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This chapter will summarize abnormal human central nervous system (CNS) formation and will describe the genetic aberrations that cause congenital malformations of the CNS. Without being exhaustive, the proteins believed to be involved in the individual components of CNS development and those involved in pathologic alterations of normal development will be listed.
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NEURAL TUBE CLOSURE AND PATTERNING DEFECTS
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Encephaloceles (brain substance outside of the skull) and meningoceles (meninges and cerebrospinal fluid [CSF] outside of the skull) vary in location, in the amount of brain involved, and therefore, in the clinical manifestations of the lesions. In most cases, the neural tube is closed, and the gyral pattern of the protruding brain appears normal. In the Western Hemisphere, most encephaloceles are occipital and midline. In the Eastern Hemisphere, anterior encephaloceles (nasal and frontal) surpass posterior lesions. One should avoid nasogastric tube placement in the situation of a nasal mass in a newborn due to the possibility of a nasal encephalocele; it is possible in this situation to place the tube in the brain substance.
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Meckel syndrome, a genetic disorder that involves an occipital encephalocele, cerebellar malformations (molar tooth anomaly; see discussion below under Joubert syndrome), microcephaly, renal dysplasia (polycystic kidneys), polydactyly, retinal dystrophy, and other malformations, appears to be caused by pathogenic variants in genes involved in ciliary function. Meckel syndrome is allelic with Joubert syndrome, and the same genetic aberrations are present in both disorders. Most of these disorders are inherited in an autosomal recessive fashion, although can be inherited in an autosomal dominant, or X-linked dominant fashion. The genes involved are part of a ciliary complex that determines cell polarity and are important for the migration of early neurons in the posterior fossa.
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Schizencephaly, a cleft in the brain, may extend from the pia to the ventricle and is lined with polymicrogyric gray matter. The defect is termed open-lipped if the cleft walls are separated by CSF and closed-lipped if the walls appose. These clefts may be unilateral or bilateral, and the prognosis appears to be dependent on location, bilateral occurrence, or extent of the lesion. Bilateral schizencephaly is associated with intellectual disability and spastic cerebral palsy; affected patients often are microcephalic. Seizures almost always accompany severe lesions, especially the open-lipped and bilateral schizencephalic clefts.
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Septo-Optic Dysplasia
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Septo-optic dysplasia (de Morsier syndrome) is a disorder characterized by absence of the septum pellucidum, optic nerve hypoplasia, and hypothalamic dysfunction. This disorder should be considered in any patient who exhibits at least 2 of these, and all such patients should have hypothalamic function screening. Fifty percent of patients with septo-optic dysplasia have schizencephaly. Although this is a rare disorder, genetic syndromes with this phenotype and with some risk of recurrence have been described. For instance, pathogenic variants in HESX1 have caused a dominantly inherited disorder in siblings. This disorder can be suspected in utero, but magnetic resonance imaging (MRI) of the fetus may be necessary to assure a proper diagnosis. The prognosis for development is highly variable, with learning, intellectual, and motor impairments often described. Asymptomatic patients probably only come to medical attention if there are needs for neuroimaging. Pathogenic variants in COL11A2 and PAX6 have also been described. Since most of the genes related to this phenotype are undiscovered and no genetic panels exist, it is recommended that clinicians consider exome sequencing to delineate the recurrence risk in a family.
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VENTRAL INDUCTION AND TELENCEPHALIC DIVISION
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Normal Prosencephalon Division
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The cerebral cortices are formed by medial division of a rostral, single, tube-like structure, the prosencephalon, and the 2 vesicles, or telencephalon, formed in this division become the 2 cerebral hemispheres. The ventral and anterior portions of this division are induced by midline facial structures and the notochord via soluble factors. Abnormalities of this induction and division lead to midline abnormalities of the brain such as holoprosencephaly. These disruptions of normal development occur before 42 days of gestation.
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Sonic hedgehog, which was described first in Drosophila as a soluble factor (protein) that influences dorsoventral patterning of the developing embryo, is probably the most important of the soluble factors influencing ventral induction. It is expressed in the notochord as well as in the ventral forebrain and floor plate—future facial structures—and interacts through a well-defined signaling pathway that includes PTCH, a human homolog of patched. It then alters the expression of transcriptional factors (homeobox and other related gene products).
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Other molecules of interest in this inductive process are the retinoids, which are lipids capable of crossing membranes and have been shown to exist in gradients across embryos. Retinoic acid can alter the pattern of transcriptional factors in neuroepithelial cells, and it can also downregulate sonic hedgehog, perhaps explaining some of the midfacial defects and holoprosencephaly seen in retinoid embryopathy. In addition, cholesterol and cholesterol-derived lipids serve as a cofactor for sonic hedgehog, thus perhaps explaining the occurrence of holoprosencephaly in Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency).
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The holoprosencephaly syndromes are heterogeneous disorders of ventral induction and telencephalic cleavage that result from a failure of the prosencephalic vesicle to medially cleave normally. At least 3 forms of this disorder have been described: alobar, semilobar, and lobar. In the alobar form, the telencephalic vesicle completely fails to divide, producing a single horseshoe-shaped ventricle, sometimes with a dorsal cyst, fused thalami, and a malformed cortex. In the semilobar form, the interhemispheric fissure is present posteriorly, but the frontal and, sometimes, parietal lobes continue across the midline. In the lobar form, only minor changes may be seen: The anterior falx is absent, the frontal lobes and horns are hypoplastic, there is partial fusion of the thalamus, and the genu of the corpus callosum may be abnormal.
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Holoprosencephaly is the most common human malformation leading to miscarriage (Fig. 541-1). Holoprosencephaly is associated with a spectrum of midline facial defects. These include cyclopia, in which there is a single central eye and a supraorbital proboscis; ethmocephaly, in which the nose is replaced by a proboscis located above hypoteloric eyes; cebocephaly, in which hypotelorism and a nose with a single nostril are seen; and premaxillary agenesis, with hypotelorism, a flat nose, a single frontal incisor, and a midline cleft lip.
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Only children who have the semilobar and lobar forms of holoprosencephaly are known to survive for more than a few months. An infant affected with the severe form is microcephalic (unless aqueduct stenosis and hydrocephalus are present), hypotonic, and visually inattentive. In infants with the less severe forms of holoprosencephaly, myoclonic seizures frequently develop and, if the infant survives, autonomic dysfunction, failure to thrive, psychomotor retardation, and atonic or spastic cerebral palsy often are present. Some infants with the lobar form may be only mildly affected. Pituitary defects may be associated with these malformations and may result in neuroendocrine dysfunction.
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Holoprosencephaly has been reported to be associated with maternal diabetes, retinoic acid exposure, cytomegalovirus, and rubella. Chromosomal abnormalities associated with this disorder include trisomies 13 and 18; duplications in 3p, 13q, and 18q; and deletions in 2p, 7q, 13q, and 18q. Autosomal dominant forms exist in which the pathogenic variant is in the sonic hedgehog gene on chromosome 7. In this form, the clinical features vary. In its mildest form, presence of a single central incisor, attention deficit disorder, or a choroid fissure coloboma may be the only clinical manifestation of autosomal dominant risk of holoprosencephaly in a family.
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NEURONAL AND GLIAL PROLIFERATION
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Megalencephaly and Hemimegalencephaly
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The terms megalencephaly and hemimegalencephaly refer to disorders in which the brain volume is greater than normal (not due to the abnormal storage of material); usually, the enlarged brain is accompanied by macrocephaly, or a large head. Although considered by some to be a migration disorder, the increase in brain size in these disorders appears to be attributable to errors in neuroepithelial proliferation, as the microscopic appearance of the brain is that of an increase in number of cells (both neurons and glia) and in cell size.
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Typically, patients are noted to have large heads at birth and may manifest accelerated head growth in the first few months of life. Children with megalencephaly or hemimegalencephaly may come to medical attention when presenting with seizures, a developmental disorder (intellectual disability), hemihypertrophy, or a hemiparesis (opposite the affected hemisphere). Seizures vary both in onset and in type and usually are the most problematic symptom, sometimes necessitating hemispherectomy.
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Approximately 50% of patients with linear sebaceous nevus syndrome have hemimegalencephaly associated with HRAS or KRAS somatic-mosaic pathogenic mutations. Many patients with hypomelanosis of Ito also have hemimegalencephaly. The neuropathologic and clinical pictures in these conditions appear to be identical to the isolated hemimegalencephalies. Interestingly, the genetic aberrations suggest an upregulation of the mammalian target of rapamycin (mTOR) pathway via a disturbance of phosphoinositide 3-kinase (PI3K).
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NEURONAL MIGRATION DISORDERS
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Near the end of the proliferative phase of normal neurodevelopment, billions of postmitotic neurons are poised along the ventricles to begin the migration to the cortical surface and to form the cerebral cortex. Many clinical entities are associated with neuronal migration disorders. In some, abnormalities are limited to the nervous system, but in others, malformations involving other organs also are present. The responsible genetic mechanism has been identified in some of these disorders, and new genetic mechanisms are being identified regularly.
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Modern neuroimaging techniques, particularly MRI, have allowed the recognition of major migration disorders. Some of these disorders are associated with typical clinical features that might alert the clinician to the presence of such abnormalities even before imaging is obtained. In other disorders, the clinical features are so varied that a strong correlation between imaging and clinical presentation does not exist.
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Although the term lissencephaly (smooth brain) refers to the external appearance of the cerebral cortex in those disorders in which a neuronal migration aberration leads to improper number of neurons at the surface of the cortex (Fig. 541-2), the most important observation in such cases is the thickened cortex with neurons in what should be white matter. In such deficits of migration, the gyri and sulci do not form properly because the cortical-cortical attractive forces that result from strong associations are decreased, owing to improper axon pathways (ie, the targets for synapses are malpositioned). It is important to note that the term lissencephaly is applied to cortical disorders in which there is a thickened cortex (migration deficit) and a cortical surface abnormality; rarely there is a completely smooth brain. At least 2 types of lissencephaly have been identified: type I, or classic, lissencephaly and type II, or cobblestone, lissencephaly. This classification is based on both the external appearance of the brain and the underlying histology.
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Type I (Classic) Lissencephaly
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Type I lissencephaly most often accompanies the Miller-Dieker syndrome. Radial migration of neurons appears to have taken place. Hallmarks on imaging are a lack of opercularization (covering of the sylvian fissure), large ventricles with colpocephaly (fetal-like configuration of the occipital horns), and agyria or pachygyria (Fig. 541-2). The corpus callosum is almost never absent, and the posterior fossa usually has a normal appearance on neuroimaging. Head size typically is in the low-normal range at birth, but most patients develop microcephaly owing to a decreased rate of brain growth over the first year of life. Nearly all patients with this disorder develop seizures within this first year, and more than 80% of them have infantile spasms. This seizure frequency is far greater than that seen in other neuronal migration disorders. Patients with this disorder typically develop seizures within this first year, and more than 80% of them have infantile spasms. This seizure frequency is far greater than that seen in other neuronal migration disorders.
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In the Miller-Dieker syndrome, facial dysmorphism, cardiac abnormalities (40%), sacral abnormalities (70%), deep palmar creases, and, in male patients, genital abnormalities (70%) may be seen. The sacral abnormalities include deep sacral dimples, sacral pits, and sacral tracks. Facial abnormalities include upturned nares, a short nose, a thin “pouty” upper lip, a long philtrum, micrognathia, and bitemporal hollowing. Although the bitemporal hollowing may be the result of the underlying brain abnormality, the other facial features are difficult to explain on the basis of the brain abnormality alone. Therefore, these abnormalities are believed to result from deficits of genes near the lissencephaly gene on the 17th chromosome. Larger deletions of the distal short arm of chromosome 17 appear to result in the full Miller-Dieker phenotype, whereas microdeletions of just the lissencephaly gene LIS1 result in isolated lissencephaly. Therefore, a deletion in the lissencephaly gene appears to be sufficient for the brain abnormalities, but other genes (14-3-3) must be deleted for the full phenotypic manifestations of the Miller-Dieker syndrome to be seen.
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Miller-Dieker lissencephaly is one of the migration disorders of the brain in which the responsible genetic defect has been identified. By both molecular and cytogenetic techniques, deletions in the terminal portion of 1 arm of chromosome 17 can be found in approximately 90% of Miller-Dieker lissencephaly cases. These patients typically have dysmorphic features and other congenital anomalies (see earlier discussion). The deletions of the terminal part of chromosome 17 in these cases have included microdeletions, ring 17 chromosome, pericentric inversions, and a partial monosomy of 17p13.3, the result of an inherited unbalanced translocation from a parent with a balanced translocation involving this region of chromosome 17. Multiple mechanisms of inheritance similar to this have been described for this disorder. In families that are affected in this manner, screening with amniocentesis can be performed in subsequent pregnancies because parents are at a greatly increased risk of having another child with Miller-Dieker lissencephaly.
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Current chromosomal microarray testing will detect deletions of LIS1 and of the neighboring 14-3-3 gene, thus genetically distinguishing Miller-Dieker syndrome from isolated lissencephaly. Some patients with isolated lissencephaly (no facial, skeletal, or cardiac abnormalities) also have deletions (often submicroscopical) of the terminal portion of the short arm of chromosome 17.
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The brain malformations in LIS1 deficiencies are usually worse posteriorly as compared with X-linked lissencephaly, which is worse anteriorly, as discussed below. However, in Miller-Dieker syndrome, the malformation may be equally severe anteriorly and posteriorly, thus making a distinction phenotypically difficult. This lesion can be detected in utero, but late and beyond the time for termination of a pregnancy. The life expectancy is dependent on the severity of the neurologic impairment.
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X-linked lissencephaly appears nearly identical to the LIS1 deletion form of this disorder: Patients have classic lissencephaly, and their neurologic presentation is the same. However, the malformation is usually worse anteriorly, and the skeletal and other anomalies seen in the Miller-Dieker syndrome are not noted. In addition, X-linked lissencephaly occurs mostly in boys. Girls who are heterozygous for the same gene variants have band heterotopia. Women with band heterotopia have been noted to give birth to boys with lissencephaly.
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The X-linked lissencephaly–band heterotopia syndrome has been linked to Xq22.3. In females, the less severe phenotype probably is attributable to random X inactivation, such that in a variable percentage of cells, normal gene expression is seen and, in the remaining cells, the mutated gene for X-linked lissencephaly, Doublecortin, is expressed. This is a microtubule-associated protein that appears to stabilize the cytoskeletal structure. It appears that this is a cell-autonomous disorder; in other words, the cell expressing the abnormal X chromosome manifests aberrant migration or disturbed substrate on which cells can migrate.
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The band heterotopia or double-cortex syndrome is a unique form of a neuronal migration defect that almost exclusively occurs in girls and is allelic with X-linked lissencephaly in boys. Patients with band heterotopia typically present with seizures and a developmental disorder. The seizure type is variable, and the onset of epilepsy usually is between 2 months and 11 years of age. Patients may present with infantile spasms, or even though the migration abnormality is diffuse, some patients may present with focal seizures. Control of the epilepsy varies, with some patients being controlled with monotherapy and others being entirely refractory to all agents.
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Most patients with the X-linked band heterotopia syndrome (double-cortex) have impaired intellectual development that ranges from severe retardation to low-normal IQ. Generally, individuals with this syndrome are less impaired than are patients with other diffuse neuronal migration defects such as lissencephaly. Patients in whom seizures are of later onset generally have less developmental impairment. Neurologic findings include mild dysarthria and mild bilateral pyramidal syndromes.
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Type I lissencephaly may also be caused by mutations in tubulin genes.
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Type II (Cobblestone) Lissencephaly
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In type II lissencephaly, the brain may have a smooth appearance or may exhibit polymicrogyria and pachygyria. The underlying cortical histology is that of a bizarre arrangement of neurons. In addition, cells seem to penetrate the surface of the developing brain and may spill into the subarachnoid space as if part of a volcanic eruption. This deposition of neurons in the subarachnoid space imparts a cobblestone street–like appearance to the brain surface; thus, the term cobblestone lissencephaly has been used to describe the cortex in these disorders. The Walker-Warburg, muscle-eye-brain, and Fukuyama muscular dystrophy syndromes are genetically distinct. Abnormalities that may or may not be seen in these disorders include muscular dystrophy, ocular anterior chamber abnormalities, retinal dysplasias (abnormal electroretinogram and visual evoked responses), hydrocephalus (usually of an obstructive type, requiring shunting), and encephaloceles. The Walker-Warburg syndrome or muscle-eye-brain disorder might be diagnosed even if the ocular examination and muscle biopsies are normal. On MRI, an abnormal white matter signal, hypoplastic brain stem and cerebellum, and thickened falx suggest the Walker-Warburg diagnosis. Neuroimaging of the muscle-eye-brain disorders might reveal focal white matter abnormalities. This disorder and other cobblestone lissencephalies have been diagnosed in utero.
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In the cobblestone lissencephaly spectrum, despite having widespread cortical abnormalities, only one-third of patients develop seizures. The typical clinical presentation is that of a child with marked hypotonia, macrocephaly (obstructive hydrocephalus), and eye abnormalities. Depending on the degree of brain and muscle involvement, this disorder may be fatal, and long-term survival is rare. Syndromes accompanying type II lissencephaly include the Walker-Warburg syndrome, HARD-1-E (hydrocephalus, agyria, retinal dysplasia, with or without eye [anterior chamber] abnormalities) syndrome, muscle-eye-brain disease, and Fukuyama muscular dystrophy. These are all the result of recessive inheritance of pathogenic variants in extracellular matrix proteins or in the cell receptors for the extracellular matrix.
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Fukuyama muscular dystrophy is distinguished from the Walker-Warburg–like syndromes by the severity of the muscular dystrophy, by the cortical malformation that includes polymicrogyria, and by Japanese inheritance. This disorder is seen more often in Japan than in the Western Hemisphere, probably because it is the result of a founder pathogenic variant (a viral transposone insertion) in a gene termed FUKUTIN.
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Zellweger syndrome is an autosomal recessive, peroxisomal disorder characterized by neuronal migration abnormalities, hepatomegaly, renal cysts, and stippled calcification of the patella. The neuronal migration defects include pachygyria and polymicrogyria, with underlying abnormalities best characterized as a nonlayered appearance of the cortex. Migration abnormalities are also noted in the cerebellum and in the brain stem in this disorder. Children with Zellweger syndrome present in the neonatal period with severe hypotonia, characteristic facies, hepatomegaly, and seizures. More than 12 PEX genes have been implicated in Zellweger or Zellweger-like disorders; all are inherited in an autosomal recessive pattern. Zellweger syndrome results from the body’s inability to make peroxisomes owing to a deficiency of 1 of the 12 proteins encoded by the PEX genes. A number of peroxisomal enzymes are abnormal and lead to the accumulation of very-long-chain fatty acids. Therefore, testing for this disorder includes an assay of very-long-chain fatty acids.
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Polymicrogyria (many small gyri) is a disorder often considered to be a neuronal migration disorder; it is important to recognize that this malformation may result in both genetic and destructive processes. The microscopic appearance of the lesion is that of too many small abnormal gyri. The gyri may be shallow and separated by shallow sulci, which may be associated with an apparent increased cortical thickness on neuroimaging. The multiple small convolutions may not have intervening sulci, or the sulci may be bridged by fusion of overlying molecular layer, which may give a smooth appearance to the brain’s surface; alternatively, the brain may appear to have pachygyria.
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Based on examination of fetuses in which the occurrence of the insult causing the malformation has been accurately timed, this pattern is believed to occur as a result of insults late in the first or early in the second trimester. Others believe that this is a postmigration insult resulting from distorted migration of cells through an injured area. Identical twin pregnancies discordant for polymicrogyria have been described, with the theory being that global insults can lead to polymicrogyria (such as twin-twin transfusion and steal syndromes). The common association of congenital cytomegalovirus infection with polymicrogyria supports the hypothesis that a destructive process can be involved in these disorders. Zika virus appears to similarly affect the brain.
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Polymicrogyria has also been associated with genetic and chromosomal disorders. It is found in disorders of peroxisomal metabolism such as Zellweger syndrome (see discussion above) and neonatal adrenal leukodystrophy. It has also been associated with the Bloch-Sulzberger syndrome, Meckel-Gruber syndrome, thanatophoric dysplasia, and Fukuyama congenital muscular dystrophy. Familial bilateral frontal polymicrogyria and bilateral perisylvian polymicrogyria have been reported. Therefore, if no identifiable cause of the polymicrogyric malformation is found, the recurrence risk may be that of an autosomal recessive disorder (25%) or an X-linked disorder in boys. A bilateral parasagittal parieto-occipital polymicrogyria has also been described. Multiple chromosomal deletions and duplications, including X-linked potential inheritance, have been described. Multiple recessively inherited disorders have also been identified, including GPR56 and WDR62 pathogenic variants in families with recurrences of polymicrogyria with variable phenotypes.
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The clinical picture varies depending on the location, extent, and etiology of the abnormality. Microcephaly with severe developmental delay and hypertonia may result when polymicrogyria is diffuse. When polymicrogyria is unilateral, focal deficits might be seen. Epilepsy often is present, characterized by partial-complex seizures or partial seizures that secondarily generalize. The age at presentation and severity of seizures depend on the extent of the associated pathology. The lesions are most clearly recognized by MRI and are best noted on sagittal views. They often are recognized by the rough appearance of the surface of the cortex on a thin-cut T2-weighted image. If MRI cuts are thick, these lesions may be confused with pachygyria. Because the genetic implications of pachygyria and polymicrogyria differ considerably, distinguishing between these 2 conditions is important.
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When bilateral, striking clinical features include a pseudobulbar palsy with abnormal tongue movements, dysarthria, dysphasia, mental retardation, absent or hyperactive gag reflex, drooling, and pyramidal signs in more than 70% of the reported cases. These patients may be intellectually disabled, and nearly all have severe language disorders. Dysphagia can impair proper nutrition. Seizures are present in most of the affected patients. Several patients have had infantile spasms during the first year of life.
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Heterotopias are collections of normal-appearing neurons in an abnormal location probably secondary to a disturbance in radial migration. The exact mechanism of the migration aberration has not been established. Various hypotheses include damage to the radial glial fibers, premature transformation of radial glial cells into astrocytes, or a deficiency of specific molecules on the surface of neuroblasts or of the radial glial cells (or the receptors for those molecules) that results in disruption of the normal migration process. Heterotopias often occur as isolated defects that may result in only epilepsy. However, when they are multiple, heterotopias might also be associated with a developmental disorder and cerebral palsy (usually spastic). In addition, if other migration defects such as gyral abnormalities are present, the clinical syndrome may be more profound. Usually, no cause is apparent. Occasionally, heterotopias may be found in a variety of syndromes, including neonatal adrenal leukodystrophy, glutaric aciduria type II, GM2 gangliosidosis, neurocutaneous syndromes, multiple congenital anomaly syndromes, chromosomal abnormalities, and fetal toxic exposures.
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Heterotopias may be classified by their location: subpial, within the cerebral white matter, and in the subependymal region. Leptomeningeal heterotopias often contain astrocytes mixed with ectopic neurons and may resemble a gliotic scar. White matter heterotopias may be focal, subcortical, or diffuse.
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Subependymal heterotopias often are associated only with epilepsy. Most patients will have normal intelligence and no motor deficits. These heterotopias are located just beneath and abut the ependymal lining of the lateral ventricles. They may be either bilateral or unilateral and are located most often adjacent to the occipital horns and trigones and, less commonly, within the temporal horns and frontal horns. The onset of seizures in patients with subependymal heterotopias is relatively late, often in the second decade, and more often affects women. The seizures may be partial-complex, tonic-clonic, or focal motor. Subependymal heterotopias have been identified as an X-linked dominant syndrome linked to markers in the distal Xq28 locus, and pathogenic variants in FILAMIN A have been found to be causative. FILAMIN A, a cytoskeletal protein, must be important for the initiation of migration since cells are arrested in the ventricular zone. An increased incidence of spontaneous abortions, patent ductus arteriosis, and spontaneous hemorrhage and a much higher than expected incidence of female offspring are noted in affected women, suggesting that inheritance of FILAMIN A pathogenic variants may be lethal for male embryos.
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Cortical dysgenesis refers to disorders of cortical formation. In general, many of the disorders just discussed are considered to be within the spectrum of this entity. In this section, an emphasis on those focal macroscopic and microscopic lesions that do not fit into the preceding classifications will be discussed.
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The terms cortical dysplasia and cortical dysgenesis often are used synonymously for the same disorders. These terms include the obvious malformations such as smooth gyri and clefts as well as lesions classified as focal cortical dysplasias and microdysgenesis. Focal cortical dysplasia may involve a major part of a lobe and may be characterized by the congregation of large, bizarre neurons and abnormal glial cells in the subadjacent white matter.
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Cortical dysgenesis has also been associated with hippocampal sclerosis, leading some to believe that hippocampal sclerosis is a disorder of brain formation. Clearly, migration aberrations need not be manifested by abnormal motor function; rather, epilepsy and intellectual disability might be the only clinical symptoms in these disorders.
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The severity of the migration disorder correlates with clinical symptoms. Patients with milder forms of neuronal migration defects (ie, focal cortical dysplasias, heterotopias, microdysgenesis) may appear normal. Most often, migration disorders are diagnosed in patients with epilepsy, as neuroimaging is performed for seizure. These patients generally have partial seizures and normal life expectancies. Some patients with these disorders will have developmental delays, mild intellectual deficits, or spastic or atonic cerebral palsy. Profound defects are associated with more severe symptoms.
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Children presenting with intractable epilepsy, significant intellectual disability, and neurologic signs more often have diffuse migration abnormalities on MRI scanning. Therefore, not surprisingly, the degree of abnormality on MRI scans correlates well with the degree of neurologic involvement. The age of onset of seizures varies from early childhood to young adult life. Generally, the severity of the seizures and the severity of the pathology correlate positively. Severe abnormalities are associated with seizures in the first year of life, whereas microdysgenesis may be associated with adult onset of seizures. Later-onset seizures also tend to correlate with subependymal heterotopias.
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Although the pathogenic mechanisms involved in focal dysgenesis remain poorly understood, the mechanisms underlying this disease are likely to resemble those involved in global or more extensive migration disorders. Therefore, it is important to define the pathogenic mechanisms causing these disorders. An important insight into the pathogenesis of focal developmental lesions may have come from the observation that the human papillomavirus (HPV) 16 RNA and its oncogenic protein E6 are present in focal cortical dysplasia type IIb resected for epilepsy. This fascinating observation potentially ties HPV with tuberous sclerosis since the E6 protein encoded by HPV exerts its oncogenic effect via depression of TSC2, thereby upregulating mTOR as occurs in tuberous sclerosis. In support of this hypothesis is the fact that cortical dysplasia type IIB also occurs in tuberous sclerosis. Indeed, other viruses could have similar effects upon the developing nervous system and could explain microdysgenesis and other lesions of the nervous system described above.
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POSTERIOR FOSSA FORMATION AND MALFORMATION
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For the purposes of this chapter, posterior fossa malformations are divided into predominantly neuronal structural malformations and malformations of the foramina, ventricular, and transient cyst structures of the developing brain. This division is in all likelihood further defined by the genetic abnormalities that are involved in neuronal genesis, migration, and patterning (predominantly neuronal structural malformations) and those of mesenchymal support structures that are important in the formation of the transient cyst of the developing posterior fossa.
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Joubert, Meckel-Gruber, and Other Ciliopathies
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In the classic form, Joubert syndrome is a disorder with a recessive mode of inheritance, and with clinical features of variable intellectual impairment, respiratory rate dysregulation, oculomotor movement abnormalities (classically oculomotor apraxia), hypotonia, and ataxia. Kidney, liver, renal, and retinal abnormalities may accompany these symptoms and signs. Radiologically, Joubert syndrome is recognized by the molar tooth anomaly and accompanying vermian hypoplasia or aplasia. The molar tooth malformation results from thin cerebellar peduncles that extend dorsally at right angles to the brain stem and absence or hypoplasia of the vermis, giving the appearance of roots of a molar tooth on axial imaging of the posterior fossa. Absence of the cerebellar peduncle decussation and disturbance of the cortical spinal tract decussation combined with brain stem nuclei abnormalities result in a thinning of the brain stem with a prominent isthmus, giving the ventral brain stem the appearance of the crown of a molar tooth. Cerebellar foliation defects may be noted along with other brain stem abnormalities.
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The Meckel-Gruber syndrome may include the brain stem and cerebellar abnormalities seen in patients with Joubert syndrome, but is distinguished by the presence of an occipital encephalocele that is usually located near the level of the torcula and may contain supratentorial contents or infratentorial contents or both. This may accompanied by syndactyly and renal, liver, retinal, or kidney problems, and the developmental outcomes are more severe than those of Joubert syndrome.
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Genetically, Joubert and Meckel-Gruber syndromes are caused by recessive loss-of-function pathogenic variants in primary ciliary genes. The primary cilia are the polarity antenna of many cells do not have motility functions other than to determine directionality in development.
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Rhombencephalosynapsis
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Rhombencephalosynapsis refers to the fusion of the cerebellar hemispheres with absence of the vermis. Its precise mode of development is poorly understood, but apparently results from a dorsal lack of division of the developing cerebellum. Clinical manifestations may be developmental in some cases, but it may also be asymptomatic. To date, the genetics of this lesion are undetermined with the exception of an implication of ZIC2 in a combination of holoprosencephaly and rhombencephalosynapsis noted in 2 half-sisters concordant for a pathogenic variant in this gene.
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The Dandy-Walker malformation possibly arises from failure to form the foramina of Magendie or failure to involute the anterior membranous area results in an enlargement of the fourth ventricle, thereby lifting, externally rotating, and compressing the vermis. The cerebellar hemispheres are splayed outward, and the torcula may be elevated. The posterior fossa is enlarged, and in 80% of cases, there is obstructive hydrocephalus requiring postnatal shunting from either failure to form the foramina and therefore outflow from the fourth ventricle or from compression of the aqueduct of Silvius. Surprisingly, this lesion is associated with good neurologic outcomes if there are no accompanying distinct malformations of the brain or if not accompanying trisomy 9, 13, 18, or 21 or other chromosomal aberrations. Some of the genes associated with this disorder are expressed in meninges and developing skull (FOXC1) and others in the dorsal cerebellum during development (ZIC1, ZIC4). The single-gene defects thus far associated with this brain lesion are heterozygote deletions or loss-of-function mutations.
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PROCESS OUTGROWTH AND SYNAPSE FORMATION
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Callosal formation begins surprisingly early in human development, with the first axons crossing from 1 developing hemisphere to the other becoming apparent at 6 weeks of gestation. By 11 to 12 weeks, there is an identifiable corpus callosum, and by 18 to 20 weeks, all of the structures of the corpus callosum are present (rostrum, body, splenium). Errant formation of this structure can result in complete agenesis, so-called partial agenesis or dysgenesis. The corpus callosum continues to form, and differences in appearance may be seen through adolescence owing to myelination and pruning of crossing fibers.
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The outcome depends on the genetic disorder, and outcome data are heavily biased toward poor outcomes. There is an ascertainment bias in many brain developmental disorders, but perhaps none more than in callosal disorders. Most patients with callosal agenesis/dysgenesis have neuroimaging because they have presented to a neurologist owing to developmental or neurologic issues. Asymptomatic people with callosal agenesis or dysgenesis are therefore not recognized. However, with common fetal imaging, it is possible that more accurate data regarding outcomes in these disorders may be noted. In fact, in a French cohort of 20 patients with agenesis or dysgenesis of the corpus callosum identified in utero (without prejudice), 80% have had normal outcomes up to 10 years later.
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Multiple etiologies of agenesis/dysgenesis of the corpus callosum have been described, and the potential etiologies are many and could deserve their own chapter. For the clinician, the division into accompanying other brain malformations, isolated, and symptomatic seems the most useful. Examples of accompanying other brain malformations include Walker-Warburg and other muscle-eye-brain disorders, ciliopathies (see posterior fossa malformations), X-linked lissencephaly with ambiguous genitalia (ARX pathogenic variants), and Aicardi syndrome.
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Aicardi syndrome occurs mostly in females (and in XXY males), is accompanied by other brain anomalies (polymicrogyria, intracranial cysts, nodular heterotopia), and is defined by chorioretinal lacunae; the genetic basis of this disorder is unknown. The prognosis is poor, and epilepsy is nearly a certainty.
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It is important for the clinician to recognize that structural brain disease can result from metabolic disorders. Nonketotic hyperglycinemia may result in agenesis/dysgenesis of the corpus callosum. With the structural brain disease and lack of acidosis, the neurologist and neonatologist may easily assume that the seizures, hypotonia, and depressed mental status at birth are the result of the brain malformation. Similarly, pyruvate dehydrogenase complex deficiency may result in callosal agenesis/dysgenesis with or without lactic acidosis.
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A reasonable evaluation of a patient symptomatic from a callosal dysgenesis would include an ophthalmologic exam if female to rule out Aicardi syndrome, metabolic studies to include CSF glycine–to–serum glycine ratios, urine organic acids, and chromosomal microarray, and if these are negative, consideration for whole-exome sequencing should be made.
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Fetal recognition of isolated agenesis of the corpus callosum may carry a different prognosis from that discussed earlier; 80% of the fetuses so identified will be normal in follow-up. It is important to recognize that Aicardi syndrome, with its poor prognosis, needs to be considered as a possibility for females.
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New insights into the genetic and molecular aspects of nervous system development and disturbances in that development have led to this attempt to give the clinician the framework to understand malformations of the human CNS and to evaluate patients afflicted by these disorders. Obtaining an etiology in such situations is of value to the patient, the family, and potentially society. With new technologies such as exome sequencing, the potential for obtaining an etiology is vastly enhanced.
+
Chen
J, Tsai
V, Parker
WE,
et al. Detection of human papillomavirus in human focal cortical dysplasia type IIb.
Ann Neurol. 2012;72:881–892.
[PubMed: 23280839]
+
Darling
DL, Yingling
J, Wynshaw-Boris
A. Role of 14-3-3 proteins in eukaryotic signaling and development.
Curr Top Dev Biol. 2005;68:281–315.
[PubMed: 16125003]
+
Dobyns
WB, Stratton
RF, Parke
JT,
et al. Miller-Dieker syndrome: lissencephaly and monosomy 17p.
J Pediatr. 1983;102:552–558.
[PubMed: 6834189]
+
Gleeson
JG. Classical lissencephaly and double cortex (subcortical band heterotopia): Lis1 and Doublecortin.
Curr Opin Neurol. 2000;13:121–125.
[PubMed: 10987567]
+
Gleeson
JG, Allen
KM, Fox
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: 9489700]
+
Kobayashi
K, Nakahori
Y, Miyake
M,
et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.
Nature. 1998;394:388–392.
[PubMed: 9690476]
+
Ledbetter
SA, Kuwano
A, Dobyns
WB, Ledbetter
DH. Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly.
Am J Hum Genet. 1992;50:182–189.
[PubMed: 1346078]
+
Mayer
S, Rowland
LP, Louis
E. Merritt’s Neurology. 13th ed. Philadelphia, PA: Wolters Kluwer; 2015.
+
Moutard
ML, Kieffer
V, Feingold
J,
et al. Isolated corpus callosum agenesis: a ten-year follow-up after prenatal diagnosis (how are the children without corpus callosum at 10 years of age?).
Prenat Diagn. 2012;32:277–283.
[PubMed: 22430728]
+
Novarino
G, Akizu
N, Gleeson
JG. Modeling human disease in humans: the ciliopathies.
Cell. 2011;147:70–79.
[PubMed: 21962508]
+
Ramocki
MB, Scaglia
F, Stankiewicz
P,
et al. Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2.
Am J Med Genet A. 2011;155A:1574–1580.
[PubMed: 21638761]
+
Sattar
S, Gleeson
JG. The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders.
Dev Med Child Neurol. 2011;53:793–798.
[PubMed: 21679365]