirzaa GM, Aldinger K, Parrini E, Olds C, Barkovich AJ, Guerrini R, Dobyns WB. Lissencephaly: Expanded imaging and clinical classification. American journal of medical genetics. Part A. 2017 Jun:173(6):1473-1488. doi: 10.1002/ajmg.a.38245. Epub 2017 Apr 25     [PubMed PMID: 28440899]


[2]

Fry AE, Cushion TD, Pilz DT. The genetics of lissencephaly. American journal of medical genetics. Part C, Seminars in medical genetics. 2014 Jun:166C(2):198-210. doi: 10.1002/ajmg.c.31402. Epub 2014 May 23     [PubMed PMID: 24862549]


[3]

Blazejewski SM, Bennison SA, Smith TH, Toyo-Oka K. Neurodevelopmental Genetic Diseases Associated With Microdeletions and Microduplications of Chromosome 17p13.3. Frontiers in genetics. 2018:9():80. doi: 10.3389/fgene.2018.00080. Epub 2018 Mar 23     [PubMed PMID: 29628935]


[4]

Tan AP, Chong WK, Mankad K. Comprehensive genotype-phenotype correlation in lissencephaly. Quantitative imaging in medicine and surgery. 2018 Aug:8(7):673-693. doi: 10.21037/qims.2018.08.08. Epub     [PubMed PMID: 30211035]


[5]

Bershteyn M, Nowakowski TJ, Pollen AA, Di Lullo E, Nene A, Wynshaw-Boris A, Kriegstein AR. Human iPSC-Derived Cerebral Organoids Model Cellular Features of Lissencephaly and Reveal Prolonged Mitosis of Outer Radial Glia. Cell stem cell. 2017 Apr 6:20(4):435-449.e4. doi: 10.1016/j.stem.2016.12.007. Epub 2017 Jan 19     [PubMed PMID: 28111201]


[6]

Leruez-Ville M, Ville Y. Fetal cytomegalovirus infection. Best practice & research. Clinical obstetrics & gynaecology. 2017 Jan:38():97-107. doi: 10.1016/j.bpobgyn.2016.10.005. Epub 2016 Oct 20     [PubMed PMID: 27923540]


[7]

Pavone L, Gullotta F, Incorpora G, Grasso S, Dobyns WB. Isolated lissencephaly: report of four patients from two unrelated families. Journal of child neurology. 1990 Jan:5(1):52-9     [PubMed PMID: 2299140]


[8]

Iefremova V, Manikakis G, Krefft O, Jabali A, Weynans K, Wilkens R, Marsoner F, Brändl B, Müller FJ, Koch P, Ladewig J. An Organoid-Based Model of Cortical Development Identifies Non-Cell-Autonomous Defects in Wnt Signaling Contributing to Miller-Dieker Syndrome. Cell reports. 2017 Apr 4:19(1):50-59. doi: 10.1016/j.celrep.2017.03.047. Epub     [PubMed PMID: 28380362]


[9]

Egan MJ, Tan K, Reck-Peterson SL. Lis1 is an initiation factor for dynein-driven organelle transport. The Journal of cell biology. 2012 Jun 25:197(7):971-82. doi: 10.1083/jcb.201112101. Epub 2012 Jun 18     [PubMed PMID: 22711696]


[10]

Friocourt G, Kappeler C, Saillour Y, Fauchereau F, Rodriguez MS, Bahi N, Vinet MC, Chafey P, Poirier K, Taya S, Wood SA, Dargemont C, Francis F, Chelly J. Doublecortin interacts with the ubiquitin protease DFFRX, which associates with microtubules in neuronal processes. Molecular and cellular neurosciences. 2005 Jan:28(1):153-64     [PubMed PMID: 15607950]


[11]

Moslehi M, Ng DCH, Bogoyevitch MA. Dynamic microtubule association of Doublecortin X (DCX) is regulated by its C-terminus. Scientific reports. 2017 Jul 12:7(1):5245. doi: 10.1038/s41598-017-05340-x. Epub 2017 Jul 12     [PubMed PMID: 28701724]


[12]

Venø MT, Venø ST, Rehberg K, van Asperen JV, Clausen BH, Holm IE, Pasterkamp RJ, Finsen B, Kjems J. Cortical Morphogenesis during Embryonic Development Is Regulated by miR-34c and miR-204. Frontiers in molecular neuroscience. 2017:10():31. doi: 10.3389/fnmol.2017.00031. Epub 2017 Feb 9     [PubMed PMID: 28232790]


[13]

D'Agostino MD, Bernasconi A, Das S, Bastos A, Valerio RM, Palmini A, Costa da Costa J, Scheffer IE, Berkovic S, Guerrini R, Dravet C, Ono J, Gigli G, Federico A, Booth F, Bernardi B, Volpi L, Tassinari CA, Guggenheim MA, Ledbetter DH, Gleeson JG, Lopes-Cendes I, Vossler DG, Malaspina E, Franzoni E, Sartori RJ, Mitchell MH, Mercho S, Dubeau F, Andermann F, Dobyns WB, Andermann E. Subcortical band heterotopia (SBH) in males: clinical, imaging and genetic findings in comparison with females. Brain : a journal of neurology. 2002 Nov:125(Pt 11):2507-22     [PubMed PMID: 12390976]


[14]

Gécz J, Cloosterman D, Partington M. ARX: a gene for all seasons. Current opinion in genetics & development. 2006 Jun:16(3):308-16     [PubMed PMID: 16650978]

Level 3 (low-level) evidence

[15]

Colombo E, Galli R, Cossu G, Gécz J, Broccoli V. Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons. Developmental dynamics : an official publication of the American Association of Anatomists. 2004 Nov:231(3):631-9     [PubMed PMID: 15376319]


[16]

Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A, Kusaka M, Omichi K, Suzuki R, Kato-Fukui Y, Kamiirisa K, Matsuo M, Kamijo S, Kasahara M, Yoshioka H, Ogata T, Fukuda T, Kondo I, Kato M, Dobyns WB, Yokoyama M, Morohashi K. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nature genetics. 2002 Nov:32(3):359-69     [PubMed PMID: 12379852]


[17]

Hong SE, Shugart YY, Huang DT, Shahwan SA, Grant PE, Hourihane JO, Martin ND, Walsh CA. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature genetics. 2000 Sep:26(1):93-6     [PubMed PMID: 10973257]


[18]

Parrini E, Conti V, Dobyns WB, Guerrini R. Genetic Basis of Brain Malformations. Molecular syndromology. 2016 Sep:7(4):220-233     [PubMed PMID: 27781032]


[19]

Joseph LD, Pushpalatha, Kuruvilla S. Cytomegalovirus infection with lissencephaly. Indian journal of pathology & microbiology. 2008 Jul-Sep:51(3):402-4     [PubMed PMID: 18723971]


[20]

Leventer R. Lissencephaly type I. Handbook of clinical neurology. 2008:87():205-18. doi: 10.1016/S0072-9752(07)87013-8. Epub     [PubMed PMID: 18809027]


[21]

de Rijk-van Andel JF, Arts WF, Hofman A, Staal A, Niermeijer MF. Epidemiology of lissencephaly type I. Neuroepidemiology. 1991:10(4):200-4     [PubMed PMID: 1745330]


[22]

Di Donato N, Timms AE, Aldinger KA, Mirzaa GM, Bennett JT, Collins S, Olds C, Mei D, Chiari S, Carvill G, Myers CT, Rivière JB, Zaki MS, University of Washington Center for Mendelian Genomics, Gleeson JG, Rump A, Conti V, Parrini E, Ross ME, Ledbetter DH, Guerrini R, Dobyns WB. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genetics in medicine : official journal of the American College of Medical Genetics. 2018 Nov:20(11):1354-1364. doi: 10.1038/gim.2018.8. Epub 2018 Apr 19     [PubMed PMID: 29671837]


[23]

Mazurkiewicz-Bełdzińska M, Szmuda M, Matheisel A. Correlation of neuroradiological, electroencephalographic and clinical findings in cortical dysplasias in children. Folia neuropathologica. 2006:44(4):314-8     [PubMed PMID: 17183458]


[24]

Chang J, Zhao L, Chen C, Peng Y, Xia Y, Tang G, Bai T, Zhang Y, Ma R, Guo R, Mei L, Liang D, Cao Q, Wu L. Pachygyria, seizures, hypotonia, and growth retardation in a patient with an atypical 1.33Mb inherited microduplication at 22q11.23. Gene. 2015 Sep 10:569(1):46-50. doi: 10.1016/j.gene.2015.04.090. Epub 2015 Jun 20     [PubMed PMID: 26099517]


[25]

Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, Hehr U, Uyanik G, Aigner L, Couillard-Despres S, Winkler J. DCX-Related Disorders. GeneReviews(®). 1993:():     [PubMed PMID: 20301364]


[26]

Tonni G, Pattacini P, Bonasoni MP, Araujo Júnior E. Prenatal Diagnosis of Lissencephaly Type 2 using Three-dimensional Ultrasound and Fetal MRI: Case Report and Review of the Literature. Revista brasileira de ginecologia e obstetricia : revista da Federacao Brasileira das Sociedades de Ginecologia e Obstetricia. 2016 Apr:38(4):201-6. doi: 10.1055/s-0036-1582126. Epub 2016 Apr 18     [PubMed PMID: 27088705]

Level 3 (low-level) evidence

[27]

Dobyns WB. The neurogenetics of lissencephaly. Neurologic clinics. 1989 Feb:7(1):89-105     [PubMed PMID: 2646523]


[28]

Menascu S, Weinstock A, Farooq O, Hoffman H, Cortez MA. EEG and neuroimaging correlations in children with lissencephaly. Seizure. 2013 Apr:22(3):189-93. doi: 10.1016/j.seizure.2012.12.001. Epub 2013 Jan 6     [PubMed PMID: 23298604]


[29]

Devisme L, Bouchet C, Gonzalès M, Alanio E, Bazin A, Bessières B, Bigi N, Blanchet P, Bonneau D, Bonnières M, Bucourt M, Carles D, Clarisse B, Delahaye S, Fallet-Bianco C, Figarella-Branger D, Gaillard D, Gasser B, Delezoide AL, Guimiot F, Joubert M, Laurent N, Laquerrière A, Liprandi A, Loget P, Marcorelles P, Martinovic J, Menez F, Patrier S, Pelluard F, Perez MJ, Rouleau C, Triau S, Attié-Bitach T, Vuillaumier-Barrot S, Seta N, Encha-Razavi F. Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. Brain : a journal of neurology. 2012 Feb:135(Pt 2):469-82. doi: 10.1093/brain/awr357. Epub 2012 Feb 9     [PubMed PMID: 22323514]


[30]

Viot G, Sonigo P, Simon I, Simon-Bouy B, Chadeyron F, Beldjord C, Tantau J, Martinovic J, Esculpavit C, Brunelle F, Munnich A, Vekemans M, Encha-Razavi F. Neocortical neuronal arrangement in LIS1 and DCX lissencephaly may be different. American journal of medical genetics. Part A. 2004 Apr 15:126A(2):123-8     [PubMed PMID: 15057976]


[31]

Dobyns WB, Truwit CL, Ross ME, Matsumoto N, Pilz DT, Ledbetter DH, Gleeson JG, Walsh CA, Barkovich AJ. Differences in the gyral pattern distinguish chromosome 17-linked and X-linked lissencephaly. Neurology. 1999 Jul 22:53(2):270-7     [PubMed PMID: 10430413]


[32]

Okumura A, Hayashi M, Tsurui H, Yamakawa Y, Abe S, Kudo T, Suzuki R, Shimizu T, Shimojima K, Yamamoto T. Lissencephaly with marked ventricular dilation, agenesis of corpus callosum, and cerebellar hypoplasia caused by TUBA1A mutation. Brain & development. 2013 Mar:35(3):274-9. doi: 10.1016/j.braindev.2012.05.006. Epub 2012 May 26     [PubMed PMID: 22633752]