Realizing the Potential of Behavioral Neurogenetics Research

MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 6: 186–197 (2000)

BRAIN IMAGING IN NEUROGENETIC CONDITIONS:REALIZING THE POTENTIAL OF BEHAVIORAL NEUROGENETICS RESEARCH

Allan L. Reiss,* Stephan Eliez, J. Eric Schmitt, Anil Patwardhan, and Michael Haberecht Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California

Behavioral neurogenetics research is a new method of scientific research methods as applied to both anatomical and functional inquiry that focuses on investigation of neurodevelopmental dysfunction brain imaging. associated with specific genetic conditions. This research method provides a powerful tool for scientific inquiry into human gene–brain–behavior link- In this article we review five important genetic conditions ages that complements more traditional research approaches. In particular, that give rise to developmental, cognitive, and neuropsychiatric the use of specific genetic conditions as models of common behavioral and dysfunction during childhood: fragile X syndrome, velo-cardio- cognitive disorders occurring in the general population can reveal insights facial syndrome, Williams syndrome, Turner syndrome, and into neurodevelopmental pathways that might otherwise be obscured or Klinefelter syndrome. Although emphasis is placed on neuro- diluted when investigating more heterogeneous, behaviorally defined subject groups. In this paper, we review five genetic conditions that commonly anatomical findings derived from imaging studies, relevant data give rise to identifiable neurodevelopmental and neuropsychiatric disability obtained from molecular genetic, postmortem, and neurobehav- in children: fragile X syndrome, velo-cardio-facial syndrome, Williams syn- ioral investigations of individuals with these conditions also are drome, Turner syndrome, and Klinefelter syndrome. While emphasis is provided. Accordingly, the goal of this review is to illustrate placed on describing the brain morphology associated with these conditions as revealed by neuroimaging studies, we also include information how behavioral neurogenetics investigation can lead to an im- pertaining to molecular genetic, postmortem, and neurobehavioral investi- proved understanding of complex linkages among genetic, neuro- gations to illustrate how behavioral neurogenetics research can contribute biological, and behavioral variables that contribute to neurode- to an improved understanding of brain disorders in childhood. velopmental and neuropsychiatric dysfunction in children. © 2000 Wiley-Liss, Inc. MRDD Research Reviews 2000;6:186–197. FRAGILE X SYNDROME In one of every 2,000 to 4,000 live births [Gustavson et Key Words: fragile X syndrome; velo-cardio-facial syndrome; Turner syndrome; Klinefelter syndrome; neuroimaging; neurodevelopmental disor- al., 1986; de Vries et al., 1997], a specific single gene mutation ders alters the course of brain development resulting in the fragile X syndrome, one of the most common inherited causes of developmental disability. The fragile X mutation influences developmental pathways that modulate physical appearance, cognitive esearch efforts focused on subdividing behaviorally or ability, and adaptive behavior. Physical manifestations of the phenomenologically defined syndromes into etiologi- syndrome, although variable, include a long and narrow face, Rcally meaningful subgroups are essential to our eventual large ears, and a prominent jaw [Meryash et al., 1984; Loesch understanding of the pathogenesis of childhood-onset neurode- and Hay, 1988; Davids et al., 1990]. These features, combined velopmental and neuropsychiatric disorders. However, a com- with macroorchidism, often are observed among postpubertal plementary research strategy that our laboratory has promoted males [Lachiewicz and Dawson, 1994]. However, physical char- over the past decade focuses on multi-level scientific study of acteristics are particularly variable among prepubertal children individuals with known or suspected homogenous genetic eti- and females and thus are insufficient for making a reliable ology for neuropsychiatric, cognitive, and developmental dys- diagnosis of the condition. function. The term “behavioral neurogenetics” was coined to Investigations of cognitive and behavioral features associ- represent this novel research approach [Baumgardner et al., ated with fragile X syndrome demonstrate a predisposition for a 1994; Reiss and Freund, 1998]. A basic premise of behavioral particular neurobehavioral profile [Turk, 1992; Freund et al., neurogenetics research is the need for multi-level investigation that includes quantitative assessment of genetic factors, brain structure and function, neurobehavioral processes, and environ- Grant sponsor: NIMH; Grant number: MH01142 (Reiss); Grant sponsor: NICHD; Grant number: HD31715 (Reiss); Grant sponsor: NIMH; Grant number MH50047 mental influences. As such, behavioral neurogenetics research (Reiss); Grant sponsor: NICHD; Grant number: HD33113 (Bellugi); Grant sponsor: necessitates the development of expertise, knowledge, and pro- M.I.N.D. Institute; Grant number: K992247-01 (Reiss); Grant sponsor: NICHD; ductive collaborations in clinical research design and method- Grant number HD10032 (Bender) *Correspondence to: Allan L. Reiss, M.D., Child Psychiatry, 401 Quarry Rd., Rm. ology, molecular, medical, and behavioral genetics, psychoneu- 1114, Stanford, CA 94305-5719. roendocrinology, computers and software programming, and

© 2000 Wiley-Liss, Inc. 1993; Einfeld et al., 1994; Warren and tion responsible for the syndrome was and not in glial cells, axons, or oligoden- Ashley, 1995]. This phenotype is differ- identified [Rousseau et al., 1991; trocytes [Feng et al., 1997; Tamanini et ent for males and females, potentiated by Verkerk et al., 1991], spurring an in- al., 1997]. the fact that the syndrome is X-linked. crease in molecular genetic research re- Magnetic resonance imaging Females, heterozygous for the fragile X garding fragile X syndrome. The syn- (MRI) studies of both children and adults full mutation, typically have either mild drome most often results from an have further localized the neuroanatomi- mental retardation or normal cognitive expansion of the number of cytosine- cal effects of the FMR1 full mutation. functioning accompanied by learning guanine-guanine (CGG) triplet repeats Structural MRI studies of the posterior difficulties, particularly math, [Riddle et occurring within the initial (5Ј) untrans- fossa of the brain show that the cerebellar al., 1998]. Behaviorally, females with lated portion of FMR1—the Fragile X vermis is decreased in size (particularly fragile X syndrome often exhibit atten- Mental Retardation gene [Kremer et al., lobules VI and VII) in both males and tion deficit, anxiety, and difficulties with 1991]. Inheritance of an instability in the females and that the fourth ventricle is socialization [Freund et al., 1993]. Reli- CGG region causes an increase from the enlarged [Reiss et al., 1991a; 1991b; ant upon a single X chromosome in each normal number of CGG repeats (Ϸ6– Mostofsky et al., 1998]. The study by cell (i.e., hemizygous), males with the full 40) to premutated status (50–200) or Mostofsky et al. [1998] also separately mutation almost always function cogni- from premutation to full mutation (Ͼ200 investigated the effect of the FMR1 gene tively in the range of mental retardation. CGG repeat). The stability of the CGG methylation on the development of the Their IQ scores usually reflect moderate repeat depends primarily on its length vermis in females with fragile X and to severe mental retardation and may de- (i.e., number of repeats), and probably demonstrated a significant correlation cline during middle childhood [Hodapp also on the presence of AGG islets an- between posterior vermis size and activa- et al., 1990]. Specific areas of cognitive choring the region [Zhong et al., 1995]. tion ratio. Moreover, decreased size of deficit for males include visual-spatial The gender of the individual who passes the vermis is significantly associated with abilities, visual-motor coordination, and the mutation to their offspring can influ- lower scores on verbal and performance short-term memory [Kemper et al., ence CGG stability. When over 200 IQ scales [Mostofsky et al., 1998] and 1988; Crowe and Hay, 1990; Freund et CGG repeats are present, hyper-methyl- with increased stereotypic behavior al., 1993]. Males experience develop- ation of the promoter region of FMR1 is [Mazzocco et al., 1998]. Mostofsky sug- mental delays in communication and highly probable [Oberle et al., 1991]. gested two possible explanations for the cognition more frequently than in motor Consequently, the transcription and correlation between the reduction of and adaptive behaviors [Bailey et al., translation of FMR1 is not possible. This posterior vermis with cognitive perfor- 1998]. Common behavioral patterns ob- “transcriptional silencing” of the gene mance. First, posterior vermis and cere- served among males with fragile X syn- and the subsequent diminished or absent bellum might be directly contributing to drome include hyperactivity, autistic fea- production of the FMR1 protein results deficits since this area is putatively in- tures, difficulties with peer interaction, in aberrant brain development and func- volved in higher order function [Hallett abnormal social communication, gaze tion [Devys et al., 1993; Tamanini et al., and Grafman, 1997; Parsons and Fox, avoidance, and motor stereotypies 1997]. [Lachiewicz and Dawson, 1994; Baum- To date, few neuropathology re- 1997]. Second, posterior vermis alter- gardner et al., 1995; Turk and Cornish, search studies have investigated the frag- ation could serve as a temporal marker, 1998]. Although these findings suggest a ile X mutation’s effect on brain develop- indicating a period of time in which the specific cognitive and behavioral profile, ment. A small number of autopsy studies fragile X mutation has the most promi- the variability in observations and the have indicated abnormalities in the den- nent effect. Dysgenesis of other brain re- shared characteristics with other disorders dritic arborization in the cerebral cortex gions, sharing a similar time course with such as autism [Feinstein and Reiss, of affected males [Rudelli et al., 1985; the cerebellar vermis, would explain the 1998] prohibit accurate identification of Hinton et al., 1991; Wisniewski et al., cognitive deficits associated with this the presence of the condition based 1991]. Studies investigating the localiza- condition. In investigations of mesio- merely upon particular cognitive and be- tion of FMR1 mRNA during mamma- temporal structures, our lab has reported havioral features. lian development have pointed to neu- that volumes of the hippocampus, a Valid diagnosis of fragile X syn- ronal localization and particularly high structure known for its role in learning drome is reliant upon genetic testing gene expression in the hippocampus, cer- and memory, are increased among indi- [Rousseau et al., 1991], and methods for ebellum (Purkinje cells), and nucleus viduals with fragile X syndrome [Reiss et diagnosis have improved considerably basalis [Devys et al., 1993; Tamanini et al., 1994; Kates et al., 1997]. However, over the past 10 years. Initially, early al., 1997]. Deficits in the expression of Jakala et al. [1997] found no differences investigations showed that the fragile X the FMR1 protein in neurons appears to in hippocampal volumes but subjectively phenotype cosegregated with an unusual result in abnormal dendritic density assessed atypical appearance of hip- morphological disruption of the X chro- [Comery et al., 1997; Feng et al., 1997]. pocampal morphology. Relatively small mosome [Lubs, 1969]. Karyotyping of The increased density may reflect abnor- sample sizes in both these studies remains cells grown in folate-depleted cell culture mal development of the organizational a serious limitation. Further replication media revealed that many patients had a process of synapse development and sta- to measure the magnitude of volumetric ’fragile’ site on one of their X chromo- bilization and decrement in synaptic change in the hippocampus in fragile X somes that appeared as a constriction on pruning [Comery et al., 1997]. Observed syndrome is necessary. Volumetric aber- the distal long arm [Lubs, 1969]. In the similarities in cerebral white matter de- rations have been detected in other im- past decade, knowledge of the molecular velopment between typically developing portant brain regions, including the cau- genetics of the fragile X syndrome has children and children with fragile X date nucleus [Reiss et al., 1995a]. increased dramatically [Devys et al., [Reiss et al., 1995a] is consistent with the Increased lateral ventricular volumes 1992; Eichler et al., 1993; Kunst et al., fact that the FMR1 protein is normally have been observed among males with 1997]. In 1991 the most common muta- expressed only in the neuronal bodies the full mutation, and enlargement of the

MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. 187 thalamus has been noted among females et al., 1992; Driscoll et al., 1993; Lindsay form in the range of mild to moderate [Reiss et al., 1995a]. et al., 1995; Carlson et al., 1997]. The mental retardation [Golding-Kushner et Collectively, these studies have major features of VCFS include cardiac al., 1985; Goldberg et al., 1993; Ryan et utilized advanced methodology and have malformations, cleft palate or velo- al., 1997; Moss et al., 1999]. Moreover, provided important initial findings con- pharyngal insufficiency, a characteristic an affected child will frequently have a cerning the FMR1 gene, brain develop- facial appearance, and learning disabili- Verbal IQ score that exceeds Perfor- ment, and neurobehavioral phenotype ties. More than 40 physical anomalies mance IQ, a profile suggestive of a non- among persons with fragile X syndrome. have been observed in association with verbal learning disability [Swillen et al., These findings will ultimately help define VCFS [Goldberg et al., 1993; Ryan et al., 1997; 1999; Moss et al., 1999]. better and more targeted treatment. 1997]. The behavioral deficits of the However, more definitive conclusions Genes deleted in the critical region VCFS phenotype have been observed regarding the association between mo- of chromosome 22 are likely to influence with relative consistency and are possibly lecular changes and structural anomalies neurodevelopment in humans. At least related to the deficits in cognitive ability await advances of future research. A 30 genes are encoded in the commonly described above. In a recent study utiliz- comprehensive model of the developmen- deleted segment [Dunham et al., 1999], a ing a preschool pediatric sample, behav- tal impact of the fragile X mutation re- few of which are highly expressed in iors of 9 out of 12 affected children were quires research on four levels: (1) intracel- brain tissue and are likely to be essential rated as highly active, impulsive, highly lular changes relating to protein expression for normal brain development [Gottlieb emotional, or disorganized [Gerdes et al., and function; (2) changes in individual cell et al., 1997; Yamagishi et al., 1999]. For 1999]. Prior studies also have docu- functioning and morphology; (3) subre- example, the UFD1L gene probably mented difficulties with social interac- gional brain tissue development and cytol- plays a key role in the embryonic devel- tions [Golding-Kushner et al., 1985; ogy; and (4) the effects of tissue organiza- opment of the heart and brain [Yamag- Swillen et al., 1997], as well as labile tion on brain volume and function. Recent ishi et al., 1999]. Ufd1 (the mouse ho- behavior ranging from disinhibition to efforts have advanced our knowledge of mologue gene) is expressed specifically in shyness [Golding-Kushner et al., 1985]. the first [Comery et al., 1997; Feng et al., palatal precursors, fronto-nasal regions, Compared to normative data, behavioral 1997; Tamanini et al., 1997], and fourth and neural crest-derived cells forming the ratings of children with VCFS on the levels [Reiss et al., 1994; Kates et al., conotrocal part of the heart. In the brain, Child Behavioral Checklist have indi- 1997; Mostofsky et al., 1998], whereas Ufd1 is expressed with marked specificity cated significant behavioral problems, the mediating pathways between these in the medial telencephalon that forms primarily in the domains of social inter- stages has yet to be elucidated. the hippocampus. Another gene, GSCL action and attention, but also in areas of is expressed in the anterior portion of the thought problems and withdrawn behav- VELO-CARDIO-FACIAL embryo and, in the brain, it is most ex- iors [Swillen et al., 1997; 1999]. It is SYNDROME (VCFS) pressed in the pons and dorsal thalamus possible that these behavioral features are As a subject of scientific interest [Gottlieb et al., 1997; 1998] and thus is premorbid indicators of severe psychiat- and investigation, velo-cardio-facial syn- likely to be involved in the abnormal drome (VCFS) has received increased at- development of the inferior brain and ric disorders in adulthood. Indeed, chil- tention in the recent genetic and psychi- posterior fossa that is observed in VCFS. dren with VCFS are at an increased risk atric literature. For example, 20% of the Although several studies have de- for psychoses including schizophrenia total number of publications on VCFS lineated the physical phenotype associ- [Shprintzen et al., 1992; Chow et al., were published in the past year alone. ated with VCFS, fewer have investigated 1994; Pulver et al., 1994; Bassett and This phenomenon is partially due to the the neurobehavioral and psychiatric phe- Chow, 1999; Gothelf et al., 1999; Mur- acknowledgement of the high frequency notype. Cognitive ability, learning, and phy et al., 1999] and perhaps bipolar dis- of VCFS, making it one of the most speech and language are clearly affected orders as well [Papolos et al., 1996]. One common identifiable causes of cognitive by the 22q11.2 deletion [Golding-Kush- of the first investigations of VCFS and disability. However, this rapid accelera- ner et al., 1985; Scherer et al., 1999]. risk for psychopathology noted an ele- tion in VCFS research is likely attribut- Learning disorders are prevalent among vated incidence of schizophrenia and able to the fact that this condition is the VCFS population and have been schizoaffective disorders among adults associated with an increased risk for man- documented in nearly all neurobehav- with this genetic disorder [Shprintzen et ifestation of specific neuropsychiatric ioral investigations of the syndrome al., 1992]. A subsequent investigation symptoms and may represent a genetical- [Goldberg et al., 1993; Ryan et al., 1997; [Papolos et al., 1996] asserted an etiolog- ly-mediated subtype of schizophrenia Swillen et al., 1997; Moss et al., 1999]. In ical link with bipolar rather than schizo- [Bassett and Chow, 1999]. Additionally, an early clinical study, learning disabilities phrenic disorders; 64% of subjects with the recent genetic breakthrough of the were observed in 99% of a sample of 75 velo-cardio-facial syndrome met the complete sequencing of chromosome 22 cases, making this the most prevalent of DSM-III-R criteria for bipolar disorders, [Dunham et al., 1999] will undoubtedly the identified physical and neurodevel- while only 6% were diagnosed with motivate additional interest in VCFS. opmental features [Goldberg et al., schizoaffective disorder. Recently, evi- Velo-cardio-facial syndrome, a 1993]. Potentially underlying these dence has pointed again towards a pre- congenital, autosomal dominant condi- learning problems, significant deficits in disposition for schizophrenia within the tion first defined by Shprintzen [Shprint- overall cognitive ability resulting in de- VCFS population [Gothelf et al., 1997; zen et al., 1978], is estimated to occur in creased educational achievement have Bassett et al., 1998; Murphy et al., 1999]. at least one per 2,000 to 4,500 live births been commonly observed [Golding- A study of 46 patients with childhood- [Tezenas Du Montcel et al., 1996]. In Kushner et al., 1985; Swillen et al., 1997; onset schizophrenia found that 6.4% had most affected individuals, a de novo 3 Bassett and Chow, 1999]. Children with the 22q11.2 deletion [Nicolson and Rap- Mb deletion at chromosome 22q11.2 is VCFS have IQ scores that are lower than oport, 1999]. Another study detected the responsible for the syndrome [Scambler the population average, and many per- 22q11.2 deletion among 2% of subjects

188 MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. in a random sample of 100 patients with tion among persons with VCFS. curring in WMS are attributable to the schizophrenia [Karayiorgou et al., 1995]. Specifically, frontal lobe tissue tended to hemizygous deletion of ELN, a gene that Despite the observation of serious be enlarged relative to overall reduction codes for the structural protein elastin neurocognitive and psychiatric symp- in brain volume. Normal symmetry of [Ewart et al., 1993]. Elastin is highly ex- toms associated with VCFS, little infor- parietal lobe tissue observed in the com- pressed in skin, connective and cardio- mation exists concerning the neurobiol- parison group was not evident in the vascular tissue, and is the most common ogy and brain development of persons VCFS group. This loss of symmetry was target gene for florescent in situ hybrid- with the syndrome. Most of the studies attributable to a significant reduction of ization (FISH) tests used to confirm the and reported cases rely on qualitative gray matter in the left parietal lobe. The presence of WMS [Oxlund et al., 1988; methods and, for this reason, are re- authors also observed a decrease in right Lowery et al., 1995]. stricted to an anecdotal level of analysis. cerebellar tissue volume due to a dispro- The extent of the deletion in A qualitative analysis of MRI data [Mit- portionate reduction in white matter for WMS is highly consistent from one af- nick et al. 1994], however, concluded this area. The crucial role of the parietal fected individual to another [Brondum- that 9 of 11 study participants with VCFS lobe in memory processes has been dem- Nielsen et al., 1997; Wu et al., 1998]. (mean age ϭ 9.5 years) had visible brain onstrated in many functional imaging This “critical” deletion usually is associ- abnormalities. The most common find- studies [Ungerleider, 1995]. Eliez et al. ated with mild to moderate mental retar- ing in five patients was a small cerebellar hypothesized that, because of the in- dation, with a mean IQ of 60 and ranging vermis. Additionally, reduced volume of volvement of parietal lobe in episodic from 40–100 [Bellugi et al., 1994; 1999]. the posterior fossa was found in four memory retrieval [Shallice et al., 1994], Studies by Bellugi and others have re- cases, and cysts adjacent to the anterior working memory tasks, implicit or ex- vealed that individuals with WMS have a horns of the ventricles were found in plicit recognition memory [Rugg et al., characteristically uneven neurocognitive three. In another study, Chow [Chow et 1998], and long-term memory consoli- profile, with severe deficits in visual-spa- al., 1999b] described 11 adults (mean dation [Shadmehr and Holcomb, 1997], tial ability but with relative preservation age ϭ 28.4, SD ϭ 6.5) with VCFS and alteration of this structure may result in of linguistic competence, particularly in schizophrenia. The most common find- aberrant information storage and retrieval semantics, vocabulary, and affective pros- ing (Ϸ90% of the cases) was the presence and contribute to learning difficulties ob- ody [Udwin et al., 1987; Wang and Bel- of bilateral white matter hyperintensities, served in VCFS. Since functional imag- lugi, 1994; Bellugi et al., 2000]. It is this distributed mainly within the frontal ing studies have demonstrated the role of rare combination of a relatively small ge- lobes. Forty-five percent of the cases had the parietal lobe in the semantic process- netic deletion (approximately 25 genes either cavum septum pellucidum or ca- ing of words [Vandenberghe et al., 1996; spanning a genetic distance of only 2 vum vergae suggesting midline develop- Schlosser et al., 1998], the specific lan- cM), and a strong dissociation between mental defects and 36% had cerebellar guage deficits observed in VCFS could visual and linguistic abilities that has hypoplasia. A number of additional case be partially explained by the reduced pa- prompted some researchers to consider studies [Altman et al., 1995; Lynch et al., rietal lobe volumes found in this syn- WMS a putative genetic model of cog- 1995; Devriendt et al., 1996] also are drome. nitive modularity [Pinker, 1991; Pater- consistent with results from these two Recent investigations of the geno- son et al., 1999]. investigations. type, and the neuroanatomic and neu- However, the neurobehavioral Investigations using quantitative robehavioral phenotype of VCFS have phenotype associated with WMS is more methods are necessary to more accurately led to a better understanding of the path- complex than a simple verbal/visual con- gauge the strength of associations be- ways leading to the cognitive and psychi- trast. Though visual-spatial ability is pro- tween abnormal brain morphology and atric profile observed in this population. foundly impaired, individuals with WMS components of the VCFS neurobehav- Nevertheless, there is a great need for perform facial processing tasks at or ioral phenotype. Only two abstracts and continued research that targets the im- above the level of typically developing one regular publication thus far have re- pact of the VCFS deletion on brain de- controls [Wang and Bellugi, 1994]. Such ported quantitative data in children [Eliez velopment and function. Ideally, refined a large disparity between visual-spatial et al., 2000] or adults [Chow et al., imaging techniques might provide bio- perception and facial recognition suggests 1999a; van Amelsvoort et al., 1999] with logical markers for increased risk of cog- a dissociation between the dorsal VCFS. Chow et al. [1999a] reported an nitive impairment or psychiatric disorder (“where”) and the ventral (“what”) visual overall decrease of gray but not white among affected children and adults. pathways in this syndrome [Wang et al., matter in 11 subjects with VCFS and 1995]. The ability to recognize faces may schizophrenia, even after covarying for WILLIAMS SYNDROME be related to the strong attraction to peo- total brain size. Van Amelsvoort et al. Williams syndrome (WMS) is a ple and social situations that individuals [1999] described smaller total and left relatively rare (one in approximately with WMS typically show [Reilly et al., temporal lobe size and loss of ventricular 20,000 live births) [Grimm and Wessel- 1990; Jones et al., 2000], though unusual asymmetry among seven adults with hoeft, 1980] neurogenetic disorder social behaviors accompanying this hy- VCFS compared to eight matched con- caused by a hemizygous microdeletion persociality often interfere with the abil- trols. Eliez et al. [2000] compared 15 on chromosome 7 (7q11.23). The phys- ity to successfully interact with other children and adolescents with VCFS with ical characteristics of the syndrome in- people [Einfeld et al., 1997]. Perhaps the 15 individually age- and gender-matched clude distinct facies, cardiac malforma- most unique cognitive characteristic controls. Total brain volume was ap- tions, particularly supravalvular aortic found in WMS is a profound love of proximately 11% smaller in the VCFS stenosis (SVAS), hyperacusis, delayed de- music, sound, and rhythm [Sacks, 1995; group due to a significant decrease in velopment, short stature, hypercalcemia, Levitin and Bellugi, 1998]. both gray and white matter volume. In- and a failure to thrive in infancy [Morris Individuals with WMS are at risk vestigation of lobar morphology indi- et al., 1988; Einfeld et al., 1997; Bellugi for a variety of psychiatric and neurolog- cated a distinct pattern of regional varia- et al, 1999]. Many physical problems oc- ical problems. In particular, anxiety is

MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. 189 commonly found in WMS [Einfeld et al., 1997]. Problems with distractability and impulsivity also are frequently reported [Chapman et al, 1996; Bawden et al., 1997; Power et al., 1997]. Indeed, attention deficit hyperactivity disorder (ADHD) was diagnosed in 84% of children with WMS in an initial study by Morris [Morris et al., 1988] and at a rate that was four times that of a control group in a study by Finegan [Finegan et al., 1994]. Significant advances recently have been made in identifying and character- izing the genes found in the critical WMS deletion region. As expected, many genes are expressed in human brain tissue. Of these, several (STX1A, FZD3, and LIM-1, among others) have well- documented roles in brain development and synaptic transmission and are there- fore possible contributors to the neurocognitive and neuroanatomic phenotype of WMS. STX1A, for example, codes for syntaxin 1A, a docking protein for synaptic vesicle exocytosis [Nakayama et al., 1998]. The mouse homolog of FZD3 has a known function in rostrocaudal neurodevelopment and cell differentiation [Chapman et al., 1996; Bawden et al., 1997; Power et al., 1997; Wang et al., 1997; 1999]. Finally, LIM-1 kinase plays a role in axon guidance, and its partial Fig. 1. Neuroanatomy of Williams syndrome (WMS) as demonstrated by a typical subject with expression has been linked to the visual- WMS and an age- and gender-matched typically developing control (CON). The midsagittal view spatial problems observed in WMS demonstrates the characteristically decreased posterior corpus callosum and relatively increased cerebellar vermis associated with WMS, while the superior and lateral rendered surfaces show [Frangiskakis et al., 1996; Wang et al., decreased parietal volumes and dorsolateral curtailment, respectively. 1998]. While over 30 genetics papers have been published on WMS in the last two years alone, only a handful of neuro- pared to typically developing controls pathological and neuroimaging studies vermal lobules VI-VII [Bellugi et al., [Wang et al., 1992a]. exist. Nevertheless, these studies reveal a 1990; Jernigan and Bellugi, 1990], and The posterior cerebrum (parietal unique neuroanatomy that appears con- preservation of the neocerebellar tonsils and occipital lobes) in WMS is signifi- sistent with the cognitive profile of in WMS [Wang et al., 1992b]. cantly more reduced than frontal and WMS and with what is known about More recent imaging studies using temporal regions [Reiss et al., 2000]. human brain function. Initial imaging high-resolution scanning techniques, This posterior reduction is undoubtedly studies comparing small numbers of sub- larger samples, and advanced tissue seg- related to brain shape differences in jects with WMS to subjects with Down mentation and parcellation protocols WMS that have been described recently syndrome (DS) showed global cerebral have helped to further quantify the shape [Schmitt et al., 2000]. Specifically, both tissue reduction in subjects with WMS, and structure of the WMS brain [Reiss et cerebral hemispheres and the corpus cal- but with preservation of temporal-limbic al., 2000] (Fig. 1). In addition to con- losum show reduced curvature in indi- structures [Jernigan et al., 1993] and the firming earlier findings of decreased ce- viduals with WMS compared to age- and cerebellum [Bellugi et al., 1990; Jernigan rebral and preserved cerebellar volumes gender-matched typically developing and Bellugi, 1990; Jernigan et al., 1993]. (13%), these studies also have found spe- controls, seemingly owed to truncated Both the DS and WMS groups had brain cific reductions in the right occipital lobe posterior cerebral development (P Ͼ tissue reductions that were significantly and brainstem, and bilateral preservation 0.001). Gross anatomical studies by Ga- smaller than the typically developing of the superior temporal gyrus (STG) in laburda and Bellugi [2000] also show ev- control group. Subjects with DS ap- WMS when compared to typically de- idence of posterior cerebral hypoplasia, peared to have a more even reduction in veloping controls. Overall, white matter particularly in the superior-inferior (dor- cerebral brain volume (including signifi- is more significantly reduced in volume sal/ventral) dimension (see Fig. 1). cantly reduced cerebellar volumes), while in WMS when compared to gray matter. It is intriguing to speculate on how subjects with WMS appeared to have Supporting evidence for white matter neuroanatomical variations in WMS may volume reductions centered in posterior differences in WMS also comes from re- be associated with the neurocognitive cerebral regions. Further investigation of ports of decreased size of the corpus cal- and neurobehavioral profiles that have the cerebellum revealed preservation of losum in 11 subjects with WMS com- been described. For example, neuroana-

190 MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. tomic reductions in posterior cerebral ability [Waber, 1979; Downey et al., investigation that inquired whether im- and callosal regions may be related to 1989; Reiss et al., 1995b; Romans et al., printing of a genetic locus on the X chro- visual-spatial deficits in WMS. Findings 1998]. Difficulties with visual-motor mosome may influence outcome in TS of preserved volume of the superior tem- drawing and visual memory have been [Skuse et al., 1999]. Skuse et al. reported poral gyrus appears to correlate well with demonstrated using the Rey-Osterreith that individuals with TS and a paternally preserved linguistic functions, face recog- Complex Figure Test [Netley and retained X chromosome possess better nition, and musical abilities found in Rovet, 1982a; Downey et al., 1989; Ro- verbal, executive, and social skills when WMS. Other brain regions also are of mans et al., 1998]. Researchers also have compared to individuals with a maternal interest. The cerebellum, consistently shown that children with TS perform X chromosome. The authors postulated preserved in WMS, is enjoying new at- relatively poorly on cognitive tasks that that these skills together mediate im- tention as a structure that performs are linked to executive function such as proved social interaction in the subgroup higher cognitive functions in addition to the Wisconsin Card Sorting Test, Tower of patients with a paternal X chromo- balance and motor coordination [Leiner of Hanoi, and tests of verbal fluency some and may account for phenotypic et al., 1993; Ackermann et al., 1998; [Waber, 1979; Romans et al., 1998]. variability in social cognition in TS. Dolan, 1998]. In particular, lesion and Previous investigations have as- Abnormalities in cognitive and functional imaging studies have found sessed hypotheses proposing cerebral lat- psychosocial abilities in TS subjects likely evidence for a cerebellar role in verbal eralization of cognitive impairments in reflect underlying aberrant brain devel- working memory and social function TS. While several studies have found opment and function in this disorder. [Desmond et al., 1997; Schmahmann and atypical cortical organization in TS com- Neuropathological information collected Sherman, 1998]. It is possible that cere- pared to controls, the neuroanatomical from a small number of postmortem ex- bellar hyperplasia is at least partially re- localization of cognitive impairments to aminations of the brain has revealed vari- sponsible for hypersocial behavior and either the left or right hemisphere has able results although it suggests overall linguistic preservation in WMS. This hy- been inconsistent. A spectrum of cerebral decreased cortical organization. More pothesis is further supported by reports of specialization has been reported, ranging specifically, changes in the posterior fossa cerebellar hypoplasia in VCFS, fragile X from focal right parietal dysfunction and possible neuronal migration deficits syndrome, and autism, all which typically [Money, 1973] to bilateral hemispheric were observed [Gullotta and Rehder, result in withdrawn, hyposocial behav- deficits in the frontal and parietal lobes 1974; Molland and Purcell, 1975; Urich, iors [Courchesne et al., 1988; Reiss et al., [Waber, 1979]. The variability of cere- 1979; Reske-Nielsen et al., 1982; Della 1988; Saitoh and Courchesne, 1998; bral lateralization in TS may be explained Giustina et al., 1985]. Eliez et al., 2000]. by a neurodevelopmental hypothesis With the advent of neuroimaging, proposed by Rovet [1990]. This model structural studies have been used to char- TURNER SYNDROME suggests that TS individuals undergo ab- acterize the neuroanatomical basis of ex- Turner syndrome (TS), a genetic errant neural development that results in ecutive and visual-spatial cognition in disorder characterized by partial or com- altered cerebral specialization. Many fac- TS. An early volumetric MRI study plete absence of one of the two X chro- tors that regulate neuronal migration or showed decreased size of the right pari- mosomes in a phenotypic female, occurs cellular organization may influence the etal lobe as well as a number of other in approximately one in 2,500 to 5,000 mature neurocognitive phenotype in TS structures including the caudate, hip- live births [Nyborg and Nielsen, 1977; and may explain in part the inter-indi- pocampus, and cerebellum [Murphy et Hook and Warburton, 1983]. Atypical vidual variability in cerebral and hemi- al., 1993]. In a case study of 10-year-old physical and neurocognitive characteris- spheric specialization. prepubertal monozygotic twins discor- tics result from the expression of one Despite manifesting relative defi- dant for X monosomy and TS, there copy of a selected number of X-chromo- cits in the visual-spatial domain of cog- were decreased gray matter volumes in some genes rather than the two copies nition, individuals with TS generally the right prefrontal, right and left poste- required for normal development. Af- possess intact verbal skills. Reports of rior parietal and right occipital cortices fected females share common physical standardized cognitive tests indicate that [Reiss et al., 1993] in the affected twin. characteristics including short stature, average verbal IQ is in the low normal to Furthermore, the affected twin had in- webbed neck, low-set ears, shield chest, normal range, whereas average perfor- creased overall CSF and fourth ventricu- infertility, gonadal dysgenesis, and the mance IQ is almost one standard devia- lar volume, and decreased size of the absence of estrogen, progesterone and tion below the population mean [Garron, cerebellar vermis, medulla, and pons. secondary sexual production. More vari- 1977; Rovet, 1990; Reiss et al., 1995b]. Subsequently, Reiss et al. [1995b] exam- able than the associated physical features, In addition to impairment in non- ined a group of 30 girls with TS for the cognitive phenotype is often marked verbal cognitive processing, many studies volumetric differences in brain structures by deficits in visual-spatial/perceptual have focused on psychosocial behavior in that are known to be linked to executive skills and attention [Pennington et al., the TS population. These investigations and spatial impairments. Consistent with 1985; Romans et al., 1998]. have shown that individuals with TS may earlier studies, decreased relative volumes A number of neuropsychological be more prone to attention deficits and were observed primarily in the region of studies have addressed visual-spatial in- hyperactivity [Rovet, 1986] as well as the parietal lobe (Fig. 2). These three formation processing in females with TS. decreased facial affect recognition and so- volumetric studies reveal proportionally Results indicate that individuals with TS cial flexibility [McCauley et al., 1987]. smaller volumes in the parietal lobe but are particularly impaired in the coding Problems with social cognition may re- variable structural differences in frontal and transforming of visual-spatial infor- sult in maladaptive behavior in school and subcortical structures. An early func- mation. Individuals with TS typically and poor peer relations [Rovet, 1990]. tional imaging study using positron emis- show relative neurocognitive weakness Phenotypic variability in spatial sion tomography (PET) measured cere- for tests assessing roadmap skills, mental cognition and social function within the bral glucose metabolism in five subjects rotation, line orientation, and arithmetic TS population was addressed in a recent with TS. Consistent with the aforemen-

MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. 191 tioned structural studies, this pilot investigation showed decreased glucose metabolism in the right parietal and occipital lobes but not in the frontal lobes [Clark et al., 1990].

KLINEFELTER SYNDROME Occurring in an estimated one in 800 newborn male infants [Abramsky and Chapple, 1997], the 47,XXY karyotype is the most common form of sex- chromosomal aneuploidy. The supernumerary X-chromosome in individuals with 47,XXY is acquired either through an error of nondisjunction during parental gametogenesis or, less frequently, from an error in division during mitosis Fig. 2. The images illustrate the relative decreased proportion of the parietal lobe (outlined in in the zygote [Jacobs et al., 1989]. The white) in a typically developing 13-year-old girl (left) and an age- and gender-matched girl with resulting extra X-chromosome material Turner syndrome (right). Cortical surfaces were rendered from high-resolution 3D SPGR MRI scans using BrainImage 4.x. in phenotypic males is often associated with a collection of atypical physical features commonly referred to as Klinefelter syndrome (KS). 1982b; Ratcliffe et al., 1994] and are con- established, most evidence offering sup- Clinical recognition of KS during sistent with the high incidence of reading port for the effects of KS on brain devel- childhood remains unusual [Ratcliffe et al., disabilities diagnosed in children with KS opment and anatomy has been 1982], with most overt features being iden- [Bender et al., 1986]. Specific deficits in KS inferential. Reduced scores on tests of tified during later sexual maturation and include impairments of verbal memory and language skills [Netley and Rovet, 1984] early adulthood. As originally described by verbal processing speed [Bender et al., and the diagnosis of reading disabilities Klinefelter et al. [1942], hypogonadism and 1989] and reduced performance on tests of [Bender et al., 1986] in KS have led to infertility due to reduced or absent sper- retrieval, reading skill, and verbal IQ [Net- speculation that a left-hemisphere dys- matogenesis continue to be the hallmark ley and Rovet, 1982b]. Delayed speech function is involved. Autopsy studies features of this disorder. Individuals with development also is common in children [Galaburda, 1993] of dyslexic brains, KS also are described as having a gener- with KS [Ratcliffe, 1999] as well as dem- whose cognitive phenotype is similar to ally typical appearance, with taller stature onstrated deficits of auditory processing that of KS men, reveal a loss of the typical [Stewart et al., 1986], smaller head cir- and auditory short-term memory [Graham leftward asymmetry seen in control cumference [Ratcliffe et al., 1994], and et al., 1988]. brains, particularly in the area of the pla- an increased incidence of gynecomastia. There also is an increased inci- num temporale. Men with KS also seem Men with KS have low basal testosterone dence of psychiatric disorders in KS, to be predisposed to the development of levels, and increased follicle stimulating ranging from anxiety and depression to cerebral germ cell tumors although the hormone (FSH), leutinizing hormone psychosis [Mandoki et al., 1991; Bender pathogenic relevance of a supernumerary (LH), and prolactin levels [Schiavi et al., et al., 1995]. Adolescents and young men X-chromosome is still unclear [Arens et 1984] compared to euploidic men. with KS have reduced activity levels, al., 1988; Prall et al., 1995]. Peripubertal increases in estrogen levels self-esteem, and sexual interest compared Despite the high incidence of the [Salbenblatt et al., 1985] also have been to euploidic peer groups [Bancroft et al., 47,XXY karyotype compared to other documented. 1982; Ratcliffe et al., 1982] and often forms of chromosomal aneuploidy, only Although the behavioral and cogni- describe themselves as being more sensi- two imaging investigations on this disor- tive features associated with KS are variable tive, introspective, and insecure [Rat- der have been conducted to date and and often subtle, results from several large- cliffe et al., 1982; Mandoki et al., 1991]. they have produced conflicting results. scale prospective studies of newborns A tendency for passivity and social reluc- Both of these studies involve adult men screened for aneuploidy of the sex chro- tance [Walzer et al., 1978, Theilgaard, with KS recruited from unselected birth- mosome [Sergovich et al., 1969; Lubs and 1984; Stewart et al., 1986] also is seen in cohort populations, resulting in clinically Ruddle, 1970; Bell and Corey, 1974; Ja- men with KS, although the behavioral unbiased yet relatively small samples. In a cobs et al., 1974; Nielsen and Sillesen, phenotype is highly variable. Testoster- high-resolution MR imaging study, 1975; Goad et al., 1976; Walzer and Ger- one supplementation, a common therapy Warwick et al. [1999] first reported re- ald, 1977; Buckton et al., 1980] have for young adolescents and adults with duced whole brain volumes and enlarged helped produce a comprehensive pheno- KS, seems to mitigate these behavioral lateral ventricles in a group of young typic description. These studies provide ev- problems [Mandoki and Sumner, 1991]. adults with 47,XXY compared to idence that men with KS perform normally Elevated mood and energy, increased matched controls. A weak correlation on tests of nonverbal abilities and general sexual drive, and better interpersonal re- between whole brain volumes and IQ, as intelligence but are specifically impaired on lations [Myhre et al., 1970; Nielsen et al., measured by the New Adult Reading measures of language skills [Funderburk 1988] during testosterone treatment have Test (NART) [Nelson and O’Connell, and Ferjo, 1978; Graham et al., 1988]. been reported even when initiation of 1978] and Quick IQ test [Ammons and These deficits seem to be most apparent in treatment is delayed into adulthood. Ammons, 1962], was seen in these sub- areas of verbal fluency and expression Although the clinical features of jects. The neurodevelopmental signifi- [Walzer et al., 1978; Netley and Rovet, the 47,XXY karyotype are now well- cance of these findings remains unclear;

192 MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. DSM or ICD diagnostic criteria that define these important disorders. Accord- ingly, as a field, we are in great need of biological markers and new methodology to improve our understanding of etiolog- ically meaningful subgroups and the pathophysiology of childhood onset brain disorders. As an important complement to on- going scientific inquiry into the etiologies of behaviorally defined syndromes, behavioral neurogenetics research provides a powerful tool for investigation into human gene–brain–behavior linkages. This approach, which combines genetic, neurobi- ological, and neurobehavioral investigation, is designed to improve our knowledge of neural mechanisms underlying human neurodevelopmental and neuropsychiatric dysfunction. In addition to providing critical information about individuals affected with specific genetic conditions, behavioral neurogenetics re- Fig. 3. Left Temporal Lobe Gray volumes and Verbal Fluency scores in men with Klinefelter syndrome treated with testosterone (KSϩT) and without testosterone (KSϪT) [Patwardhan et al., search has potentially wider applicability 2000]. Reprinted with permission from Neurology. as these conditions are looked upon as models of behavioral and cognitive conditions occurring in the general population; for example, fragile X syndrome as however, it does demonstrate that a su- temporal lobe gray matter tissue in a model for autism, social anxiety disor- pernumerary X chromosome seems to KSϪT men compared to controls. Con- der and math disability, VCFS as a model have an adverse effect on brain develop- versely KSϩT men were not signifi- for psychosis, and Klinefelter syndrome ment. Given the apparent excess of the cantly different for any areas of the brain as a model for specific language disability 47,XXY genotypes in people with compared to controls, including the left and dyslexia. schizophrenia [DeLisi et al., 1994], War- temporal lobe. Results from this study Our research, and that of others, wick discusses these findings in compar- show that the 47,XXY karyotype is as- demonstrates that neuropsychology, neu- ison to similar neuroanatomical features sociated with reductions of left temporal ropsychiatry, genetics, and neuroanat- found in schizophrenia [Ward et al., lobe gray matter—an area of the brain omy are all merely different perspectives 1996; Lawrie and Abukmeil, 1998]. Al- thought to be responsible for the verbal on the same intriguing biological puzzle. though their significance remains un- and language impairments often seen in The vast and growing body of knowl- clear, areas of high intensity signal (HIS) men with KS. Moreover, testosterone edge about the etiology of these condi- foci also were increased in 47,XXY sub- supplementation was associated with tions is providing explanations for the jects compared to matched controls. preservation of the left temporal lobe unique behaviors and the cognitive Warwick suggests that their presence volumes to within control values. The strengths and weaknesses that affected in- may reflect the susceptibility of a devel- superior temporal gyrus (STG), an area dividuals manifest. Imaging and other opmentally abnormal brain to brain in- thought to be essential for reading, was techniques that elucidate neuroanatomi- jury or an increased rate of head trauma not found to be principally responsible cal structure and function will, undoubt- in 47,XXY individuals. for the temporal gray matter reductions edly, continue to be key components in In a second high-resolution MR in KSϪT subjects. Reduced scores on a obtaining a more complete understand- study, Patwardhan et al. [2000] investi- test for verbal fluency also were seen in ing of how genetic variations contribute gated the neuroanatomical consequences KSϪT subjects yet were preserved in to the complex human intellect. f of the 47,XXY karyotype in the presence KSϩT men, indicating diminished ver- and absence of testosterone supplemen- bal abilities in untreated men. Scores of ACKNOWLEDGMENTS tation. In contrast to previously pub- verbal fluency and left temporal lobe vol- In addition to grants from the lished findings [Warwick et al., 1999], umes are shown in Fig. 3. NIMH, NICHD, and M.I.N.D Insti- Patwardhan and colleagues measured tute, this research was supported by The segmented areas of the entire brain and CONCLUSIONS David and Lucile Packard Foundation, found that whole brain and lateral ven- Several decades of research on be- The Lynda and Scott Canel Fund for tricular volumes were not significantly haviorally defined syndromes such as au- Fragile X Research, and The Sinclair different between men with 47,XXY tism, attention deficit hyperactivity dis- Foundation. and matched controls. Additionally, sub- order (ADHD), mental retardation, and jects involved in this cohort study were learning disabilities suggest that rapid REFERENCES subdivided into two groups: men with progress toward understanding underly- Abramsky L, Chapple J. 1997. 47,XXY (Klinefelter syndrome) and 47,XYY: estimated rates of KS who received testosterone therapy ing contributory factors may be impeded and indication for postnatal diagnosis with (KSϩT) and those that did not (KSϪT). by the etiological heterogeneity of indi- implications for prenatal counseling [see com- There was a significant reduction in left viduals meeting the widely accepted ments]. Prenat Diagn 17:363–368.

MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. 193 Ackermann H, Wildgruber D, Daum I, et al. 1998. Carlson C, Sirotkin H, Pandita R, et al. 1997. plications for genetic counseling and prenatal Does the cerebellum contribute to cognitive Molecular definition of 22q11 deletions in diagnosis. J Med Genet 30:813–817. aspects of speech production? A functional 151 velo-cardio-facial syndrome patients. Dunham I, Shimizu N, Roe BA, et al. 1999. The magnetic resonance imaging (fMRI) study in Am J Hum Genet 61:620–629. DNA sequence of human chromosome 22. humans. Neurosci Lett 247:187–190. Chapman CA, du Plessis A, Pober BR. 1996. Neu- Nature 402:489–495. Altman DH, Altman NR, Mitnick RJ, et al. 1995. rologic findings in children and adults with Eichler EE, Richards S, Gibbs RA, et al. 1993. Fine Further delineation of brain anomalies in Williams syndrome. J Child Neurol 11:63– structure of the human FMR1 gene. Hum velo-cardio-facial syndrome. Am J Med 65. Mol Genet 2:1147–1153. Genet, 60:174–175. Chow EW, Bassett AS, Weksberg R. 1994. Velo- Einfeld SL, Tonge BJ, Florio T. 1994. Behavioural Ammons RB, Ammons CH. 1962. Quick IQ test. cardio-facial syndrome and psychotic disor- and emotional disturbance in fragile X syn- Arens R, Marcus D, Engelberg S, et al. 1988. ders: implications for psychiatric genetics. drome. Am J Med Genet 51:386–391. Cerebral germinomas and Klinefelter syn- Am J Med Genet 54:107–112. Einfeld SL, Tonge BJ, Florio T. 1997. Behavioral drome. A review. Cancer 61:1228–1231. Chow E, Zipursky RB, Mikulis D, et al. 1999a. and emotional disturbance in individuals with Bailey DB, Jr., Hatton DD, Skinner M. 1998. Early MRI findings in adults with 22q11 deletion Williams syndrome. Am J Ment Retard 102: developmental trajectories of males with frag- syndrome (22qDS) and schizophrenia. 45–53. ile X syndrome. Am J Ment Retard, 103:29– Schizophr Res 36:89. Eliez S, Schmitt JE, White C, et al. 2000. Children 39. Chow EW, Mikulis DJ, Zipursky RB, et al. 1999b. and adolescents with velo-cardio-facial syn- Bancroft J, Axworthy D, Ratcliffe S. 1982. The Qualitative MRI findings in adults with drome: A volumetric Study. Amer J Psychi- personality and psycho-sexual development 22q11 deletion syndrome and schizophrenia. atry 157:409–415. of boys with 47 XXY chromosome constitu- Biol Psychiatry 46:1436–1442. Ewart AK, Morris CA, Atkinson D, et al. 1993. tion. J Child Psychol Psychiatry, 23:169–180. Clark C, Klonoff H, Hayden M. 1990. Regional Hemizygosity at the elastin locus in a devel- Bassett AS, Chow EW. 1999. 22q11 deletion syn- cerebral glucose metabolism in Turner syn- opmental disorder, Williams syndrome. Nat drome: a genetic subtype of schizophrenia. drome. Can J Neurol Sci 17:140–144. Genet 5:11–16. Biol Psychiatry 46:882–891. Comery TA, Harris JB, Willems PJ, et al. 1997. Feinstein C, Reiss AL. 1998. Autism: the point of Bassett AS, Hodgkinson K, Chow EW, et al. 1998. Abnormal dendritic spines in fragile X knock- view from fragile X studies. J Autism Dev 22q11 deletion syndrome in adults with out mice: maturation and pruning deficits. Disord 28:393–405. schizophrenia. Am J Med Genet 81:328–337. Proc Natl Acad SciUSA94:5401–5404. Feng Y, Gutekunst CA, Eberhart DE, et al. 1997. Baumgardner TL, Green KE, Reiss AL. 1994. A Courchesne E, Yeung-Courchesne R, Press GA, et Fragile X mental retardation protein: nucleo- behavioral neurogenetics approach to devel- al. 1988. Hypoplasia of cerebellar vermal lob- cytoplasmic shuttling and association with opmental disabilities: gene-brain-behavior as- ules VI and VII in autism. N Engl J Med somatodendritic ribosomes. J Neurosci 17: sociations. Curr Opin Neurol 7:172–178. 318:1349–1354. 1539–1547. Baumgardner TL, Reiss AL, Freund LS, et al. 1995. Crowe SF, Hay DA. 1990. Neuropsychological Finegan J, Sitarenios G, Smith M, et al. 1994. Specification of the neurobehavioral pheno- dimensions of the fragile X syndrome: sup- Attention deficit hyperactivity disorder in type in males with fragile X syndrome. Pedi- port for a non-dominant hemisphere dysfunc- Children with Williams syndrome: Prelimi- atrics 95:744–752. tion hypothesis. Neuropsychologia 28:9–16. nary findings. Paper presented at the Williams Bawden HN, MacDonald GW, Shea S. 1997. Davids JR, Hagerman RJ, Eilert RE. 1990. Ortho- Syndrome Association Annual Professional Treatment of children with Williams syn- paedic aspects of fragile-X syndrome. J Bone Conference, San Diego. drome with methylphenidate. J Child Neurol Joint Surg [Am] 72:889–896. Frangiskakis JM, Ewart AK, Morris CA, et al. 1996. 12:248–252. de Vries BB, van den Ouweland AM, Mohkamsing LIM-kinase1 hemizygosity implicated in im- Bell AG, Corey PN. 1974. A sex chromatin and Y S, et al. 1997. Screening and diagnosis for the paired visuospatial constructive cognition. body survey of Toronto newborns. Can fragile X syndrome among the mentally re- Cell 86:59–69. J Genet Cytol 16:239–250. tarded: an epidemiological and psychological Freund LS, Reiss AL, Abrams MT. 1993. Psychi- Bellugi U, Bihrle A, Jernigan T, et al. 1990. Neu- survey. Collaborative Fragile X Study Group. atric disorders associated with fragile X in the ropsychological, neurological, and neuroana- Am J Hum Genet 61:660–667. young female. Pediatrics 91:321–329. tomical profile of Williams syndrome. Am J DeLisi LE, Friedrich U, Wahlstrom J, et al. 1994. Funderburk SJ, Ferjo N. 1978. Clinical observa- Med Genet Suppl 6:115–125. Schizophrenia and sex chromosome anoma- tions in Klinefelter (47,XXY) syndrome. J Bellugi U, Wang PP, Jernigan TL. 1994. Williams lies. Schizophr Bull 20:495–505. Ment Defic Res 22:207–212. syndrome: an unusual neurocognitive profile. Della Giustina E, Forabosco A, Botticelli AR, et al. Galaburda A, Bellugi U. 2000. Multi-level analysis In Broman S and Grafman J, editors. Atypical 1985. Neuropathology of the Turner syn- of cortical neuroanatomy in Williams syn- cognitive deficits in developmental disorders: drome. Pediatr Med Chir 7:49–55. drome. J Cog Neurosci 12(suppl):74–88. Implications for brain function. Hillsdale, NJ: Desmond JE, Gabrieli JD, Wagner AD, et al. 1997. Galaburda AM. 1993. Neuroanatomic basis of de- Lawrence Erlbaum. p 23–56. Lobular patterns of cerebellar activation in velopmental dyslexia. Neurol Clin 11:161– Bellugi U, Lichtenberger L, Mills D, et al. 1999. verbal working-memory and finger-tapping 173. Bridging cognition, the brain and molecular tasks as revealed by functional MRI. J Neu- Garron DC. 1977. Intelligence among persons with genetics: evidence from Williams syndrome. rosci 17:9675–9685. Turner’s syndrome. Behav Genet, 7:105–127. Trends Neurosci 22:197–207. Devriendt K, Thienen MN, Swillen A, et al. 1996. Gerdes M, Solot C, Wang PP, et al. 1999. Cogni- Bellugi U, Lichtenberger L, Jones W, et al. 2000. Cerebellar hypoplasia in a patient with velo- tive and behavior profile of preschool chil- The neurocognitive profile of Williams syn- cardio-facial syndrome. Dev Med Child Neu- dren with chromosome 22q11.2 deletion. drome: A complex pattern of strengths and rol 38:949–953. Am J Med Genet 85:127–133. weaknesses. J Cog Neurosci 12(suppl):7–29. Devys D, Biancalana V, Rousseau F, et al. 1992. Goad WB, Robinson A, Puck TT. 1976. Incidence Bender BG, Puck MH, Salbenblatt JA, et al. 1986. Analysis of full fragile X mutations in fetal of aneuploidy in a human population. Am J Dyslexia in 47,XXY boys identified at birth. tissues and monozygotic twins indicate that Hum Genet 28:62–68. Behav Genet 16:343–354. abnormal methylation and somatic heteroge- Goldberg R, Motzkin B, Marion R, et al. 1993. Bender BG, Linden MG, Robinson A. 1989. Ver- neity are established early in development. Velo-cardio-facial syndrome: a review of 120 bal and spatial processing efficiency in 32 chil- Am J Med Genet 43:208–216. patients. Am J Med Genet 45:313–319. dren with sex chromosome abnormalities. Pe- Devys D, Lutz Y, Rouyer N, et al. 1993. The Golding-Kushner KJ, Weller G, Shprintzen RJ. diatr Res 25:577–579. FMR-1 protein is cytoplasmic, most abundant 1985. Velo-cardio-facial syndrome: language Bender BG, Harmon RJ, Linden MG, et al. 1995. in neurons and appears normal in carriers of a and psychological profiles. J Craniofac Genet Psychosocial adaptation of 39 adolescents fragile X premutation. Nat Genet 4:335–340. Dev Biol 5:259–266. with sex chromosome abnormalities. Pediat- Dolan RJ. 1998. A cognitive affective role for the Gothelf D, Frisch A, Munitz H, et al. 1997. Velo- rics 96:302–308. cerebellum [editorial; comment]. Brain 121: cardiofacial manifestations and microdeletions Brondum-Nielsen K, Beck B, Gyftodimou J, et al. 545–546. in schizophrenic inpatients. Am J Med Genet 1997. Investigation of deletions at 7q11.23 in Downey J, Ehrhardt AA, Gruen R, et al. 1989. 72:455–461. 44 patients referred for Williams-Beuren syn- Psychopathology and social functioning in Gothelf D, Frisch A, Munitz H, et al. 1999. Clinical drome, using FISH and four DNA polymor- women with Turner syndrome. J Nerv Ment characteristics of schizophrenia associated phisms. Hum Genet 99:56–61. Dis 177:191–201. with velo-cardio-facial syndrome. Schizophr Buckton KE, O’Riordan ML, Ratcliffe S, et al. 1980. Driscoll DA, Salvin J, Sellinger B, et al. 1993. Res 35:105–112. A G-band study of chromosomes in live-born Prevalence of 22q11 microdeletions in Di- Gottlieb S, Emanuel BS, Driscoll DA, et al. 1997. infants. Ann Hum Genet 43:227–239. George and velocardiofacial syndromes: im- The DiGeorge syndrome minimal critical re-

194 MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. gion contains a goosecoid-like (GSCL) ho- fragile X syndrome. Am J Med Genet 30: Molland EA, Purcell M. 1975. Biliary atresia and meobox gene that is expressed early in human 191–200. the Dandy-Walker anomaly in a neonate with development. Am J Hum Genet 60:1194– Klinefelter HF, Reifenstein EC, Albright F. 1942. 45,X Turner’s syndrome. J Pathol 115:227– 1201. Syndrome characterized by gynecomastia, 230. Gottlieb S, Hanes SD, Golden JA, et al. 1998. aspermatogenesis without a-Leydigism and Money J. 1973. Turner’s syndrome and parietal Goosecoid-like, a gene deleted in DiGeorge increased secretion of follicle-stimulating hor- lobe functions. Cortex 9:387–393. and velocardiofacial syndromes, recognizes mone. J Clin Endocrinol Metab 2:615–622. Morris CA, Demsey SA, Leonard CO, et al. 1988. DNA with a bicoid-like specificity and is Kremer EJ, Pritchard M, Lynch M, et al. 1991. Natural history of Williams syndrome: phys- expressed in the developing mouse brain. Mapping of DNA instability at the fragile X ical characteristics. J Pediatr 113:318–326. Hum Mol Genet 7:1497–1505. to a trinucleotide repeat sequence p(CCG)n. Moss EM, Batshaw ML, Solot CB, et al. 1999. Graham JM, Jr., Bashir AS, Stark RE, et al. 1988. Science 252:1711–1714. Psychoeducational profile of the 22q11.2 mi- Oral and written language abilities of XXY Kunst CB, Leeflang EP, Iber JC, et al. 1997. The crodeletion: A complex pattern. J Pediatr 134: boys: implications for anticipatory guidance. effect of FMR1 CGG repeat interruptions on 193–198. Pediatrics 81:795–806. mutation frequency as measured by sperm Mostofsky SH, Mazzocco MM, Aakalu G, et al. Grimm T, Wesselhoeft H. 1980. The genetic as- typing. J Med Genet 34:627–631. 1998. Decreased cerebellar posterior vermis pects of Williams-Beuren syndrome and the Lachiewicz AM, Dawson DV. 1994. Do young size in fragile X syndrome: correlation with isolated form of the supravalvular aortic ste- boys with fragile X syndrome have macro- neurocognitive performance. Neurology 50: nosis. Investigation of 128 families (author’s orchidism? Pediatrics 93:992–995. 121–130. transl). Z Kardiol 69:168–172. Lawrie SM, Abukmeil SS. 1998. Brain abnormality Murphy DG, DeCarli C, Daly E, et al. 1993. X- Gullotta F, Rehder H. 1974. Chromosomal anom- in schizophrenia. A systematic and quantita- chromosome effects on female brain: a mag- alies and central nervous system. Beitr Pathol tive review of volumetric magnetic resonance netic resonance imaging study of Turner’s 152:74–80. imaging studies [see comments]. Br J Psychi- syndrome [see comments]. Lancet 342:1197– Gustavson KH, Blomquist HK, Holmgren G. atry 172:110–120. 1200. 1986. Prevalence of the fragile-X syndrome Leiner HC, Leiner AL, Dow RS. 1993. Cognitive Murphy KC, Jones LA, Owen MJ. 1999. High in mentally retarded boys in a Swedish and language functions of the human cerebel- rates of schizophrenia in adults with velo- county. Am J Med Genet 23:581–587. lum [see comments]. Trends Neurosci 16: cardio-facial syndrome. Arch Gen Psychiatry Hallett M, Grafman J. 1997. Executive function 444–447. 56:940–945. and motor skill learning. Int Rev Neurobiol Levitin D, Bellugi U. 1998. Musical abilities in Myhre SA, Ruvalcaba RH, Johnson HR, et al. 41:297–323. individuals with Williams syndrome. Music 1970. The effects of testosterone treatment in Hinton VJ, Brown WT, Wisniewski K, et al. 1991. Percept 15:357–389. Klinefelter’s syndrome. J Pediatr 76:267–276. Analysis of neocortex in three males with the Lindsay EA, Greenberg F, Shaffer LG, et al. 1995. Nakayama T, Matsuoka R, Kimura M, et al. 1998. fragile X syndrome. Am J Med Genet 41: Submicroscopic deletions at 22q11.2: vari- Hemizygous deletion of the HPC-1/syntaxin 289–294. ability of the clinical picture and delineation 1A gene (STX1A) in patients with Williams Hodapp RM, Dykens EM, Hagerman RJ, et al. of a commonly deleted region. Am J Med syndrome. Cytogenet Cell Genet 82:49–51. 1990. Developmental implications of chang- Genet 56:191–197. Nelson HE, O’Connell A. 1978. Dementia: the ing trajectories of IQ in males with fragile X Loesch DZ, Hay DA. 1988. Clinical features and estimation of premorbid intelligence levels syndrome. J Am Acad Child Adolesc Psychi- reproductive patterns in fragile X female het- using the New Adult Reading Test. Cortex atry 29:214–219. erozygotes. J Med Genet 25:407–414. 14:234–244. Hook EB, Warburton D. 1983. The distribution of Lowery MC, Morris CA, Ewart A, et al. 1995. Netley C, Rovet J. 1982a. Atypical hemispheric chromosomal genotypes associated with Strong correlation of elastin deletions, de- lateralization in Turner syndrome subjects. Turner’s syndrome: livebirth prevalence rates tected by FISH, with Williams syndrome: Cortex 18:377–384. and evidence for diminished fetal mortality evaluation of 235 patients. Am J Hum Genet Netley C, Rovet J. 1982b. Verbal deficits in chil- and severity in genotypes associated with 57:49–53. dren with 47,XXY and 47,XXX karyotypes: structural X abnormalities or mosaicism. Lubs HA. 1969. A marker X chromosome. Am J Hum Genet 64:24–27. Hum Genet 21:231–244. a descriptive and experimental study. Brain Jacobs P, Hassold T, Harvey J, et al. 1989. The Lubs HA, Ruddle FH. 1970. Chromosomal abnor- Lang 17:58–72. origin of sex chromosome aneuploidy. Prog malities in the human population: estimation Netley C, Rovet J. 1984. Hemispheric lateraliza- Clin Biol Res 311:135–151. of rates based on New Haven newborn study. tion in 47,XXY Klinefelter’s syndrome boys. Jacobs PA, Melville M, Ratcliffe S, et al. 1974. A Science 169:495–497. Brain Cogn 3:10–18. cytogenetic survey of 11,680 newborn in- Lynch DR, McDonald-McGinn DM, Zackai EH, Nicolson R, Rapoport JL. 1999. Childhood-onset fants. Ann Hum Genet 37:359–376. et al. 1995. Cerebellar atrophy in a patient schizophrenia: rare but worth studying. Biol Jakala P, Hanninen T, Ryynanen M, et al. 1997. with velocardiofacial syndrome. J Med Genet Psychiatry 46:1418–1428. Fragile-X: neuropsychological test perfor- 32:561–563. Nielsen J, Sillesen I. 1975. The incidence of chro- mance, CGG triplet repeat lengths, and hip- Mandoki MW, Sumner GS. 1991. Klinefelter syn- mosome aberrations among 11,148 newborn pocampal volumes. J Clin Invest 100:331– drome: the need for early identification and children. Humangenetik 30:1–12. 338. treatment. Clin Pediatr (Phila) 30:161–164. Nielsen J, Pelsen B, Sorensen K. 1988. Follow-up Jernigan TL, Bellugi U. 1990. Anomalous brain Mandoki MW, Sumner GS, Hoffman RP, et al. of 30 Klinefelter males treated with testoster- morphology on magnetic resonance images in 1991. A review of Klinefelter’s syndrome in one. Clin Genet 33:262–269. Williams syndrome and Down syndrome. children and adolescents [published erratum Nyborg H, Nielsen J. 1977. Sex chromosome ab- Arch Neurol 47:529–533. appears in J Am Acad Child Adolesc Psychi- normalities and cognitive performance: III. Jernigan TL, Bellugi U, Sowell E, et al. 1993. atry 1991 May;30(3):516]. J Am Acad Child Field dependence, frame dependence, and Cerebral morphologic distinctions between Adolesc Psychiatry 30:167–172. failing development of perceptual stability in Williams and Down syndromes. Arch Neurol Mazzocco MM, Pulsifer M, Fiumara A, et al. 1998. girls with Turner’s syndrome. J Psychol 96: 50:186–191. Brief report: autistic behaviors among chil- 205–211. Jones W, Bellugi U, Lai Z, et al. 2000. Hyperso- dren with fragile X or Rett syndrome: impli- Oberle I, Rousseau F, Heitz D, et al. 1991. Insta- ciability in Williams Syndrome. J Cog Neu- cations for the classification of pervasive de- bility of a 550-base pair DNA segment and rosci 12(suppl):30–46. velopmental disorder. J Autism Dev Disord abnormal methylation in fragile X syndrome. Karayiorgou M, Morris MA, Morrow B, et al. 28:321–328. Science 252:1097–1102. 1995. Schizophrenia susceptibility associated McCauley E, Kay T, Ito J, et al. 1987. The Turner Oxlund H, Manschot J, Viidik A. 1988. The role of with interstitial deletions of chromosome syndrome: cognitive deficits, affective dis- elastin in the mechanical properties of skin. 22q11. Proc Natl Acad SciUSA92:7612– crimination, and behavior problems. Child J Biomech 21:213–218. 7616. Dev 58:464–473. Papolos DF, Faedda GL, Veit S, et al. 1996. Bipolar Kates WR, Abrams MT, Kaufmann WE, et al. Meryash DL, Cronk CE, Sachs B, et al. 1984. An spectrum disorders in patients diagnosed with 1997. Reliability and validity of MRI mea- anthropometric study of males with the frag- velo-cardio-facial syndrome: does a hemizy- surement of the amygdala and hippocampus ile-X syndrome. Am J Med Genet 17:159– gous deletion of chromosome 22q11 result in in children with fragile X syndrome. Psychi- 174. bipolar affective disorder? Am J Psychiatry atry Res 75:31–48. Mitnick RJ, Bello JA, Shprintzen RJ. 1994. Brain 153:1541–1547. Kemper MB, Hagerman RJ, Altshul-Stark D. anomalies in velo-cardio-facial syndrome. Parsons LM, Fox PT. 1997. Sensory and cognitive 1988. Cognitive profiles of boys with the Am J Med Genet 54:100–106. functions. Int Rev Neurobiol 41:255–271.

MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. 195 Paterson SJ, Brown JH, Gsodl MK, et al. 1999. Riddle JE, Cheema A, Sobesky WE, et al. 1998. Shprintzen RJ, Goldberg RB, Lewin ML, et al. Cognitive modularity and genetic disorders Phenotypic involvement in females with the 1978. A new syndrome involving cleft palate, [see comments]. Science 286:2355–2358. FMR1 gene mutation. Am J Ment Retard cardiac anomalies, typical facies, and learning Patwardhan AJ, Eliez S, Bender B, et al. 2000. 102:590–601. disabilities: velo-cardio-facial syndrome. Cleft Brain morphology in Klinefelter syndrome: Romans SM, Stefanatos G, Roeltgen DP, et al. Palate J 15:56–62. Extra-X chromosome and testosterone sup- 1998. Transition to young adulthood in Ull- Skuse D, Elgar K, Morris E. 1999. Quality of life in plementation. Neurology 54(12):2218–2223. rich-Turner syndrome: neurodevelopmental Turner syndrome is related to chromosomal Pennington BF, Heaton RK, Karzmark P, et al. changes. Am J Med Genet 79:140–147. constitution: implications for genetic counsel- 1985. The neuropsychological phenotype in Rousseau F, Heitz D, Biancalana V, et al. 1991. ling and management. Acta Paediatr Suppl Turner syndrome. Cortex 21:391–404. Direct diagnosis by DNA analysis of the frag- 88:110–113. Pinker S. 1991. Rules of language. Science 253: ile X syndrome of mental retardation. N Engl Stewart DA, Bailey JD, Netley CT, et al. 1986. 530–535. J Med 325:1673–1681. Growth and development from early to mi- Power TJ, Blum NJ, Jones SM, et al. 1997. Brief Rovet J. 1986, May 25–28, 1986. Processing defi- dadolescence of children with X and Y chro- report: response to methylphenidate in two cits in 45,X females. Paper presented at the mosome aneuploidy: the Toronto Study. children with Williams syndrome. J Autism Meeting of the American Association for the Birth Defects Orig Artic Ser 22:119–182. Dev Disord 27:79–87. Advancement of Science, Philadelphia, PA. Swillen A, Devriendt K, Legius E, et al. 1997. Prall JA, McGavran L, Greffe BS, et al. 1995. Rovet J. 1990. The cognitive and neuropsycholog- Intelligence and psychosocial adjustment in Intracranial malignant germ cell tumor and ical characteristics of females with Turner velocardiofacial syndrome: a study of 37 chil- the Klinefelter syndrome. Case report and syndrome. In Berch D, Bender B, editors. Sex dren and adolescents with VCFS. J Med review of the literature. Pediatr Neurosurg chromosome abnormalities and human be- Genet 34:453–458. 23:219–224. havior: Psychological studies. Boulder: West- Swillen A, Devriendt K, Legius E, et al. 1999. The Pulver AE, Nestadt G, Goldberg R, et al. 1994. ern Press & the Ameican Association for the behavioural phenotype in velo-cardio-facial Psychotic illness in patients diagnosed with Advancement of Science. p 38-77. syndrome (VCFS): from infancy to adoles- velo-cardio-facial syndrome and their rela- Rudelli RD, Brown WT, Wisniewski K, et al. cence. Genet Couns 10:79–88. tives. J Nerv Ment Dis 182:476–478. 1985. Adult fragile X syndrome. Clinico- Tamanini F, Willemsen R, van Unen L, et al. 1997. Ratcliffe S. 1999. Long-term outcome in children neuropathologic findings. Acta Neuropathol Differential expression of FMR1, FXR1 and of sex chromosome abnormalities. Arch Dis 67:289–295. FXR2 proteins in human brain and testis. Child 80:192–195. Rugg MD, Mark RE, Walla P, et al. 1998. Disso- Hum Mol Genet 6:1315–1322. Ratcliffe S, Bancroft J, Axworthy D, et al. 1982. ciation of the neural correlates of implicit and Tezenas Du Montcel S, Mendizabai H, Ayme S, et Klinefelter’s syndrome in adolescence. Arch explicit memory. Nature 392:595–598. al. 1996. Prevalence of 22q11 microdeletion. Dis Child 57:6–12. Ryan AK, Goodship JA, Wilson DI, et al. 1997. J Med Genet 33:719. Ratcliffe SG, Masera N, Pan H, et al. 1994. Head Spectrum of clinical features associated with Theilgaard A. 1984. A psychological study of the circumference and IQ of children with sex interstitial chromosome 22q11 deletions: a personalities of XYY- and XXY-men. Acta chromosome abnormalities. Dev Med Child European collaborative study. J Med Genet Psychiatr Scand Suppl 315:1–133. Neurol 36:533–544. 34:798–804. Turk J. 1992. The fragile-X syndrome. On the way Reilly J, Klima ES, Bellugi U. 1990. Once more Sacks O. 1995. Musical ability. Science 268:621. to a behavioural phenotype. Br J Psychiatry with feeling: Affect and language in atypical Saitoh O, Courchesne E. 1998. Magnetic reso- 160:24–35. populations. Dev Psychopathol 2:367–391. nance imaging study of the brain in autism. Turk J, Cornish K. 1998. Face recognition and Reiss AL, Patel S, Kumar AJ, et al. 1988. Prelimi- Psychiatry Clin Neurosci 52:S219–222. emotion perception in boys with fragile-X nary communication: neuroanatomical varia- Salbenblatt JA, Bender BG, Puck MH, et al. 1985. syndrome. J Intellect Disabil Res 42:490– tions of the posterior fossa in men with the Pituitary-gonadal function in Klinefelter syn- 499. fragile X (Martin-Bell) syndrome. Am J Med drome before and during puberty. Pediatr Udwin O, Yule W, Martin N. 1987. Cognitive Genet 31:407–414. Res 19:82–86. abilities and behavioural characteristics of Reiss A, Freund L. 1998. Behavioral neurogenetics research: A method for analyzing linkages Scambler PJ, Kelly D, Lindsay E, et al. 1992. Velo- children with idiopathic infantile hypercal- among gene, brain and behavior. In Hann D, cardio-facial syndrome associated with chro- caemia. J Child Psychol Psychiatry 28:297– Huffman L, Lederhendler I, Meinecke D, ed- mosome 22 deletions encompassing the Di- 309. itors. Advancing research on developmental George locus. Lancet 339:1138–1139. Ungerleider LG. 1995. Functional brain imaging plasticity: integrating the behavioral science Scherer NJ, D’Antonio LL, Kalbfleisch JH. 1999. studies of cortical mechanisms for memory. and neuroscience of mental health . Bethesda: Early speech and language development in chil- Science 270:769–775. National Institutes of Health.) p. 83–95. dren with velocardiofacial syndrome. Am J Med Urich H. 1979. Cerebellar malformations: some Reiss AL, Aylward E, Freund LS, et al. 1991a. Genet 88:714–723. pathogenetic considerations. Clin Exp Neurol Neuroanatomy of fragile X syndrome: the Schiavi RC, Theilgaard A, Owen DR, et al. 1984. 16:119–131. posterior fossa. Ann Neurol 29:26–32. Sex chromosome anomalies, hormones, and van Amelsvoort T, Daly E, Critchley H. 1999. A Reiss AL, Freund L, Tseng JE, et al. 1991b. Neu- aggressivity. Arch Gen Psychiatry 41:93–99. human genetic model for schizophrenia: roanatomy in fragile X females: the posterior Schlosser R, Hutchinson M, Joseffer S, et al. 1998. brain, structure and function of people with fossa. Am J Hum Genet 49:279–288. Functional magnetic resonance imaging of velo-cardio-facial syndrome. Schizophr Res Reiss AL, Freund L, Plotnick L, et al. 1993. The human brain activity in a verbal fluency task. 36:213. effects of X monosomy on brain develop- J Neurol Neurosurg Psychiatry 64:492–498. Vandenberghe R, Price C, Wise R, et al. 1996. ment: monozygotic twins discordant for Schmahmann JD, Sherman JC. 1998. The cerebel- Functional anatomy of a common semantic Turner’s syndrome. Ann Neurol 34:95–107. lar cognitive affective syndrome [see com- system for words and pictures. Nature 383: Reiss AL, Lee J, Freund L. 1994. Neuroanatomy of ments]. Brain 121:561–579. 254–256. fragile X syndrome: the temporal lobe. Neu- Schmitt J, Eliez S, Bellugi U, et al. 2000. Analysis of Verkerk AJ, Pieretti M, Sutcliffe JS, et al. 1991. rology 44:1317–1324. cerebral shape in Williams syndrome. Arch Identification of a gene (FMR-1) containing a Reiss AL, Abrams MT, Greenlaw R, et al. 1995a. Neurol (in press). CGG repeat coincident with a breakpoint Neurodevelopmental effects of the FMR-1 full Sergovich F, Valentine GH, Chen AT, et al. 1969. cluster region exhibiting length variation in mutation in humans. Nat Med 1:159–167. Chromosome aberrations in 2159 consecutive fragile X syndrome. Cell 65:905–914. Reiss AL, Mazzocco MM, Greenlaw R, et al. newborn babies. N Engl J Med 280:851–855. Waber DP. 1979. Neuropsychological aspects of 1995b. Neurodevelopmental effects of X Shadmehr R, Holcomb HH. 1997. Neural corre- Turner’s syndrome. Dev Med Child Neurol monosomy: a volumetric imaging study. Ann lates of motor memory consolidation. Science 21:58–70. Neurol 38:731–738. 277:821–825. Walzer S, Gerald PS. 1977. A chromosome survey Reiss A, Eliez S, Schmitt J, et al. 2000. Neuroanat- Shallice T, Fletcher P, Frith CD, et al. 1994. Brain of 13,751 male newborns. In: Hook EB, Por- omy of Williams syndrome: A High-resolu- regions associated with acquisition and re- ter IH, editor. Population cytogenetics. New tion MRI study. J Cog Neurosci 12(suppl): trieval of verbal episodic memory. Nature York: Academic Press. p 45–61. 65–73. 368:633–635. Walzer S, Wolff PH, Bowen D, et al. 1978. A Reske-Nielsen E, Christensen AL, Nielsen J. 1982. Shprintzen RJ, Goldberg R, Golding-Kushner KJ, method for the longitudinal study of behav- A neuropathological and neuropsychological et al. 1992. Late-onset psychosis in the velo- ioral development in infants and children: the study of Turner’s syndrome. Cortex 18:181– cardio-facial syndrome. Am J Med Genet 42: early development of XXY children. J Child 190. 141–142. Psychol Psychiatry 19:213–229.

196 MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. Wang JY, Frenzel KE, Wen D, et al. 1998. Trans- cerebellar hemispheric preservation. Neu- study of the brain in subjects with sex chro- membrane neuregulins interact with LIM ki- rology 42:1999–2002. mosome aneuploidies. J Neurol Neurosurg nase 1, a cytoplasmic protein kinase impli- Wang YK, Samos CH, Peoples R, et al. 1997. A Psychiatry 66:628–632. cated in development of visuospatial novel human homologue of the Drosophila Wisniewski KE, Segan SM, Miezejeski CM, et al. cognition. J Biol Chem 273:20525–20534. frizzled wnt receptor gene binds wingless pro- 1991. The Fra(X) syndrome: neurological, Wang PP, Bellugi U. 1994. Evidence from two tein and is in the Williams syndrome deletion electrophysiological, and neuropathological genetic syndromes for a dissociation between at 7q11.23. Hum Mol Genet 6:465–472. abnormalities. Am J Med Genet 38:476–480. verbal and visual-spatial short-term memory. Wang YK, Sporle R, Paperna T, et al. 1999. Char- Wu YQ, Sutton VR, Nickerson E, et al. 1998. J Clin Exp Neuropsychol 16:317–322. acterization and expression pattern of the friz- Delineation of the common critical region Wang PP, Doherty S, Hesselink JR, et al. 1992a. zled gene Fzd9, the mouse homolog of FZD9 in Williams syndrome and clinical correla- Callosal morphology concurs with neurobe- which is deleted in Williams-Beuren syn- tion of growth, heart defects, ethnicity, and havioral and neuropathological findings in drome. Genomics 57:235–248. parental origin. Am J Med Genet 78:82–89. two neurodevelopmental disorders. Arch Ward KE, Friedman L, Wise A, et al. 1996. Meta- Yamagishi H, Garg V, Matsuoka R, et al. 1999. A Neurol 49:407–411. analysis of brain and cranial size in schizo- molecular pathway revealing a genetic basis Wang PP, Doherty S, Rourke SB, et al. 1995. phrenia. Schizophr Res 22:197–213. for human cardiac and craniofacial defects. Unique profile of visuo-perceptual skills in a Warren ST, Ashley CT, Jr. 1995. Triplet repeat Science 283:1158–1161. genetic syndrome. Brain Cogn 29:54–65. expansion mutations: the example of fragile X Zhong N, Yang W, Dobkin C, et al. 1995. Fragile Wang PP, Hesselink JR, Jernigan TL, et al. syndrome. Annu Rev Neurosci 18:77–99. X gene instability: anchoring AGGs and 1992b. Specific neurobehavioral profile of Warwick MM, Doody GA, Lawrie SM, et al. 1999. linked microsatellites. Am J Hum Genet 57: Williams’ syndrome is associated with neo- Volumetric magnetic resonance imaging 351–361.

MRDD RESEARCH REVIEWS ● BRAIN IMAGING IN NEUROGENETIC CONDITIONS ● REISS ET AL. 197