0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Neurological Review |

Genetic Basis of Developmental Malformations of the Cerebral Cortex FREE

Ganeshwaran H. Mochida, MD, MMSc; Christopher A. Walsh, MD, PhD
[+] Author Affiliations

From the Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center and the Department of Neurology, Harvard Medical School (Drs Mochida and Walsh), and the Pediatric Neurology Unit, Department of Neurology, Massachusetts General Hospital (Dr Mochida), Boston, Mass.


Section Editor: David E. Pleasure,, MD

More Author Information
Arch Neurol. 2004;61(5):637-640. doi:10.1001/archneur.61.5.637.
Text Size: A A A
Published online

Widespread use of noninvasive brain imaging techniques, in particular magnetic resonance imaging, has led to increased recognition of genetic disorders of cortical development in recent years. The causative genes for many of these disorders have been identified through a combination of detailed clinical and radiological analyses and molecular genetic approaches. These disease genes have been found to affect different steps of cortical development, including proliferation of neuronal progenitor cells, neuronal migration, and maintaining integrity of the pial surface. In many cases, syndromes with similar clinical phenotypes are caused by genes with related biochemical functions. In this article, we review the recent advances in molecular genetic studies of the disorders of cortical development. The identification and functional studies of the genes associated with these developmental disorders will likely lead to improvement in diagnosis and facilitate our understanding of the mechanisms of cortical development.

The large cerebral cortex that executes complex cognitive functions is a striking feature that distinguishes the human brain from that of other mammals. However, even now, relatively little is known about the genetic mechanisms that control the development of the human cerebral cortex. In recent years, molecular genetic studies of malformations of the human cerebral cortex have shed light on the genetic control of cerebral cortical development. Table 1 lists genes that are associated with malformations of the human cerebral cortex. These disorders are also clinically important because they are individually rare but collectively account for a number of cases of epilepsy, mental retardation, and other cognitive disorders.

Table Graphic Jump Location Genes Associated With Malformations of the Human Cerebral Cortex* 116

The neurons of the cerebral cortex are produced in the ventricular zone, which is a specialized proliferative region surrounding the ventricles. Then the postmitotic neurons leave the ventricular zone to migrate a considerable distance toward the surface to form the cerebral cortex. This migration takes place on a scaffold of specialized glial cells, called radial glia, though a mode of neuronal migration not dependent on radial glia is also known.17 Once the neurons reach the cerebral cortex, newly arrived neurons have to pass the older neurons to form a normal 6-layered cortex. Therefore, the upper layers of the cerebral cortex are made up of later-born neurons, creating an "inside-out" pattern of cortical layering. Migration of neurons into the cerebral cortex appears to peak between the 11th and 15th week of gestation in humans.18 It is not entirely clear when neuronal migration is finally completed, but the majority of the neurons appear to reach the cortex by the 24th week of gestation.19 Genetic defects affecting these different steps of development lead to distinct disorders, which are discussed herein.

Genetic Microcephaly Syndromes

Microcephaly, literally meaning "small head," refers to a condition in which the brain fails to achieve normal growth. Clinically, microcephaly is present when the occipitofrontal circumference is less than −2 SDs below the mean for the person's age and sex, though sometimes a stricter cutoff of −3 SD is used. The causes of microcephaly are diverse.20 Here we limit our discussion to microcephaly syndromes with abnormalities limited to the central nervous system.

Microcephaly vera (primary autosomal recessive microcephaly) is characterized by microcephaly at birth, relatively normal early motor milestones, and mental retardation of variable severity. Epilepsy is uncommon. So far, 6 genetic loci that lead to clinically indistinguishable phenotypes have been identified, and these loci were named MCPH1 through MCPH6.21,22 Other pedigrees that do not map to these loci suggest that 1 or more additional loci are yet to be identified.21

The causative gene has recently been identified in 2 of the recessive microcephaly syndromes. The gene for MCPH1, microcephalin, encodes a novel protein of unknown function.1 It contains 3 BRCT (BRCA1 C-terminal) domains. Many proteins containing this domain function in DNA repair, and perhaps microcephalin has a related function. The MCPH5 gene, ASPM, is the homologue of a Drosophila gene, asp (abnormal spindle).2Drosophila Asp localizes to the centrosome during cell division and seems to be important in maintaining the integrity of the centrosomal microtubule organizing center.23ASPM functions in mammals have not been studied, but the mouse Aspm gene is highly expressed in the areas of the brain with active neurogenesis, suggesting its role in the proliferation of neuronal progenitor cells.2ASPM and its homologues contain small (about 20 amino acids) motifs called IQ domains (because they contain conserved isoleucine and glutamine residues), and the number of IQ domains is consistently larger in organisms with larger brain size. This suggests an interesting possibility that this increase in the IQ domains in the ASPM homologues has played a role in the evolutionary expansion of the brain, though other mechanisms might explain this correlation.

Classical Lissencephaly

The word lissencephaly derives from the Greek words lissos, meaning "smooth," and enkephalos, meaning "brain." In classical lissencephaly, normal gyration of the cerebral cortex is absent or severely reduced and the surface of the brain appears smooth. Pathologically, the cortex is greatly thickened and shows 4 layers instead of the normal 6 layers. Patients with classical lissencephaly usually have severe developmental delay, epilepsy, and are often microcephalic.

Classical lissencephaly is seen in association with abnormalities of 2 genes: LIS1 on chromosome 17p8 and DCX (doublecortin) on chromosome Xq.9,10 Deletions of the genomic region including LIS1 cause Miller-Dieker syndrome, a syndrome with lissencephaly and unique facial features, whereas small deletions or point mutations in LIS1 cause the "isolated lissencephaly sequence," in which facial features of Miller-Dieker syndrome are absent.24DCX causes lissencephaly in males, which is almost indistinguishable from LIS1 mutations, whereas females with heterozygous DCX mutations have "double cortex" syndrome. In double cortex syndrome, the gyral formation of the brain is essentially normal, but there is a band of heterotopic neurons (also called "subcortical band heterotopia") halfway between the cortical surface and the lateral ventricles. These female patients usually have epilepsy and mild to moderate mental retardation.

Both LIS1 and DCX proteins appear to be regulators of microtubules. Microtubules are dynamic components of the intracellular cytoskeleton and are important in regulating cell shape and motility. DCX is expressed in the postmitotic neurons and has been shown to interact directly with and increase the stability of microtubules.2527 On the other hand, regulation of microtubules by LIS1 appears more complicated. Interestingly, insights into the function of LIS1 came from its homologue in the filamentous fungus, Aspergillus nidulans. In Aspergillus, the LIS1 homologue, nudF, is involved in translocation of the nucleus through pathways involving other nuclear migration proteins, such as nudE. Translocation of the nucleus is necessary for a neuron to migrate, and a remarkably similar biochemical pathway appears to be present in migrating neurons. In mammals, mNudE, a homologue of nudE, interacts with LIS1, and defects in central nervous system lamination were observed when this interaction was disrupted in Xenopus embryos.28 The function of mNudE appears to involve regulation of the microtubule organizing center, and it may act as a link between LIS1 and α-tubulin, which plays a key role in initiating microtubule polymerization at the microtubule organizing center.

Lissencephaly With Cerebellar Hypoplasia

This condition is characterized by an abnormally thick and simplified gyral pattern of the cerebral cortex as well as hypoplasia of the cerebellum. It shows autosomal recessive inheritance, and clinical features include hypotonia, severe developmental delay, seizures, and nystagmus. Mutations in the RELN (reelin) gene have been found in some of these patients.11RELN is the human homologue of a mouse gene, Reln (reelin), which was identified as the causative gene for the "reeler" mutant mouse.29 Reeler mutants show severe hypoplasia of the cerebellum (leading to a "reeling" gait) and disorganized layering of the cerebral cortex. Reelin protein is secreted by Cajal-Retzius cells, which are early-born neurons of the cerebral cortex. There is evidence that reelin functions in arresting migrating neurons at the proper position,30 but its exact function is still not completely understood.

X-linked Lissencephaly With Abnormal Genitalia

Most recently, yet another lissencephaly syndrome has come into focus. X-linked lissencephaly with abnormal genitalia is associated with agenesis of the corpus callosum and ambiguous or underdeveloped genitalia. Recently, mutations in the Aristaless-related homeobox transcription factor gene, ARX, have been found in these patients.12 Studies in mice suggest that this gene is important for neuronal proliferation, as well as migration and differentiation of interneurons, in the embryonic forebrain.12 The identification of ARX mutations greatly broadens the potential range of mechanisms that ultimately lead to loss of cerebral gyrification.

Periventricular Nodular Heterotopia

In this condition, clusters of neurons fail to migrate out of the ventricular region and form neuronal nodules along the walls of the lateral ventricles. Therefore, it most likely represents a deficit in the initiation of migration. It is also a genetically heterogeneous condition, but many cases are associated with mutations in the FLNA (filamin A) gene on the X chromosome.13 Females affected with heterozygous FLNA mutations typically have epilepsy, but usually there are no cognitive abnormalities. It is speculated that some neurons are not affected by the mutations because of the process of X chromosome inactivation in females. On the other hand, males with hemizygous FLNA mutations are thought to usually die in utero, though there are rare cases of surviving males.31FLNA is a large cytoplasmic actin-binding protein, which probably acts as a link between extracellular signals and actin cytoskeleton.32 The actin cytoskeleton, like microtubules, is important in regulating cell shape and motility. Recently, cases of periventricular nodular heterotopia that are not due to FLNA mutations have also been reported.33,34

Cobblestone Dysplasia

Cobblestone dysplasia (also known as type II lissencephaly) is a type of cortical malformation characterized by disorganization of the cortical layers, overmigration of neurons through the pial surface onto the outside of the brain, and proliferation of gliovascular tissue on the surface of the brain. The term cobblestone is applied because of the nodular appearance caused by its surface abnormalities.

Cobblestone dysplasia is seen in association with at least 3 human genetic disorders, which show some clinical overlap: Fukuyama type congenital muscular dystrophy, muscle-eye-brain disease, and Walker-Warburg syndrome. All 3 disorders are transmitted as autosomal recessive traits and associated with cobblestone dysplasia, muscular dystrophy, and various ophthalmologic abnormalities. Cerebellar polymicrogyria, with or without cyst, is also seen in all 3 conditions, suggesting widespread abnormalities in the central nervous system.

In recent years, causative genes for these conditions have been reported: the FCMD (fukutin) gene in Fukuyama type congenital muscular dystrophy14; the protein O-mannose β-1, 2-N-acetylglucosaminyltransferase (POMGNT1) gene in muscle-eye-brain disease15; and the protein O-mannosyltransferase (POMT1) gene in some cases of Walker-Warburg syndrome.16 POMGNT1 and POMT1 proteins are glycosyltransferases, and although the biochemical properties of the FCMD protein are not well understood, sequence analysis suggests that it may also be an enzyme that modifies cell-surface glycoproteins or glycolipids.35 Recent evidence suggests that functional disruption of dystroglycan is central to pathogenesis of these disorders.36 In patients with Fukuyama type congenital muscular dystrophy and muscle-eye-brain disease, hypoglycosylation of dystroglycan has been demonstrated, and this disrupts the ability for dystroglycan to bind its ligands such as laminin.37 It is speculated that this loss of binding leads to the disruption of the integrity of the pial surface, and neurons migrate through these breaches.

Recent advances in molecular genetic studies of malformations of the human cerebral cortex have led to identification of many genes that are important regulators of cortical development. It has become clear that syndromes with similar clinical phenotypes are often caused by genes with related biochemical functions (eg, DCX and LIS1, glycosyltransferases). However, as we have seen, many of the biological pathways involving these genes are still not completely understood. Cloning of new disease genes and studies of the functions of the known disease genes will likely lead to further elucidation of important biological pathways in the development of the human cerebral cortex.

Corresponding author and reprints: Christopher A. Walsh, MD, PhD, Howard Hughes Medical Institute, Beth Israel Deaconess Medical Center, and Department of Neurology, Harvard Medical School, 4 Blackfan Cir, HIM 816, Boston, MA 02115 (e-mail: cwalsh@bidmc.harvard.edu).

Accepted for publication December 30, 2003.

Author contributions: Study concept and design (Drs Mochida and Walsh); acquisition of data (Dr Mochida); analysis and interpretation of data (Drs Mochida and Walsh); drafting of the manuscript (Dr Mochida); critical revision of the manuscript for important intellectual content (Drs Mochida and Walsh); obtained funding (Drs Mochida and Walsh); administrative, technical, and material support (Dr Walsh); study supervision (Dr Walsh).

This study was supported by the William Randolph Hearst Fund, Boston, Mass (Dr Mochida), grants 2R37NS35129 and P01NS39404 from the National Institute of Neurological Disease and Stroke, Bethesda, Md (Dr Walsh), and the March of Dimes, White Plains, NY (Dr Walsh).

Dr Mochida is a Medical Foundation research fellow of the Charles H. Hood Foundation, Boston. Dr Walsh is a Howard Hughes Medical Institute investigator.

Jackson  APEastwood  HBell  SM  et al Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet.2002;71:136-142.
PubMed
Bond  JRoberts  EMochida  GH  et al ASPM is a major determinant of cerebral cortical size. Nat Genet.2002;32:316-320.
PubMed
Varon  RVissinga  CPlatzer  M  et al Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell.1998;93:467-476.
PubMed
Matsuura  STauchi  HNakamura  A  et al Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet.1998;19:179-181.
PubMed
Brunelli  SFaiella  ACapra  V  et al Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet.1996;12:94-96.
PubMed
van Slegtenhorst  Mde Hoogt  RHermans  C  et al Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science.1997;277:805-808.
PubMed
The European Chromosome 16 Tuberous Sclerosis Consortium Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell.1993;75:1305-1315.
PubMed
Hattori  MAdachi  HTsujimoto  MArai  HInoue  K Miller-Dieker lissencephaly gene encodes a subunit of brain platelet activating factor acetylhydrolase [corrected]. Nature.1994;370:216-218.
PubMed
des Portes  VPinard  JMBilluart  P  et al A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell.1998;92:51-61.
PubMed
Gleeson  JGAllen  KMFox  JW  et al Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell.1998;92:63-72.
PubMed
Hong  SEShugart  YYHuang  DT  et al Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet.2000;26:93-96.
PubMed
Kitamura  KYanazawa  MSugiyama  N  et al Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet.2002;32:359-369.
PubMed
Fox  JWLamperti  EDEksioglu  YZ  et al Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron.1998;21:1315-1325.
PubMed
Kobayashi  KNakahori  YMiyake  M  et al An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature.1998;394:388-392.
PubMed
Yoshida  AKobayashi  KManya  H  et al Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell.2001;1:717-724.
PubMed
Beltran-Valero de Bernabe  DCurrier  SSteinbrecher  A  et al Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet.2002;71:1033-1043.
PubMed
Walsh  CCepko  CL Widespread dispersion of neuronal clones across functional regions of the cerebral cortex. Science.1992;255:434-440.
PubMed
Sidman  RLRakic  P Neuronal migration, with special reference to developing human brain: a review. Brain Res.1973;62:1-35.
PubMed
Marin-Padilla  M Origin, formation, and prenatal maturation of the human cerebral cortex: an overview. J Craniofac Genet Dev Biol.1990;10:137-146.
PubMed
Mochida  GHWalsh  CA Molecular genetics of human microcephaly. Curr Opin Neurol.2001;14:151-156.
PubMed
Roberts  EHampshire  DJPattison  L  et al Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J Med Genet.2002;39:718-721.
PubMed
Leal  GFRoberts  ESilva  EOCosta  SMHampshire  DJWoods  CG A novel locus for autosomal recessive primary microcephaly (MCPH6) maps to 13q12.2. J Med Genet.2003;40:540-542.
PubMed
do Carmo Avides  MGlover  DM Abnormal spindle protein, Asp, and the integrity of mitotic centrosomal microtubule organizing centers. Science.1999;283:1733-1735.
PubMed
Lo Nigro  CChong  CSSmith  ACDobyns  WBCarrozzo  RLedbetter  DH Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Hum Mol Genet.1997;6:157-164.
PubMed
Francis  FKoulakoff  ABoucher  D  et al Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron.1999;23:247-256.
PubMed
Gleeson  JGLin  PTFlanagan  LAWalsh  CA Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron.1999;23:257-271.
PubMed
Horesh  DSapir  TFrancis  F  et al Doublecortin, a stabilizer of microtubules. Hum Mol Genet.1999;8:1599-1610.
PubMed
Feng  YOlson  ECStukenberg  PTFlanagan  LAKirschner  MWWalsh  CA LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron.2000;28:665-679.
PubMed
D'Arcangelo  GMiao  GGChen  SCSoares  HDMorgan  JICurran  T A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature.1995;374:719-723.
PubMed
Dulabon  LOlson  ECTaglienti  MG  et al Reelin binds α3β1 integrin and inhibits neuronal migration. Neuron.2000;27:33-44.
PubMed
Sheen  VLDixon  PHFox  JW  et al Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet.2001;10:1775-1783.
PubMed
Tu  YWu  SShi  XChen  KWu  C Migfilin and mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation. Cell.2003;113:37-47.
PubMed
Sheen  VLTopcu  MBerkovic  S  et al Autosomal recessive form of periventricular heterotopia. Neurology.2003;60:1108-1112.
PubMed
Sheen  VLWheless  JWBodell  A  et al Periventricular heterotopia associated with chromosome 5p anomalies. Neurology.2003;60:1033-1036.
PubMed
Aravind  LKoonin  EV The fukutin protein family—predicted enzymes modifying cell-surface molecules. Curr Biol.1999;9:R836-R837.
PubMed
Moore  SASaito  FChen  J  et al Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature.2002;418:422-425.
PubMed
Michele  DEBarresi  RKanagawa  M  et al Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature.2002;418:417-422.
PubMed

Figures

Tables

Table Graphic Jump Location Genes Associated With Malformations of the Human Cerebral Cortex* 116

References

Jackson  APEastwood  HBell  SM  et al Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet.2002;71:136-142.
PubMed
Bond  JRoberts  EMochida  GH  et al ASPM is a major determinant of cerebral cortical size. Nat Genet.2002;32:316-320.
PubMed
Varon  RVissinga  CPlatzer  M  et al Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell.1998;93:467-476.
PubMed
Matsuura  STauchi  HNakamura  A  et al Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet.1998;19:179-181.
PubMed
Brunelli  SFaiella  ACapra  V  et al Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. Nat Genet.1996;12:94-96.
PubMed
van Slegtenhorst  Mde Hoogt  RHermans  C  et al Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science.1997;277:805-808.
PubMed
The European Chromosome 16 Tuberous Sclerosis Consortium Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell.1993;75:1305-1315.
PubMed
Hattori  MAdachi  HTsujimoto  MArai  HInoue  K Miller-Dieker lissencephaly gene encodes a subunit of brain platelet activating factor acetylhydrolase [corrected]. Nature.1994;370:216-218.
PubMed
des Portes  VPinard  JMBilluart  P  et al A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell.1998;92:51-61.
PubMed
Gleeson  JGAllen  KMFox  JW  et al Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell.1998;92:63-72.
PubMed
Hong  SEShugart  YYHuang  DT  et al Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet.2000;26:93-96.
PubMed
Kitamura  KYanazawa  MSugiyama  N  et al Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat Genet.2002;32:359-369.
PubMed
Fox  JWLamperti  EDEksioglu  YZ  et al Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron.1998;21:1315-1325.
PubMed
Kobayashi  KNakahori  YMiyake  M  et al An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature.1998;394:388-392.
PubMed
Yoshida  AKobayashi  KManya  H  et al Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell.2001;1:717-724.
PubMed
Beltran-Valero de Bernabe  DCurrier  SSteinbrecher  A  et al Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet.2002;71:1033-1043.
PubMed
Walsh  CCepko  CL Widespread dispersion of neuronal clones across functional regions of the cerebral cortex. Science.1992;255:434-440.
PubMed
Sidman  RLRakic  P Neuronal migration, with special reference to developing human brain: a review. Brain Res.1973;62:1-35.
PubMed
Marin-Padilla  M Origin, formation, and prenatal maturation of the human cerebral cortex: an overview. J Craniofac Genet Dev Biol.1990;10:137-146.
PubMed
Mochida  GHWalsh  CA Molecular genetics of human microcephaly. Curr Opin Neurol.2001;14:151-156.
PubMed
Roberts  EHampshire  DJPattison  L  et al Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J Med Genet.2002;39:718-721.
PubMed
Leal  GFRoberts  ESilva  EOCosta  SMHampshire  DJWoods  CG A novel locus for autosomal recessive primary microcephaly (MCPH6) maps to 13q12.2. J Med Genet.2003;40:540-542.
PubMed
do Carmo Avides  MGlover  DM Abnormal spindle protein, Asp, and the integrity of mitotic centrosomal microtubule organizing centers. Science.1999;283:1733-1735.
PubMed
Lo Nigro  CChong  CSSmith  ACDobyns  WBCarrozzo  RLedbetter  DH Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Hum Mol Genet.1997;6:157-164.
PubMed
Francis  FKoulakoff  ABoucher  D  et al Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron.1999;23:247-256.
PubMed
Gleeson  JGLin  PTFlanagan  LAWalsh  CA Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron.1999;23:257-271.
PubMed
Horesh  DSapir  TFrancis  F  et al Doublecortin, a stabilizer of microtubules. Hum Mol Genet.1999;8:1599-1610.
PubMed
Feng  YOlson  ECStukenberg  PTFlanagan  LAKirschner  MWWalsh  CA LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron.2000;28:665-679.
PubMed
D'Arcangelo  GMiao  GGChen  SCSoares  HDMorgan  JICurran  T A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature.1995;374:719-723.
PubMed
Dulabon  LOlson  ECTaglienti  MG  et al Reelin binds α3β1 integrin and inhibits neuronal migration. Neuron.2000;27:33-44.
PubMed
Sheen  VLDixon  PHFox  JW  et al Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet.2001;10:1775-1783.
PubMed
Tu  YWu  SShi  XChen  KWu  C Migfilin and mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation. Cell.2003;113:37-47.
PubMed
Sheen  VLTopcu  MBerkovic  S  et al Autosomal recessive form of periventricular heterotopia. Neurology.2003;60:1108-1112.
PubMed
Sheen  VLWheless  JWBodell  A  et al Periventricular heterotopia associated with chromosome 5p anomalies. Neurology.2003;60:1033-1036.
PubMed
Aravind  LKoonin  EV The fukutin protein family—predicted enzymes modifying cell-surface molecules. Curr Biol.1999;9:R836-R837.
PubMed
Moore  SASaito  FChen  J  et al Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature.2002;418:422-425.
PubMed
Michele  DEBarresi  RKanagawa  M  et al Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature.2002;418:417-422.
PubMed

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

920 Views
45 Citations

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Jobs
JAMAevidence.com

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
How Serious Is the Risk of Bias?

Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice, 3rd ed
In a Cohort Study, Aside From the Exposure of Interest, Did the Exposed and Control Groups Start and Finish With the Same Risk for the Outcome?

×