Neurogenetic Syndromes

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Genetic syndromes with well defined etiologies provide an excellent opportunity for examining the contributions of genetics to behavior and brain development. Unlike most psychiatric conditions, the behaviors associated with known syndromes can be traced to a reasonably uniform etiology. Often, the behavioral phenotype of a neurogenetic syndrome is the result of a microdeletion of a very small number of genes that is fairly consistent from one affected individual to the next; or, in some cases, can be traced to a single gene mutation. Although the most straightforward single-gene syndromes can result in complex and extensive neuroanatomical anomalies, research on neurogenetic conditions represents one of the most direct ways for looking at human gene-brain-behavior relationships. The following syndromes provide examples of the diversity of genetic mechanisms, behavioral phenotypes, and neuromorphology found within this field.

2.1. Down Syndrome

As a result of its relatively high prevalence and distinct cranio-facial features, Down syndrome (DS) is perhaps the most widely recognized genetic syndrome (1). DS is almost always caused by a complete trisomy of chromosome 21 that results from a non-disjunction event, usually with a maternal origin (2). Occurring once in approx 800 live births, DS is the most common genetic cause of mental retardation. In addition to low IQ scores, problems related to memory, language, speech, and motor coordination are frequently reported (3-6).There is now a renewed interest in DS because persons with this condition are at an increased risk for developing Alzheimer-like dementia beginning at a young age.

Geneticists have been able to estimate that chromosome 21 contains only 225 genes (7). However, the genes that are involved in the cognitive pheno-type have not yet been identified; multiple genes may be involved. DS has a distinct neuroanatomical phenotype. Postmortem studies indicate that microcephaly and brachycephaly are common in DS (8). MRI studies suggest disproportionate volume reductions in the cerebellum, beyond the decrease in general intracranial volume (9). When examining neuroanatomical differences in greater detail, specific reductions are found in the frontal and temporal lobes (10). Hand measurements (rather than computer or automated measurements) have found significant reductions in the superior temporal sulcus and hippocampus (11,12). Preservations in subcortical tissue and parietal-occipital tissue also are seen (13,14).

The neuroanatomical profile of DS appears to conform to its behavioral phenotype. Selective decreases in frontal lobe volumes have been associated with the characteristic mental retardation seen in DS affecting executive functions. Temporal lobe and hippocampal reductions can be linked to deficits in language and memory. Decreases in the cerebellum are seen to underlie the motor control problems and hypotonia typical of DS. In contrast, the relative preservation of parietal-occipital tissue may be related to the relative sparing of visual-spatial ability in this condition. In addition, preservations in subcortical tissue conform to embryological results in DS

that indicate that brain abnormalities in DS do not begin until the third trimester of pregnancy, after the formation of subcortical structures has already taken place (8).

Interestingly, histological investigations reveal that even before the end of the second decade of life persons with DS commonly have neuropatho-logical features that are similar to those of Alzheimer disease. Young subjects with DS often display amyloid(A)-P42-containing neuritic plaques typical of much older patients with Alzheimer disease (15,16). A postmortem study of 100 subjects with DS found that 56% had amyloid plaques or plaques and neurofibrillary tangles; all subjects older than 30 years showed evidence of amyloid plaques (17). Subjects with DS overexpress amyloid P protein as early as 21 gestational wk of age (18). DS subjects typically exhibit progressive mental deterioration in the third and fourth decades of life, and there is good reason to believe that, as in Alzheimer disease, the dementia in DS is in part caused by excessive amyloid P protein deposition in the brain. However, in DS, unlike Alzheimer disease, this excess reflects the presence of the extra copy of the amyloid precursor protein gene on chromosome 21.

Investigations in DS introduce several issues that are commonly encountered in neurogenetics research. First, because the exact genes responsible for the syndrome are not yet known, the molecular mechanisms responsible for cellular and ultimately brain abnormalities remain a mystery, which makes interpretation of abnormal morphology difficult. Part of the behavioral phenotype may reflect abnormal brain structure formation, and part of it may result from subsequent changes in the brain because of additional acquired damage. Second, because the neurobehavioral phenotype of DS encompasses several cognitive and behavioral domains, and its neuroana-tomical profile includes significant differences in several regions, linking a specific behavioral feature (i.e., language difficulty) to the morphology of a single neuroanatomical structure (i.e., temporal lobe) can be quite challenging. There is the problem typical of all developmental disorders, whether genetic or acquired, by which normal organization of function, for instance, cerebral laterality, cannot necessarily be invoked, as the developing brain is apt to change markedly in response to a change in one of its components. As a result, standard localization of function may be bypassed. The challenge in DS remains trying to identify genes that alter the development of the brain, genes that modify maintenance of brain structure throughout life, and genes affecting the formation of other organs, the malfunction of which could affect brain integrity. Each change in structure thus obtained and combinations of changes need to be studied in terms of effects on behavior.

2.2. Williams Syndrome

Williams syndrome (WMS) is a rare (1/20,000 live births) and fascinating neurogenetic condition that typically results from an unequal recombination during meiosis prior to conception (19,20). The consequences of this event are that persons with WMS have only one copy of approx 20 genes in the 7q11.23 region of chromosome 7. The resulting phenotype presents a broad spectrum of unique physical and behavioral characteristics. The physical features of WMS include distinct craniofacial features, hypercalcemia in infancy, widely spaced teeth, strabismus, and narrowing of the vasculature, particularly supravalvular aortic stenosis (SVAS) (21).

However, what is perhaps most interesting in WMS is a truly unusual profile of behavioral features (22). The cognitive hallmark of WMS is a dissociation between a seemingly relatively preserved linguistic ability and profoundly impaired visual-spatial ability. In addition, a preserved social drive, and oddly, an enthusiasm for and love of music characterize WMS. Increased anxiety and attentional problems also are common in this condition (20,23).

As with DS, research into the underlying neuroanatomical features of WMS reveals patterns of alteration concordant with our current understanding of functional neuroanatomy and the behavioral phenotype of WMS. Although both autopsy and MRI studies have shown that the overall brain size of persons with WMS is substantially decreased relative to typically developing controls, certain regions are relatively spared (24-26). As expected from the observation of preserved language and musical abilities in this condition, the temporal lobe, specifically the superior temporal gyrus (STG), is relatively preserved in volume. In addition, the cerebellum is preserved in volume, and, on average, is of similar size compared to typically developing individuals (25-27). Given recent studies implicating the cerebellum in higher cognitive and social abilities (28,29), disproportionately increased cerebellum may be related to the hypersociability seen in this condition. In contrast, regions of the brain that play a large role in visual-spatial ability (i.e., parietal and occipital lobes) are disproportionately decreased compared to expectations based on total cranial volume.

More detailed investigations of WMS also have been performed on a few autopsy specimens, which allows for a much higher resolution of cortical anatomy than that permitted by MRI studies (24,30). Gross examination of the WMS brain shows that there is an overall decrease in brain weight, with parietal and occipital hypoplasia common. Other than focal changes suggestive of immaturity of development, no consistent differences were found in the cytoarchitectonic organization of the cerebral cortex of subjects with

WMS. Motor and sensory association areas are easily identifiable by architectonic features typical of these areas. However, at the histological level, changes are seen in cell packing density and cell size suggesting abnormal neuronal development and connectivity.

The shape of the WMS brain also is unique. Overall, the brains of subjects with WMS are dolichocephalic and have some anomalous gyral patterns. The most consistent gross anatomic observation is a foreshortening of the dorsal central sulcus (24). Unlike most typical brains in which the central sulcus extends fully to the interhemispheric fissure, in WMS the central sulcus usually terminates prematurely on the dorsal, but not ventral end. The second common shape difference is a bilateral forshortening of the parieto-occipital region, effectively a curtailment in the superior-inferior dimension posteriorly in the telencephalon.

Gross morphological differences observed in autopsy specimens have been supported by several recent structural MRI studies that confirmed in larger samples autopsy findings of abnormal central sulcus morphology, posterior curtailment, and anomalous gyri (31-33). Observations made on necessarily small numbers of autopsy specimens direct attention to specific brain areas that can be assessed in large numbers of living subjects. MRI provides highly automated, in vivo evidence with sample sizes that provide more statistical power that can commonly be obtained in autopsy studies. Conversely, observations made using MRI can lead to more detailed studies in autopsy specimens at the architectonic and histological levels. We have found that this cross-level combination of histology, gross anatomical observation, and MRI analyses is a productive strategy for furthering neurogenetics research.

Despite the relatively small size of the WMS deletion region, several genes have likely roles in brain development or synaptic functioning. For example, the gene STX1A encodes for syntaxinlA, a member of a gene family that has role in neurotransmitter release (34). A second gene, LIM-kinasel, has been shown to play a role in growth cone formation and axon guidance (35,36), which may partially underlie the abnormal white matter volume demonstrated by MRI in WMS. Hemizygosity for LIM-kinasel has been correlated with visual-spatial impairment for both subjects with WMS and subjects with microdeletions of only the elastin (ELN) and LIM-kinase genes (37). Another gene in the WMS critical region, FZD9 (formerly known as FZD3, the human homologue of Drosophila's frizzled gene), is expressed strongly in adult brains and appears to play a key role in global brain development (38). FZD9 is a putative receptor for the Wnt gene family, which encode for secreted signaling glycoproteins and are known to be involved in controlling early cell development, tissue differentiation, segmentation, and dorsal-ventral polarity (39).

Neuroanatomical studies on WMS suffer from many of the same methodological limitations that are seen in DS research. Specifically, the broad array of neuroanatomical differences seen in WMS make interpretation of relationships to genetics and behavior difficult. Fortunately, there are many fewer genes in the critical WMS deletion region than in DS (about 20 compared to >200), although several of these have prominent roles in brain development. In addition, as with other developmental disorders of known genetic origin, WMS is a rare condition that can lead to difficulties in gathering statistically powerful results, particularly for studies requiring tissue samples. Finally, as with other mental retardation syndromes and developmental disorders affecting emotional behavior, the noisy and relatively stressful environment of the MRI lab can be a barrier to research.

Study of the WMS neuroanatomical phenotype also raises the question of how to interpret relative involvement in neurodevelopmental conditions. For example, although the STG is relatively preserved in WMS, can it be assumed that this volume preservation is related to the relative preservations in language in this condition? First, there is a strikingly phrenological quality to this form of reasoning, whereby volume of brain tissue is assumed to be causally related to quality of performance. Second, this argument assumes that the superior temporal gyrus in WMS serves the same function as in normal individuals. Third, regional measurements may assume a greater degree of functional localization than is evident from contemporary studies using activation approaches, such as functional MRI and PET. On the other hand, focal measurements provide clues for focusing other types of studies, and it is only through convergent evidence derived from various methodologies that a clearer picture of structure-function relationships begins to emerge.

2.3. Fragile X Syndrome

In the field of neurogenetic conditions, fragile X syndrome (FXS) is somewhat unique in that the primary genetic cause of the disease has been traced to the inactivation of a single gene. Affecting approx 1/4000-6000 live births, FXS is the most common form of inherited mental retardation resulting from a known gene (40). The physical characteristics include macroorchidism, large ears, and a long face (41). A distinct neurobehavioral phenotype, which differs between males and females, is present. Males with FXS are typically quite affected, with mild to severe mental retardation and learning disability. Deficits are present in short-term memory speech and language, and stereotypic behaviors also are typical (42-44). In addition, boys with FXS often have autistic features such as social withdrawal and gaze aversion (42-45). Although females heterozygous for FXS generally have a similar phenotype compared to males with the disorder, their problems are typically less severe and more variable (46-49).

FXS is one of the recently characterized family of genetic disorders caused by trinucleotide repeat expansions. In FXS, the expansion of a (CGG)n trinucleotide sequence ultimately produces methylation in the first exon of the 5' end of the FMR1 gene, which in turn inactivates gene expression through transcriptional silencing (50). Although the function of FMRP, the protein product of FMR1, is not yet understood, its structure suggests that it binds to RNA and can enter the nuclear envelope and therefore may possibly regulate mRNA transcription (51).

Postmortem studies on brain structure in FXS have been instrumental in understanding how a genetic defect in FMR1 leads to cognitive and behavioral problems. Interestingly, gross morphological examinations report mac-rocephaly and increased brain weight in FXS (52), which is unusual in genetic conditions. In situ hybridization studies for FMR1-mRNA and immunohistochemistry and Western blot studies for FMRP have localized the regions within the body that typically express the FMR1 gene. Not surprisingly, FMR1 is expressed in brain tissue during normal human development. FMR1-mRNA is highly expressed in fetal CNS tissue at 8-9 mo of gestation, particularly in the telencephalon (53). As development continues, there is evidence that expression of FMR1-mRNA becomes more specific. Abitbol et al. found that at 25 mo of age, FMR1 mRNA is most strongly expressed in deep structures (hippocampus, putamen, diencephalon), ventricular and subventricular areas, the neocortical plate, and the cerebellum. Similarly, monoclonal antibodies to FMRP bind strongly to adult brain tissue (54). In cerebellar tissue, Purkinje cells were most reactive. Cerebral tissue showed FMRP expression most prominently in the cytoplasm and proximal regions of dendrites and axons.

Histological studies of the brain have consistently shown abnormalities of neuron structure in FXS. Specifically, the dendritic spines in brains of persons with FXS are longer and thinner when compared to the "mushroom shape" of mature spines seen in typically developing individuals (52,55-58). Long, thin spines in FXS resemble the immature spines of healthy controls and indicates that FMRP may play a role in synaptic development. This hypothesis is supported by observations that dendritic spines are more densely packed in FXS, which suggests a failure of natural synaptic pruning during dendrite formation (56). A recent study found that FMRP interacts with two other proteins, CYFIP1 and CYFIP2 (59). Although the precise functions of these proteins are not yet known, recent studies have shown that CYFIP1 interacts with other proteins (members of the Rho family of GTPases) that have roles in the dynamic reorganization of the actin cytosk-eleton (60). They also play a role in the formation and maintenance of dendritic spines (61). Thus CYFIP1 may be the important link between FMRP and the observed neuromorphological changes seen in FXS.

Imaging studies have allowed a new perspective on the global effects of the fragile X mutation. In addition to macrocephaly, MRI samples had the statistical power to detect morphological differences in localized regions of the brain. The hippocampus, in particular, has been shown to be larger in FXS (62,63). Two studies that specifically examined the posterior fossa found decreases in the size of the posterior vermis in both males and females (particularly lobules 6 and 7) compared to normally developing controls and persons with nonspecific mental retardation (64-66). Conversely, relative increases were seen in the caudate nucleus, thalamus, and lateral ventricular volumes (67).

How these anatomic changes relate to the genetic, molecular, and behavioral characteristics of FXS is still unclear. Mostofsky et al. have found significant correlations between the size of the posterior vermis and verbal (Partial regression coefficient [pr2] = 0.150; p < 0.01) and performance (pr2 = 0.099; p < 0.05) IQ in 37 females with FXS (66). Two functional imaging studies provide additional evidence of the neural substrates of the FXS behavioral phenotype. During tests of visual-spatial working memory, Kwon et al. found that whereas 15 typically developing female control subjects had increased activation in the inferior and middle frontal gyrus and superior parietal and supramarginal gyrus as task difficulty increased, 10 subjects with FXS did not (68). Subjects with FXS also performed worse than controls during the more difficult tests of working memory. Further, Menon et al. found significant correlation between both FMRP expression and activation ratio (fraction of cells with the FMRI gene active) and activation bilaterally in the middle frontal gyrus (right r = 0.71, p = 0.022; left r = 0.81, p = 0.004), right inferior frontal gyrus (r = 0.69, p = 0.027), and the right supramarginal gyrus (r = 0.7, p = 0.024) (69).

Because of excellent research on genetic, molecular, neuroanatomical, neurophysiological, and behavioral levels, FXS is a prime example demonstrating the promise of neurogenetic investigation. FXS, however, presents several difficulties and mysteries of its own. Unlike DS and WMS in which extra or missing genes usually appear within the genome de novo, the genetic mechanism that primarily causes FXS (CGG trinucleotide repeat expansion)

is not clear cut. Inactivation of FMR1 generally occurs when the number of (CGG)« repeats exceeds 200; however, typically developing individuals have approx 5-50 repeats. As the number of repeats increases, so too does the probability of transcriptional silencing. When an individual has 50-200 repeats they are considered to have a premutation. Most studies agree that the premutation is not associated with cognitive and psychiatric problems, but there is some evidence that large premutations may indeed have an abnormal effect (70). Thus, the existence of a premutation, particularly combined with the sex-linked nature of FXS and its differential effect on males and females, changes a relatively "ideal" single-gene disorder into a more challenging family of conditions.

2.4. FMR1 Knockout Mouse: Example of Animal Models in Neurogenetics

The FMR1 knockout mouse was generated to study FXS under highly controlled experimental conditions and is an excellent example of the power of this type of research. The FMR1 gene shares 97% homology between mice and humans (71), and this loss-of-function mouse model has become a valuable tool for understanding the FMR1 mutation. Since its creation in 1994 (72), studies have shown that the FMR1 knockout mouse has similar neuropathological findings and physical anomalies when compared to persons with FXS. Like males with FXS, male knockout mice have enlarged testes, learning deficits, and hyperactivity (72). Differences in learning, as assessed by a water maze task, seem to be relatively mild in these mice (73,74). Fisch et al., 1999 studied the FMR1 knockout mouse for learning capacity. In an operant conditioning paradigm, older and naive mice could learn to discriminate visual from auditory stimuli, even when the task was quite difficult, raising questions about this mutant mouse's suitability as a cognitive-genetic model. In addition, recent studies have demonstrated that the FMR1 knockout mouse has an increased likelihood for audiogenic seizures and startle responses to loud noises when compared to wild-type mice (75,76). Given that persons with FXS have increased sensitivity to sensory stimuli (which may be associated to autistic-like behavior) (71,77), audiogenic seizures in the FMR1 knockout mouse may be related to abnormal auditory processing.

Equally intriguing are investigations into the neuropathology of the FMR1 knockout mouse. As in FXS, dendritic spine abnormalities have been reported (78,79). Specifically, these mice have significantly longer, more immature dendritic spines than wild-type control mice. There is also some evidence of increased spine density in the FMR1 knockout. These findings suggest that FMR1 is necessary for normal pruning and development of dendritic spines, and is yet another similarity between FXS and the murine FMR1 model.

Thus far, abnormal dendritic morphology is the only confirmed neuroana-tomical feature of the FMR1 knockout mouse. Although the learning deficits in this mutant mouse would suggest that FMR1 plays a role in long-term potentiation (LTP), no differences compared to control mice were found when hippocampal slices were stimulated electrically (80,81). This finding is in contrast to experiments using other types of knockout mice that also perform poorly in water mazes but do show differences in LTP when compared to control mice (82,83).

Although experiments using the FMR1 knockout mouse provide a wealth of new data on the nature of FXS, several limitations are also apparent. First, the mechanism of FMR1 inactivation differs between it's the mouse model and its human counterpart; whereas FXS typically results from a CGG trinucleotide expansion, the FMR1 knockout mouse was created using homologous recombination (72). Second, the FMR1 gene homologue in mice is not identical to FMR1, raising the possibility that it may have a different function. However, two studies provide evidence that the murine homologue has a similar role as FMR1. A study using antibodies against human FMRP found that binding occurred with a high specificity for mouse neurons (84). Glial cells were not labeled. The second study used a yeast-artificial chromosome (YAC) containing the human FMR1 gene in an attempt to "rescue" FMR1 knockout mice from the affected phenotype (85). Interestingly, the presence of human FMRP in the mouse was able to prevent some alterations in physical development and produced anxiety reduction, although other behavioral problems arose as a result of FMR1 overexpression.

From the neuroanatomical and behavioral perspectives, the FMR1 knockout mouse raises several questions. Despite striking similarities with the fragile X phenotype at the cellular level, no global structural changes have been observed in the mouse (86). This is a matter of concern given the relatively robust findings of macrocephaly in FXS, as well as the findings in the hippocampus, posterior fossa, and thalamus. Similarly, the FMR1 mouse model is unlikely to explain some of the typically human aspects of higher cognition affected in FXS, such as language and social communication problems.

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