Abstract
The awesome complexity of the human brain begins its evolution after the essential external form is established by the events described in Chapters 1 and 2 . The events that follow are proliferation of the brain’s total complement of neurons, estimated at 86 billion, the migration of these neurons to specific sites throughout the central nervous system, the series of organizational events that result in the brain’s characteristically intricate circuitry, and finally the ensheathment of this circuitry with myelin, its neuron-specific membrane. These events span a period from the second month of gestation to adult life, including the perinatal period. Aberrations of brain development may be an important consequence of genetic perturbations as well as a variety of prenatal and perinatal insults at critical times during development. This chapter reviews the normal aspects of neuronal proliferation and discusses disorders encountered when normal development goes awry.
Keywords
neurogenetics, proliferation, microcephaly, macrocephaly, megalencephaly, focal cortical dysplasia
The awesome complexity of the human brain begins its evolution after the essential external form is established by the events described in Chapters 1 and 2 . The events that follow are proliferation of the brain’s total complement of neurons, estimated at 86 billion, the migration of these neurons to specific sites throughout the central nervous system (CNS), the series of organizational events that result in the intricate circuitry characteristic of the human brain, and finally the ensheathment of this circuitry with myelin, its neuron-specific membrane. These events span a period from the second month of gestation to adult life, including the perinatal period. Aberrations of brain development may be an important consequence of genetic perturbations as well as a variety of prenatal and perinatal insults at critical times during development. This chapter reviews the normal aspects of neuronal proliferation and discusses disorders encountered when normal development goes awry.
Neuronal Proliferation
Normal Development
Major proliferative events occur initially between 2 and 4 months of gestation, with the peak time period quantitatively in the third and fourth months ( Box 5.1 ). Initially, a tangential stream of migration from the ganglionic eminence leads to the formation of the marginal zone, or preplate. All radially migrating neurons and glia are derived from the ventricular and subventricular zones, present in the subependymal location at every level of the developing nervous system.
Valuable quantitative information concerning cellular proliferation is derived from studies of the deposition of brain DNA, the chemical correlate of cell number, or from direct counting by optical and stereological methods ( Fig. 5.1 ). Two phases can be distinguished: the first, occurring from approximately 2 to 4 months of gestation, is associated primarily with the generation of radial glia and neurons , initially as neuronal-glial progenitors that over time undergo cell fate decisions that define them as neurons and glial cells ; the second, occurring from approximately 5 months of gestation to 1 year (or more) of life, is associated primarily with glial multiplication (see later chapters concerning organizational events and myelination). Similarly, some continued generation of neurons occurs later than 4 months of gestation, principally in the cerebral subventricular zone and the cerebellar external granule cell layer. Finally, proliferation of the vascular tree , arterial before venous, is particularly active during the phase of neuronal proliferation. Initially, a leptomeningeal plexus of vessels appears; this is followed in the third month by radially oriented, primarily unbranched vessels, which in the fourth and later months develop horizontal branching ( Fig. 5.2 ).
The fundamental aspects of cell proliferation in the wall of the neural tube were described first on the basis of morphological observations by Sauer in 1935. They were then delineated further by the use of radioautography with [ 3 H]thymidine-labeled DNA by Sidman, Rakic, Berry, and others 2 to 3 decades later and, still later, with bromodeoxyuridine-labeled DNA by Caviness, Rakic, and coworkers. Most recently they have been demonstrated by immunocytochemistry, computer-assisted serial electron micrographic reconstruction, time-lapse multiphoton imaging, and a variety of molecular genetic techniques ( Fig. 5.3 ).
Cells at the periphery of the ventricular zone (VZ) were shown to replicate their DNA, migrate away from the ventricular (sometimes called apical ) surface, and divide ; the two daughter cells were then noted to migrate back to the periphery of the VZ. This to-and-fro migration , or interkinetic nuclear migration , is repeated each time DNA replication and mitosis occur in the VZ. In some regions of the forebrain, a subventricular zone of proliferating cells can be identified (see Fig. 5.3 ). In the monkey cerebrum, studied in detail by Rakic and coworkers and others, a
a References .
the VZ gives birth to most neurons, and the subventricular zone is the point of origin of some later-appearing neurons (e.g., upper layers of cerebral cortex and later subplate neurons) and most glia. When cells withdraw from the mitotic cycle and cease proliferative activity, they migrate into the intermediate zone on their way to forming the cortical plate (see later discussion). The elegant work of Caviness and coworkers defined the G 1 phase of the cell cycle as the molecular control point for these critical proliferative events.Rakic’s studies of cortical development in monkeys led to the conclusion that, in the earliest phases of proliferation, progenitor cells divide symmetrically into two additional progenitor cells, and that proliferative units of neuronal progenitor cells develop in this way (see later and also Box 5.1 ). This process determines the number of proliferative units in the ventricular-subventricular zones. Later, at a time comparable to the second half of the second month of gestation in the human, the number of these proliferative units becomes stable as the progenitor cells begin to divide asymmetrically (i.e., each division results in dissimilar cells, one of which is a stem cell and the other a postmitotic neuronal cell). These asymmetrical divisions determine the size of each proliferative unit (see Box 5.1 ). As the proliferative phase progresses, proportionately more postmitotic neuronal cells and fewer stem cells are produced. Rakic concluded that the neurons of these proliferative units migrate together in a column to form the neuronal columns of the cerebral cortex ( Fig. 5.4 ), but there is also evidence, from studies in the developing ferret nervous system, that there is dispersion of cells across the would-be columnar territories arising from each neuronal-glial progenitor cell. Other factors contribute to the complete functional organization of the cerebral cortex (see later discussion of migration), but the general principle is the generation of neuronal units in the ventricular-subventricular zones with subsequent migration of these groups. Rakic showed that the distinguishing features of the kinetics of neuronal proliferation in primates versus species with smaller neocortices are a longer cell cycle duration and, particularly, a more prolonged developmental period of neuronal proliferation. Thus the total number of proliferative units of neuronal cells generated is much greater in the primate.
At least two types of neuronal progenitors are present in the VZ: (1) a short neural precursor that has a ventricular endfoot and a leading process of variable length and (2) the radial glial cell that spans the entire cortical plate with contacts at both the ventricular and pial surfaces ( Fig. 5.5 ). The former progenitor was previously considered the principal neuronal precursor cell. An exciting advance in the understanding of neuronal proliferation was the identification of the radial glial cell as another major neuronal progenitor in the VZ . a
a References .
Previously, the major roles of this cell were considered to be, initially, a glial guide for migrating neurons and, later, a source of astrocytes (see further on). However, more recent studies based on immunocytochemical and molecular techniques indicate that radial glial cells give rise to many neurons generated in the VZ, particularly radially migrating excitatory projection cortical neurons. Thus the term radial glial cell (which we continue to use) may ultimately be replaced by radial glial progenitor or radial progenitor. When the radial glial cell functions as a progenitor that eventually results in differentiation into a neuron, the clonally related neuron so generated then migrates along the parent radial glial fiber (see Fig. 5.5 ).
These elegant proliferative events involving the radial glial cell as neuronal progenitor are modulated by several key signaling pathways involving the Notch receptor, the ErbB receptor (through the ligand neuregulin), and the fibroblast growth factor receptor. Other critical molecular determinants include beta-catenin, a protein that functions in the decision of progenitors to proliferate or differentiate. Finally, of particular importance in the regulation of radial glial production of neurons, are calcium waves propagating through connexin channels of the radial glial cell. Calcium entry is critical in the regulation of the cell cycle. Subsequent to neurogenesis, radial cells produce astrocytes and other glial cells (e.g., oligodendroglia). In addition, it appears likely that radial glial cells also give rise to cells that persist in the subventricular zone of adult brain as stem cells capable of producing neurons. The multiple functions of radial glial cells are summarized in Box 5.2 .
Progenitors for cortical neurons
Guides of neuronal migration
Progenitors for astrocytes and oligodendrocytes
Neural stem cells found in subventricular zone of adult brain
The classical understanding of neuronal proliferation and migration centers on the ventricular and subventricular zones and radially migrating neurons. In addition, there are important proliferative centers in the median ganglionic eminence (MGE) that give rise to tangentially migrating cortical and striatal interneurons. Although there was some early evidence from studies in the mouse that interneurons arising from the same MGE progenitor maintain some clustering, more recent evidence suggests that many progenitors in the MGE often give rise to interneurons that disperse widely across the brain. There are some important interspecies issues to consider as animal models continue to inform our understanding of human brain development, particularly regarding interneuron development and circuitry. Cell lineage studies in organotypic slice cultures of human embryonic forebrain provide evidence for two GABAergic subpopulations in humans: the first, which arises from the VZ and subventricular zone (SVZ) in the dorsal telencephalon, expresses the transcription factors Dlx1/2 and Mash1 and represents about two-thirds of human neocortical GABAergic neurons; the second, which arises from the MGE of the ventral telencephalon, contains neurons that are transcriptionally distinguished from the first in that they are Dlx1/2-positive but Mash1-negative.
Disorders
Disorders of neuronal proliferation would be expected to have a major impact on CNS function. Because of difficulties in quantitating neuronal populations, however, proliferative disorders are often difficult to define by conventional neuropathological examination. Even when the disorder is so extreme that the brain is grossly undersized (as in microcephaly) or oversized (as in macrocephaly), defining the nature and severity of the proliferative derangement is also difficult by conventional techniques. (Although theoretically there is the possibility that the disorders relate to alterations in later-occurring normal apoptotic events, we consider these to be disorders of proliferation unless evidence of an apoptotic disorder is recorded.) In the following discussion, we focus on these two extremes of apparent proliferative disorders, emphasizing that conclusions about the nature of the disorders can be drawn only cautiously.
Microcephaly
Microcephaly means “small head,” as opposed to micrencephaly , which means “small brain.” We will use the former term, since head size in living patients—measured as occipitofrontal circumference—is used as an approximation of brain size. Barring severe cranial defects resulting in premature skull closure, small brain size is generally considered the reason for small head size. We distinguish primary microcephalies , apparently related to impaired neuronal proliferation resulting in too few neurons, from microcephalies secondary to destructive disease ( Box 5.3 ). The latter relate to hypoxic-ischemic, infectious, metabolic, or other destructive events that usually occur following completion of cerebral neuronal proliferative events near the end of the fourth month of gestation (see Chapter 16 , Chapter 20 , Chapter 25 , Chapter 26 , Chapter 27 , Chapter 28 , Chapter 34 , Chapter 35 ). The primary microcephalies that have been shown most clearly to be related to impaired neuronal proliferation include the autosomal recessively inherited disorders, often categorized as microcephaly vera . Thus, in the context of this chapter, we discuss these conditions in most detail.
a Excluded are cases of congenital microcephaly secondary principally to destructive disease (hypoxia-ischemia, infection) developing after the conclusion of cerebral neuronal proliferation.
Autosomal recessive (microcephaly vera)
Autosomal dominant
X-linked recessive
Genetics as yet undetermined
Teratogenic
Irradiation
Metabolic-toxic (e.g., fetal alcohol syndrome, related to cocaine, hyperphenylalaninemia)
Infection (rubella, cytomegalovirus, HIV, Zika virus)
Syndromic (Multiple Systemic Anomalies)
Chromosomal
Familial
Sporadic
Sporadic (Nonsyndromic)
Microcephaly Vera.
Microcephaly vera refers to a heterogeneous group of disorders that appear to have, as the common denominator, small brain size because of a derangement of proliferation (see Box 5.3 ). Thus no evidence of intrauterine destructive disease or of gross derangement of other developmental events (e.g., neurulation, prosencephalic cleavage, neuronal migration) exists, and the abnormal brain size is apparent as early as the third trimester of gestation. The brain is generally well formed, although the gyrification pattern may be simplified to a variable degree, sometimes but not always commensurate with the degree of microcephaly. We first discuss radial microbrain , an informative but rare and particularly severe type of microcephaly vera, and then the more common genetically determined varieties of microcephaly vera.
Anatomical Abnormality: Radial Microbrain.
Radial microbrain is a rare disorder of particular interest because it appears to provide the first clear example of a disturbance in the number of proliferative units resulting in small brain size. The major features of the seven cases studied carefully by Evrard et al. are outlined in Box 5.4 . The extremely small brain has no marked gyral abnormality, no evidence of a destructive process, and no disturbance of cortical lamination. The conclusion that the disturbance involves the early phase of proliferative events, by which symmetrical divisions of neuronal progenitors generate the total number of proliferative units, is based on the finding of a marked reduction in number of cortical neuronal columns but an apparent normal complement of the neurons per column (i.e., normal size of columns; Fig. 5.6 ).
Term newborns: death, birth–30 days
Brain weight 16–50 g (normal, 350 g)
No evidence of destructive process
Normal residual germinal matrix at term
Normal cortical lamination
Cortical neurons 30% of normal number
Cortical neuronal columns decreased in number
Neuronal complement of each column normal
Timing and Clinical Aspects: Radial Microbrain.
The presumed timing of radial microbrain is no later than the earliest phase of proliferative events in the second month of gestation. The essential abnormality involves the symmetrical divisions of progenitors to form additional progenitors and thereby the number of proliferative units. Later proliferative events that determine the size of each column proceed normally, as evidenced not only by the normal neuronal complement of each column but also by the presence of a normal residual amount of germinal matrix at term (see Fig. 5.6 ).
The clinical features are not entirely clear because this anomaly is rare. The reported cases have involved full-term newborns who died in the first month of life. The distinction from anencephaly and aprosencephaly-atelencephaly is based on the presence of an intact skull and dermal covering, in contrast to anencephaly, and of a normal external appearance of cerebrum and ventricles, observable by ultrasonography, in contrast to aprosencephaly-atelencephaly. The disorder is notably familial, probably of autosomal recessive inheritance.
Anatomical Abnormality: Microcephaly Vera.
As noted earlier, the designation microcephaly vera refers to a heterogeneous group of autosomal recessive disorders that appear to have, as the common denominator, small brain size because of a derangement of proliferation (see Box 5.3 ). In recent years, remarkable insights into the genetics and molecular bases of these disorders have been gained (see later).
The anatomical studies of Evrard et al. provide insight into the fundamental disturbance in microcephaly vera, at least in a prototypical autosomal recessive variety ( Box 5.5 ). The brain is small (clearly more than several standard deviations below the mean) but not so strikingly as in the tiny radial microbrain. Simplification of gyral pattern exists with no other external abnormality and no evidence of a destructive process. The number of cortical neuronal columns appears normal, but the neuronal complement of each column, especially the superficial cortical layers, is decreased markedly. Additional evidence of disturbance of the later proliferative events that determine size of cortical neuronal columns is the absence of residual germinal matrix in the 26-week fetal brain studied by Evrard et al. ( Fig. 5.7 ). The deficiency in neurons of the superficial cortical layers may explain the simplification of gyral pattern (see the later discussion of gyral development in migrational disorders in Chapters 6 and 7 ).
No evidence of destructive process
No evidence of migrational defect
No apparent defect in number of cortical neuronal columns
Cortical neuronal columns with marked decrease in neurons of layers II and III
No residual germinal matrix at 26 weeks of gestation ( premature exhaustion of matrix)
Timing and Clinical Aspects: Microcephaly Vera.
The presumed timing of the microcephaly vera group of disorders involves the period of later proliferative events by asymmetrical divisions of neuronal progenitors—that is, onset at approximately 6 weeks in the human—with later rapid progression until approximately 18 weeks (see earlier). The most severely undersized brains are expected to have the earliest onsets and the most marked deficiency of neurons in each cortical column.
The clinical presentation of infants with the prototypical autosomal recessive forms of microcephaly vera is interesting in that, with the exception of the extreme microcephaly and seizures associated with recessive mutations in the gene PNKP, many affected newborns do not show striking neurological deficits or seizures. This presentation is in contrast with that of other varieties of microcephaly—that is, intrauterine destructive disease or other developmental derangement (e.g., migrational defect). Rare autosomal recessive forms of microcephaly with severe neuronal migrational defects (i.e., microlissencephaly) are more likely to be accompanied by neurological deficits and seizures (see the later discussion of disorders of neuronal migration in Chapter 6 ).
Magnetic resonance imaging (MRI) has been invaluable in the assessment of microcephaly vera, especially for evaluation of gyral development and the presence of associated migrational abnormalities. Most commonly, gyral formation is variably simplified ( Fig. 5.8 ), and the term microcephaly with simplified gyri is often used. Simplification of the gyral pattern is often not obvious. Rare cases are associated with severe migrational disturbances, such as lissencephaly, periventricular heterotopia, or posterior fossa deficits, especially cerebellar hypoplasia.
Etiology: Autosomal Recessive Microcephaly (Microcephaly Vera).
At least 16 genetic loci have been identified for autosomal recessive primary microcephaly, or microcephaly vera. Genes have been identified for the majority of the loci, though sometimes only in one family ( Table 5.1 ). Perhaps not unexpectedly, the genes play key roles in mitosis. Microcephalin is crucial for cell cycle control, chromosome condensation, and DNA repair. CDK5RAP2 is a centrosomal protein involved in microtubular function necessary for formation of the mitotic spindle. ASPM also is necessary for microtubular function at the poles of the mitotic spindle, and CENPJ is similarly involved in formation of the mitotic spindle. Of all these single-gene causes of autosomal recessive microcephaly, ASPM appears to be the most common, and mutations have been identified in nonfamilial cases as well.
| LOCUS | GENE/PROTEIN | PROCESSES AFFECTED |
|---|---|---|
| MCPH1 | MCPH1 /microcephalin | Cell cycle control |
| MCPH2 | WDR62 /WD repeating-containing protein 62 | Mitosis (centrosome) |
| MCPH3 | CDK5RAP2 /cyclin-dependent kinase-5 regulatory associated protein-2 | Mitotic spindle formation |
| MCPH4 | CASC5 /cancer-associated candidate 5 | Mitotic spindle formation |
| MCPH5 | ASPM /abnormal spindle in microcephaly | Mitotic spindle formation |
| MCPH6 | CENPJ /centromere-associated protein J | Mitotic spindle formation |
| MCPH7 | STIL /SCL/Tal1 interrupting locus | Mitotic spindle formation |
| MCPH8 | CEP135 /centrosomal protein 135 kD | Mitosis (centrosome) |
| MCPH9 | CEP152 /centrosomal protein 152 kD | Mitosis (centrosome) |
| MCPH10 | ZNF335 /zinc finger protein 335 | Regulation of neurogenesis |
There is a group of autosomal recessive microcephalies that are associated with MRI findings suggestive of a destructive process. These include microcephaly with cerebral hemorrhage and calcification as well as congenital cataracts, associated with recessive mutations in the tight-junction protein-encoding gene JAM3 . Included in this category, which is sometimes referred to as TORCH-like , is also the relatively newly identified PCDH12 -related recessive syndrome involving, progressive microcephaly with dysplasia of the hypothalamus and midbrain, the first microcephaly to be related to vascular endothelial cadherin (cell adhesion protein) dysfunction.
Etiology: Other Disorders.
The four major etiological categories for primary microcephaly, in addition to the autosomal recessive group just discussed, are familial, teratogenic, syndromic, and sporadic (see Box 5.3 ). Familial syndromes are most critical to detect because of implications for genetic counseling. In addition to the autosomal recessive group (see earlier), these inherited varieties include autosomal dominant and X-linked recessive types as well as familial types with ocular abnormalities and variable genetics. These ocular abnormalities may include chorioretinopathy, which can be confused with the chorioretinitis of intrauterine infection (see Chapter 34 ). One such disorder is Cohen syndrome , which is inherited in an autosomal recessive manner. Of the unusual cases of microcephaly with autosomal dominant inheritance, intellect is subsequently usually either spared or only mildly defective; patients generally have no facial dysmorphism, although digital anomalies and rare syndromic varieties have been reported. X-linked recessive inheritance of microcephaly has been described, albeit less commonly than autosomal recessive inheritance.
The best-documented teratogenic agent producing microcephaly is irradiation, such as that due to an atomic explosion or radiation therapy for tumor or ankylosing spondylitis, particularly before 18 weeks of gestation (see Box 5.3 ). The most critical gestational period in the Nagasaki-Hiroshima experience was 8 to 15 weeks. Maternal alcoholism or cocaine abuse (see Chapter 38 ) and maternal hyperphenylalaninemia have been associated with microcephaly. Microcephaly, usually with intellectual disability, occurs in as many as 75% to 90% of (nonphenylketonuric) children of women with phenylketonuria; the risk for the fetus correlates with the severity of the maternal hyperphenylalaninemia. With dietary treatment, the risk declines to as low as 8% when phenylalanine levels are controlled before conception and to 18% when control is achieved by 10 weeks of pregnancy. When control is not achieved until 20 to 30 weeks, the incidence of microcephaly increases to 40%. Rarer intrauterine teratogens for microcephaly include anticonvulsant drugs (see Chapter 38 ), organic mercurials, and excessive ingestion of vitamin A or vitamin A analogues (see Chapter 38 ). Finally, among intrauterine infections that may cause microcephaly (see Chapter 34 ), rubella is the best candidate for an agent that may produce microcephaly through an impairment of proliferation rather than principally through a destructive process. Cytomegalovirus infection may also act in this way, although disturbances of neuronal migration and destructive lesions contribute to the condition. Human immunodeficiency virus characteristically produces microcephaly (without major destructive lesions) after the neonatal period, although neonatal cases have been reported (see Chapter 34 ). Most recently, maternal infection with the Zika virus (ZIKV) has been associated with microcephaly with or without cerebral calcifications and varying degrees of intellectual disability.
Syndromic cases , that is, those with multiple associated systemic anomalies, may be related to chromosomal disorders or monogenic (familial) defects, or they may occur sporadically (see Box 5.3 ). In one consecutive sample of congenital microcephaly, syndromic disorders accounted for only 6% of cases. The nature of the proliferative disorder in this diverse group is generally not known, and it is not discussed further here. Clinical details are available in standard sources.
Sporadic nonsyndromic cases —that is, those with no related family history, identifiable teratogen, or recognizable syndrome—are the most common varieties of microcephaly vera (see Box 5.3 ). No associated systemic or other neural malformations can be identified. The nature of the proliferative disturbance is generally unknown. Any of the described autosomal dominant or X-linked conditions may also occur sporadically owing to a de novo mutation, which occurs typically during meiosis, while one of the gametes is being formed. Thus clinical genetic testing for known causes of microcephaly—for example with a gene panel—is indicated in otherwise unexplained cases.
Macrocephaly
Anatomical Abnormality.
The designation macrocephaly signifies a large head and, by implication, a large brain. Thus the term megalencephaly is also often used, particularly when there is neuroimaging to support the assertion that the large head size is accompanied by, and in fact presumably caused by, large brain size. Macrocephaly is a feature of a heterogeneous group of disorders that have not been well defined from the neuropathological standpoint. Nevertheless, several entities clearly exist in which the brain is generally well formed but unusually large ( Box 5.6 ). Genetic varieties, suggestive of a derangement in the developmental program for neuronal proliferation, have been defined (see following discussion). As with microcephaly, however, the conclusion that we are dealing with proliferative disorders can be drawn only tenuously until central neuronal populations can be quantified more accurately. This discussion excludes other rare disorders of macrocephaly, such as enlargement of the skull (craniometaphyseal dysplasia, hemoglobinopathy), subdural hematoma, or effusion (see Chapter 22 , Chapter 35 , Chapter 36 ), hydrocephalus (see Chapter 3 , Chapter 24 , Chapter 35 ), metabolic disorders (see Chapter 28 ), or degenerative disorders (Alexander disease, Canavan disease [see Chapter 29 ]).
Isolated Macrocephaly
Familial
Autosomal dominant (relation to “benign enlargement of extracerebral spaces” or “external hydrocephalus”)
Autosomal recessive
Sporadic
Associated Disturbance of Growth
Achondroplasia
Beckwith syndrome
Cerebral gigantism
Fragile X syndrome (see the section on chromosomal disorders , below in the box)
Marshall-Smith syndrome
Thanatophoric dysplasia
Weaver syndrome
Neurocutaneous Syndromes
Multiple hemangiomatoses
Lipomas, hemangiomas, lymphangiomas, pseudopapilledema (Bannayan-Riley-Ruvalcaba)
Asymmetrical hypertrophy, hemangiomata, varicosities (Klippel-Trenaunay-Weber)
Asymmetrical hypertrophy, telangiectatic lesions, flame nevus of the face (cutis marmorata, telangiectatica congenita)
Neurofibromatosis, a
a Neurocutaneous disorder of cellular proliferation causing macrocephaly and affecting primarily nonneuronal elements (i.e., glia).
tuberous sclerosis, b
b Neurocutaneous disorders of cellular proliferation but not usually associated with neonatal macrocephaly.
Sturge-Weber syndrome b
Epidermal nevus syndrome (see the section on unilateral macrocephaly , below)
Chromosomal Disorders
Fragile X syndrome (relative macrocephaly)
Klinefelter syndrome
Unilateral Macrocephaly (Hemimegalencephaly)
Isolated
Syndromic: epidermal nevus syndrome, Proteus syndrome (most common)
Timing and Clinical Aspects.
Although neuronal proliferation in the cerebrum is an event that occurs principally during the third and fourth months of gestation, this time period may be prolonged in disorders of excessive proliferation. Alternatively, abnormal proliferation may occur at the appropriate time during development but at an excessive rate. In addition, a later-occurring defect of normal apoptosis or programmed cell death (see later) could perhaps lead to macrocephaly. The issues of mechanism are unresolved and await development of suitable experimental models for elucidation.
The clinical syndrome in the several types of macrocephaly (see Box 5.6 ) varies from no apparent neurological deficit (e.g., autosomal dominant, isolated macrocephaly) to severe recalcitrant seizures and intellectual disability (e.g., autosomal recessive, isolated macrocephaly, or unilateral macrocephaly). In other types of the disorder, extraneural features may dominate the clinical presentation (e.g., associated growth disorders and certain neurocutaneous syndromes). Some of these individual clinical aspects are mentioned briefly in the following discussion.
Familial Isolated Macrocephaly.
Perhaps the most common variety of macrocephaly occurs in the familial setting and in the absence of any other extraneural findings. For this group, we use the term familial isolated macrocephaly . Two genetic types can be recognized: autosomal dominant and autosomal recessive; the former is much more common.
In familial, isolated macrocephaly of the autosomal dominant type , the head is usually large at birth (>90th percentile in about 50%) and continues to grow postnatally at a relatively rapid rate. Neurological deficits are rarely striking, and development and ultimate level of intelligence are in the normal range in approximately 50% to 60% of cases. Pronounced intellectual disability is present in only approximately 10%. The genetic component of this syndrome is frequently overlooked until the parents’ head circumference is measured. The diagnosis of fetal macrocephaly of this type was made in the 34th week of pregnancy in a woman with benign macrocephaly.
Related to autosomal dominant macrocephaly is a syndrome of macrocephaly categorized under several names: benign enlargement of extracerebral spaces, benign subdural effusions of infancy , and idiopathic external hydrocephalus . The clinical features described in the previous paragraph are present, and brain imaging studies show prominent extracerebral subarachnoid spaces, particularly in the frontal regions, and a large brain ( Fig. 5.9 ). The cisterna magna especially may be prominent. In some cases, subdural and subarachnoid fluid appears to be present; the distinction is best made by MRI. Head growth in the first year is rapid, and infants not overtly macrocephalic at birth attain rates of head growth at the 97th percentile or slightly higher. Accelerating head growth ceases by approximately 1 year; over the next several years extracerebral spaces become smaller, although the brain is clearly larger than average. Because of the large brain size, if the infant is first evaluated after the second year of life, isolated macrocephaly will be observed. Because as many as 90% of these infants have a parent with a large head, the genetic features are similar to those of autosomal dominant isolated macrocephaly. The similarity of the clinical features and genetics suggests that these may represent different forms of the same fundamental disorder. Those unusual patients with isolated macrocephaly that conforms to autosomal recessive inheritance are more likely to exhibit definite intellectual disability, epilepsy, and motor deficits.
Sporadic Isolated Macrocephaly.
Isolated macrocephaly, or megalencephaly, with no evidence of a familial disorder by history and after measurement of parental head circumference occurs only slightly less often than the autosomal dominant disorder described previously. The clinical course is similar.
Associated Disturbance of Growth.
Macrocephaly may be associated with generalized disorders of growth, such as achondroplasia, Beckwith syndrome, cerebral gigantism (Sotos syndrome), fragile X syndrome, Marshall-Smith syndrome, thanatophoric dysplasia, Cowden syndrome, Sotos syndrome, and Weaver syndrome (see Box 5.6 ). Except in Beckwith syndrome, which is complicated by neonatal hypoglycemia, neurological features in the neonatal period are unusual. The precise neuropathological correlates for the macrocephaly in these disorders remain to be defined. The gene mutated or deleted in Sotos syndrome, NSD1 , encodes a nuclear receptor binding protein that may be involved in proliferative events.
Neurocutaneous Syndromes.
Several of the neurocutaneous disorders are associated with evidence of excessive cellular proliferation within the CNS, sometimes with overt macrocephaly and evidence of excessive proliferation of mesodermal structures (see Box 5.6 ). Macrocephaly occurs most consistently in this context in the multiple hemangiomatosis syndromes.
In neurofibromatosis , an autosomal dominant disorder, the principal proliferative abnormality involves glia, particularly astrocytes. (Thus the onset of the proliferative disorder in this disease occurs primarily after the time period of neuronal proliferative events.) Approximately 40% of infants exhibit more than five café-au-lait spots larger than 5 mm at birth. Approximately 40% to 50% of such infants have macrocephaly, usually after the neonatal period. Consistent with the predominantly glial rather than neuronal involvement in the disorder, the megalencephaly relates primarily to increases in cerebral white matter volume, primarily in frontal and parietal areas. Relative macrocephaly with generalized glial tumors has been documented by prenatal ultrasound. Hemimegalencephaly with neonatal seizures and associated neuronal migrational defects has also been observed. Of the glial tumors that are the hallmark of this disease, optic nerve glioma and plexiform neuroma of the eyelid have been observed in the newborn, albeit rarely. The gene for this disorder, located on chromosome 17, NF1 , has been shown to encode a protein involved in the negative regulation of a key signal transduction pathway, the Ras pathway, which transmits mitogenic signals to the nucleus. Thus loss of neurofibromin, the neurofibromatosis protein, leads to increased mitogenic signaling and thereby to the proliferative abnormalities characteristic of the disorder.
In Sturge-Weber disease , a sporadic disorder, the principal abnormality affects leptomeningeal blood vessels. Thus the time of onset is probably coincident with that for neuronal proliferation. Data suggest that the fundamental defect in this disorder is a failure of development of superficial cortical veins, resulting in diversion of blood to the developing leptomeninges with the formation of abnormal vascular channels as a consequence. Abnormalities of fibronectin in cerebral vessels may play a role in the genesis of the vascular abnormality. The characteristic facial port-wine stain is described in Chapter 9 ; the overall incidence of clinical manifestations of Sturge-Weber disease (glaucoma or seizures) is 2% to 8% in patients with unilateral facial lesions and 24% in those with bilateral facial lesions. Identification of the newborn with intracranial involvement is difficult. Seizures and cerebral calcification (identified by computed tomography [CT]) have been noted only occasionally in newborns ( Fig. 5.10 ). Cerebral calcifications most commonly appear after 6 months of age and often considerably later. MRI is the most useful imaging study in the first year ; the principal findings are cerebral cortical and white matter changes in the region of the leptomeningeal angiomatosis, angiomatous alteration of overlying calvaria, and atypically located, congested deep cerebral veins. Gadolinium-enhanced MRI is the gold standard for demonstration of the leptomeningeal vascular lesion ( Fig. 5.11 ). The choroid plexus is enlarged on the side of the leptomeningeal lesion, presumably because of the diversion of venous blood into the deep venous system as a consequence of the lack of superficial cortical venous drainage (see earlier discussion). On studies by single photon emission tomography, decreased cortical perfusion may be observed in the region of the vascular lesion. MRI perfusion studies also may be useful in detecting perfusion deficits. Infants with Sturge-Weber syndrome who have bilateral cerebral disease have a much poorer outcome (8% with average intelligence) than those with unilateral cerebral disease (45% with average intelligence). a
a References .
Although it has long been suspected to be a genetic syndrome, Sturge-Weber syndrome was only relatively recently associated with somatic or postzygotic mutations in the gene GNAQ.
