The behavioral neurogenetics of fragile X syndrome...

Development and Psychopathology, 15 (2003), 927–968Copyright 2003 Cambridge University PressPrinted in the United States of AmericaDOI: 10.1017.S0954579403000464

The behavioral neurogeneticsof fragile X syndrome: Analyzinggene–brain–behavior relationshipsin child developmental psychopathologies

ALLAN L. REISS AND CHRISTOPHER C. DANTStanford University School of Medicine

AbstractAnalyzing gene–brain–behavior linkages in childhood neurodevelopmental disorders, a research approach called“behavioral neurogenetics,” has provided new insights into understanding how both genetic and environmentalfactors contribute to complex variations in typical and atypical human development. Research into etiologicallymore homogeneous disorders, such as fragile X syndrome, in particular, allows the use of more precise metricsof genetic risk so that we can more fully understand the complex pathophysiology of childhood onsetneurodevelopmental disorders. In this paper, we review our laboratory’s behavioral neurogenetics research byexamining gene–brain–behavior relationships in fragile X syndrome, a single-gene disorder that has become a well-characterized model for studying neurodevelopmental dysfunction in childhood. Specifically, we examine geneticinfluences, trajectories of cognition and behavior, variation in brain structure and function, and biological andenvironmental factors that influence developmental and cognitive outcomes of children with fragile X. Theconverging approaches across these multilevel scientific domains indicate that fragile X, which arises fromdisruption of a single gene leading to the loss of a specific protein, is associated with a cascade of aberrations inneurodevelopment, resulting in a central nervous system that is suboptimal with respect to structure and function. Inturn, structural and functional brain alterations lead to early disruption in emotion, cognition, and behavior in thechild with fragile X. The combination of molecular genetics, neuroimaging, and behavioral research have advancedour understanding of the linkages between genetic variables, neurobiological measures, IQ, and behavior. Ourresearch and that of others demonstrates that neurobehavior and neurocognition, genetics, and neuroanatomy are alldifferent views of the same intriguing biological puzzle, a puzzle that today is rapidly emerging into a morecomplete picture of the intricate linkages among gene, brain, and behavior in developing children. Understanding thecomplex multilevel scientific perspective involved in fragile X will also contribute to our understanding of normaldevelopment by highlighting developmental events throughout the life span, thereby helping us to delineate theboundaries of pathology.

The “Problem” behavior, and development? Should theseboundaries be discrete or should they be“fuzzy,” with overlap between the constructsWhat is a disorder? What is a symptom? How

should a clinician or researcher define the of “normal” and “abnormal”? Despite manydecades of intensive research on cognitive andboundaries of typical and atypical cognition,

cent Psychiatry and Child Development and BehavioralThe research presented in this article was funded by theLynda and Scott Canel Fund for Fragile X Research and Neurogenetics Research Center, Professor of Psychiatry

and Behavioral Sciences, Stanford University School ofNIH Grants MH50047, MH64708, and MH01142.Address correspondence and reprint requests to: Allan Medicine, 401 Quarry Road, Stanford, CA 94305-5719; E-

mail: [email protected]. Reiss, M.D., Director, Division of Child and Adoles-

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A. L. Reiss and C. C. Dant928

behavioral disorders occurring during child gardner, Green, & Reiss, 1994; Reiss & Freund,1998; Reiss, Eliez, Schmitt, Patwardhan, &development, there are relatively few unam-

biguous answers to these questions at present. Haberecht, 2000). This research method hasprovided a powerful tool for scientific inquiryWhy are many fundamental questions un-

derlying developmental psychopathology unan- that encompasses quantitative assessments ofgenetic risk factors, brain structure and func-swered? There is a growing impression in the

field that traditional research efforts aimed at tion, neurobehavioral and neurocognitive func-tion, psychoneuroendocrinology, and envi-understanding the pathogenesis of phenome-

nologically defined childhood-onset disorders ronmental influences in investigating andunderstanding the neurodevelopmental path-such as autism, attention-deficit/hyperactivity

disorder (ADHD), or dyslexia may be im- ways underlying learning and developmentaldisabilities. This approach complements morepeded, in part, by the etiological heterogeneity

of individuals meeting the widely accepted di- traditional research methods in cognitive–behavioral neuroscience that attempt to eluci-agnostic criteria defining these disorders.

Without reliable and valid biological markers date genetic and environmental risk factorsstarting at the point of a behaviorally definedfor the presence of a pathological condition or

state, we are often left to ponder, if not pur- disorder, as illustrated in Figure 1.In our approach of behavioral neurogene-sue, a circular approach to research methodol-

ogy. We may initially define a disorder ac- tics research, we have made two fundamentalunderlying assumptions. First, the complexcording to a consensus of experts in the field

agreeing to a diagnostic algorithm that in- pathways beginning with one or more geneticfactors affecting brain development or func-cludes the presence or absence of essential

symptoms or signs. This definition may even tion will be more accessible when studiedwith genetically homogeneous groups. Exam-have reasonable psychometric properties from

the standpoints of diagnostic reliability and ining developmental patterns within relativelyhomogeneous subgroups of individuals hasdiscriminative validity (from other phenome-

nologically defined disorders). However, the been realized as an important analytic strategyin a multilevel approach (Cicchetti & Ro-logic underlying this process is, inherently, at

risk for circularity. The fact that we can reli- gosch, 1996); studying the course of develop-mental processes within distinct homogenousably diagnose a disorder does not confer bio-

logical validity. Accordingly, the process of subpopulations is vital before we more fullyunderstand and identify individual patterns ofrevamping or parsing such behaviorally or phe-

nomenologically defined disorders into more dysfunction (Sroufe & Rutter, 1984).A second underlying assumption has beenetiologically or pathophysiologically mean-

ingful subgroups is essential before we can that the information derived from studyingthese prototypic conditions will be relevant tobegin to understand fundamental neurodevel-

opmental processes, and how these processes understanding brain–behavior associations inchildren with similar patterns of cognitive,are influenced by genetic and environmental

factors. Such progress will be particularly im- behavioral, and developmental dysfunctionfrom the general population. As such, our re-portant in childhood cognitive and behavioral

disorders that are currently defined by broad search efforts have been aimed at examiningthe behavioral neurogenetics of several well-and incomplete classifications such as “men-

tal retardation” and “learning disabilities.” characterized genetic disorders that give riseto identifiable developmental, cognitive, andSince 1994, our research strategy has fo-

cused on explicating multiple levels of scien- neuropsychiatry dysfunction in childhood; theseinclude Williams syndrome, Turner syndrome,tific inquiry to study children and adults with

known or suspected homogenous genetic risk Kleinfelter syndrome, velocardiofacial syn-drome (VCFS), and fragile X syndrome. Asfor neuropsychiatric, cognitive, behavioral and

developmental dysfunction, an approach we “experiments of nature,” these disorders haveprovided researchers with invaluable insightshave coined behavioral neurogenetics (Baum-

Behavioral neurogenetics of fragile X 929

Figure 1. Behavioral neurogenetics research in the genetic conditions as models for under-standing neuropsychiatric disorders such as fragile X syndrome.

into the developing human brain and child for example, in autism. This research providesa glimpse of the future of neuropsychiatric in-cognition and behavior that otherwise would

not be possible. A major component of this vestigation in which the complex interplay be-tween genetic risk and environment can beresearch focuses on defining the cognitive,

behavioral, and emotional developmental tra- more fully appreciated, described, and eluci-dated. Thus, while the information gainedjectories in children with these disorders, as

well as how functional outcomes are moder- from behavioral neurogenetics will have spe-cific benefit to children and adolescents withated and mediated by risk factors such as age,

family, educational environments, and neuro- fragile X syndrome, it also will have broaderrelevance to understanding how genetic–neuro-biological functioning.

In this paper, we review our work in frag- biologic pathways lead to increased risk fordistinctive profiles of cognitive and behav-ile X syndrome to demonstrate how a behav-

ioral neurogenetics approach can improve our ioral disability in children.understanding of the complex linkages be-tween genetic, neurobiological, and behav-

Fragile X Syndrome: Geneticsioral variables contributing to neurodevelop-

and Phenotypemental and neuropsychiatric dysfunction inchildren. By mapping fundamental molecular The fragile X syndrome, an X-linked semi-

dominant disorder, is the most common heri-events in fragile X to specific neurobiologicalcorrelates and phenotypic features, we open table form of neurodevelopmental disability,

second only to Down syndrome among all ge-the exciting possibility of establishing directlinks between genetic etiology and cognitive netic causes of mental retardation in males

and females (Crawford, Acuna, & Sherman,and behavioral outcomes.The opportunity to study a group of chil- 2001; Freund, Reiss, & Abrams, 1993; Nuss-

baum et al., 2001). Numerous studies havedren with a homogeneous etiology for cogni-tive and behavioral disability is rare in devel- found fragile X in every ethnic group, with

current estimates of prevalence at 1 in 4,000opmental psychopathology research. However,in an attempt to map fundamental molecular male births and 1 in 8,000 female births for

individuals with the “full mutation” (see be-events to specific changes in brain structureand function, as well as cognitive/behavioral low; Crawford, Meadows, Newman, Taft, Pet-

tay, Gold, Hersey, Hinkle, Stanfield, Holm-outcome, investigators increasingly are under-taking to study these more homogenous groups, green, Yeargin–Allsopp, Boyle, & Sherman,


1999; Turner, Webb, Wake, & Robinson, low level of FMR1 expression (Chiurazzi, Pom-poni, Pietrobono, Bakker, Neri, & Oostra, 1999).1996; Warren & Sherman, 2001).The massive expansion and methylation char-acterizing the full mutation also interfere with

Geneticsreplication and chromatin condensation, pro-ducing the characteristic “fragile” appearanceIn 1991, Verkerk et al. reported that a single

gene on the X chromosome, FMR1 (fragile X of metaphase X chromosomes under certainculture conditions.mental retardation 1), was associated with the

symptoms of fragile X (Verkerk et al., 1991). Premutation alleles are unstable and tendto expand when transmitted from parent toSubsequently, it was determined that persons

with fragile X showed dramatically increased child. A premutation can undergo a smallexpansion or it can develop into a massivenumbers of triplet CGG repeats in the 5′ un-

translated region of the first exon of FMR1 expansion to a full mutation. A large expan-sion only occurs when the premutation ison the long arm of the X chromosome (locus

Xq27.3). Unlike many single-gene inheritance transmitted from a female (Rousseau, Heitz,et al., 1994), a phenomonon known as geneticpatterns, in which the responsible mutation is

stable in form from one generation to the imprinting (Ashley–Koch, Robinson, Glicks-man, Nolin, Schwartz, Brown, Turner, &next, fragile X syndrome is one of several dis-

orders known to be caused by a dynamic gene Sherman, 1998; Malter, Iber, Willemsen, deGraaff, Tarleton, Leisti, Warren, & Oostra,mutation, resulting in instability and subse-

quent expansion of trinucleotide repeats 1997). (In this case, imprinting refers to thepresence of different epigenetic characteristicsthrough generations. In normal alleles, the

CGG repeats vary from 6 to 50, whereas expan- of male and female germ cell lines.) In addi-tion, the risk of expansion in the child in-sions of �50–200 repeats are associated with

the “premutation” form of the gene seen in creases as the premutation size in the parentincreases. Because the length of an unstablecarrier females and males. An early analysis

of 977 genetically unrelated individuals unse- CGG repeat increases during each generationif transmitted by a female, increasing numberslected for mental retardation or fragile X syn-

drome who were analyzed for FMR1 mutations of affected offspring may be seen in later gen-erations of an affected family, a phenomenonrevealed an estimated premutation frequency of

1 in 510 X chromosomes (Reiss, Kazazian, known as genetic anticipation. However, notall small premutations may be predisposed toKrebs, McAughan, Boehm, Abrams, & Nel-

son, 1994); several large, population-based expand in subsequent generations. This maybe due to AGG triplets embedded withinstudies of the premutation or carrier form of

fragile X estimate has since established pre- CGG strings, which “anchor” the gene by in-hibiting CGG expansion: analysis of premuta-mutation prevalence at 1 in 246–468 Cauca-

sian females and 1 in 1000 Caucasian males tion alleles in fragile X carriers has shown70% contain a single AGG interruption andin the general population (Crawford et al.,

2001; Warren & Sherman, 2001). Larger that loss of this triplet is an important muta-tional event leading to instability and expan-expansions of more than 200 (up to 2,000)

CGG repeats are considered a “full mutation” sion of the FMR1 gene locus (Dombrowski,Levesque, Morel, Rouillard, Morgan, & Rous-and associated with excessive methylation of

cytosines in the FMR1 promoter region. This seau, 2002; Eichler, Holden, Popovich, Reiss,Snow, Thibodeau, Richards, Ward, & Nelson,modification extinguishes transcription of the

FMR1 gene into mRNA, shutting down trans- 1994).lation of the fragile X mental retardation pro-tein (FMRP). Excess methylation is believed

Phenotypeto be primarily responsible for extinguishingFMR1 expression (Figure 2). Treatment of The fragile X mutation and decreases in

FMRP influences developmental pathwayscell lines containing the fragile X full muta-tion with methylation inhibitors reinitiates a that modulate physical appearance, cognitive


Figure 2. The genetics of fragile X syndrome. The FMR1 gene in unaffected individuals ischaracterized by approximately 50 or fewer CGG repeats, whereas the fragile X “premuta-tion” contains �50–200 repeats and normal methylation patterns. Large expansions of >200CGG repeats are typically associated with excessive methylation of the gene, thus reducingFMR1 protein expression. This state is referred to as the “full mutation.”

ability, emotional function, and adaptive be- particularly variable in prepubertal childrenand females, the definitive diagnosis of thehavior. Although quite variable, the physical

manifestations of fragile X include can in- disorder is made from both genetic testing(Southern blot) and polymerase chain reac-clude a long and narrow face, large ears, and

mildly prominent jaw (Davids, Hagerman, & tion. These tests determine FMR1 CGG repeatnumber and methylation characteristics. TheEilert, 1990; Loesch & Hay, 1988; Meryash,

Cronk, Sachs, & Gerald, 1984). These fea- severity of the fragile X phenotype dependsmostly on the degree of abnormal methylationtures, together with macroorchidism, often are

seen in postpubertal males with fragile X (La- of the FMR1 gene and, in females, the degreeof skewing of normal X-chromosome inacti-chiewicz & Dawson, 1994b). However, be-

fore puberty, children may have large heads vation (Nussbaum et al., 2001).but few other distinctive features. Childrenwith fragile X show an abnormal trajectory of

Summary and synthesisbrain development and are at increased riskfor cognitive, developmental, and behavioral Fragile X syndrome, an X-linked dominant

neurodevelopmental disorder, is the mostproblems beginning in infancy. School-ageboys with fragile X syndrome show, on aver- common heritable form of neurodevelopmen-

tal disability, with a prevalence at 1 in 4,000age, moderate mental retardation, whereas fe-males with the disorder usually demonstrate a male births and 1 in 8,000 female births. The

disorder is caused by an abnormal expansionrange of cognitive function from normal tomild mental retardation. Approximately 50% of CGG trinucleotide repeats within the

FMR1 gene located on the long arm of the Xof females with the full mutation have IQsranging from mental retardation to borderline chromosome. Repeat lengths up to approxi-

mately 40–50 triplets are normal. However,levels (Hagerman, Jackson, Amiri, Silverman,O’Connor, & Sobesky, 1992). Because these expansions of up to approximately 200 trip-

lets are associated with the “premutation”clinical findings are not unique to fragile Xsyndrome and the physical characteristics are form of the gene and over 200 (up to 2,000)


contain hypermethylated CGG repeats, which nition, behavior, and emotion in children withfragile X.results in reduced production of the FMR1

protein (FMRP). Reductions or loss of FMRP Considering the behavioral and intellectualdevelopment of individuals with fragile X iscauses a trajectory of abnormal brain develop-

ment and function, in turn leading to a cas- a complex endeavor. First, the behavioral andcognitive manifestations of fragile X are vari-cade of cognitive, behavioral, and emotional

problems in children with fragile X. Because able in males and females, and therefore, de-velopmental trajectories must be presented byrandom X inactivation occurs in females, 40–

50% of females (and nearly all males) who gender. Furthermore, because trajectories ofcognitive and behavioral development changeinherit the full mutation will exhibit identifi-

able cognitive symptoms. Some males and fe- throughout life in subjects with fragile X, aswell as those with typical development, it ismales with fragile X have a mixture of cells

with ranges of repeats (mosaicism) and there- important to present each developmental stageas a unique, albeit interrelated, phenomonon.fore, a large range of phenotypic features is

observed in affected individuals. Before pu-berty, boys with fragile X have somewhat

Infants and toddlerslarge heads but few other features; after pu-berty, the features may be more distinctive, Although efforts are beginning to identify the

developmental trajectory of infants and toddlersincluding a long face with prominent jaw andforehead, large ears, and macroorchidism. with fragile X, there is currently a relative void

of information specific to this developmentalperiod compared to school-age children oradults (Keysor & Mazzocco, 2002). StudiesThe Development of Behaviorthat have included infants and toddlers underand Cognition2 years of age have not differentiated findingsspecific to this age group (Bailey, Roberts, etFrom infancy, both female and male children

and adolescents with the fragile X full muta- al., 2001). However, recent longitudinal in-vestigations of early development in infants,tion are predisposed to manifesting a charac-

teristic set of cognitive, behavioral, and emo- toddlers, and young children with fragile Xaged 24–60 months have described early de-tional problems. Taken overall, these cognitive,

behavioral, and emotional deficits include velopment and behavior over time (Bailey,Hatton, & Skinner, 1998; Bailey, Hatton, Tas-cognitive delay with age-related declines in

IQ, disturbance in language and communica- sone, Skinner, & Taylor, 2001; Bailey, Skin-ner, Hatton, & Roberts, 2000; Hatton, Bailey,tion, reduced trajectory and abnormalities in

the development of adaptive behaviors, partic- Hargett–Beck, Skinner, & Clark, 1999).Early in infancy, fragile X is typicallyular cognitive abnormalities within the do-

mains of executive function and visual–spatial identified through the infant’s delayed or ab-normal development, but the large variabilitycognition, hyperactivity, and significant prob-

lems with hyperarousal and anxiety. Females and subtlety in its expression make identifica-tion difficult (Bailey, Roberts, et al., 2001).with the premutation do not usually manifest

symptoms; however, recent evidence suggests Parents may first notice concerns about theirinfant’s lack of gross motor coordinationthat those with large repeat sizes (>100) may

manifest a milder and more variable pheno- (Simko, Hornstein, Soukup, & Bagamery,1989) and hypotonia (Friefeld & MacGregor,type. The trajectories of these impairments

from infancy through adolescence and adult- 1993). In a recent study of 41 mothers of in-fants with fragile X, at least 10% of the in-hood are complex and variable due to vari-

ability in the interplay between complex ge- fants with fragile X displayed low muscletone and unusual motor movements, hyperac-netic, environmental, and biological risk factors.

As we will discuss, such risk factors play im- tivity, or irritability (Bailey, Skinner, 2000).In this study, these symptoms of develop-portant roles in determining outcomes of cog-


mental delay were identified by the parents at important in diagnosis of fragile X in this agegroup (Bailey, Roberts, et al., 2001).an average age of 24 months, but it was a year

later at a mean age of 35 months before frag-ile X syndrome was typically diagnosed by

Preschool childrengenetic testing in the toddler. Mothers first ex-pressed concerns about their infant’s develop- Few studies have been carried out on the cog-

nitive and behavioral profiles of preschoolment as early as 9 months of age and mostoften noticed delays in their infant’s develop- children with fragile X Compared with boys,

preschool girls with fragile X are less likelymental milestones—first speech, crawling,walking; other reported concerns about in- to come to professional attention due to lesser

severity of symptoms, although some youngfants with fragile X were problems in breath-ing, perceived pain, a lack of eye contact or girls present with developmental delay, which

signals attention. In a screening study of 534focus, a glazed look, or lack of attentiveness.Young boys with fragile X often come to the preschool children with developmental delay,

3 girls were diagnosed with fragile X; theattention of their pediatrician specifically be-cause of speech delays or abnormal language, girls displayed language delays, cognitive de-

lays (15–20 months below their age level offrequent ear infections, irritability, sensory reg-ulation problems, and frequent tantrums and 3.75 years), as well as attentional problems,

hyperactivity, tantrums, aggression, self-inju-hyperactivity (Hagerman, Staley, O’Conner,Lugenbeel, Nelson, McLean, & Taylor, 1996). rious behavior, and mood swings (Mazzocco,

Myers, Hamner, Panoscha, Shapiro, & Reiss,An analysis of 26 male infants and toddlerswith fragile X (aged 12–36 months; average = 1998). Preschool boys with fragile X also dis-

play similar behavioral and cognitive features24 months) found that Battelle DevelopmentalInventory (BDI) scores increased moderately to girls with fragile X, but the symptoms are

generally more pronounced (Bailey, Hatton,from 12 to 36 months, but over time, the de-velopmental quotient from the BDI continued Mesibov, Ament, & Skinner, 2000; Hatton et

al., 1997; Hatton et al., 1999; Hatton, Hooper,to lag behind normal age-matched infants andtoddlers so that by age 36 months, toddlers Bailey, Skinner, Sullivan, & Wheeler, 2002).with fragile X tested equivalent to a develop-mental age of 20 months (Roberts, Boccia, et Motor. Preschool-age children with fragile X

exhibit significant motor delays, with devel-al., 2001). In this study, developmental delayswere seen in some infants as early as 12 opment approximately half the rate expected

for typically developing children (Kau, Reider,months (equivalent to developmental age of 9months). As the male toddler approached 36 Payne, Meyer, & Freund, 2000). In one study,

motor as well as speech delays were found tomonths of age, motor skills appeared least de-layed, whereas communication skills were be related to levels of FMRP expression (Bai-

ley, Hatton, Tassone, 2001). That is, themost delayed: mean age of crawling, walking,sitting was delayed 2–3 months, whereas higher the FMRP (i.e., more like unaffected

individuals), the better the developmentalmean age of first spoken word was delayedby an average of 17 months. While these course. When compared to age-, IQ-, and lan-

guage-level matched controls, preschool chil-signs and symptoms of fragile X in male in-fants and toddlers are variable, detection of dren with fragile X showed greater delays and

greater variability in motor skills (Kau et al.,fragile X in female infants and toddlers is par-ticularly difficult due in part to their relatively 2000). When the fragile X group was further

divided in terms of full mutation and mosa-mild phenotype (Hatton et al., 1997). Basedon findings from longitudinal studies of in- icism, the latter condition presumably being

associated with some preservation of FMRPfants and toddlers with fragile X describingbehavioral development, Bailey created a production, the full mutation group showed a

lower, but not significant, mean age equiva-screening checklist of behavioral features thatmay help clinicians identify critical behaviors lent on the motor skills domain of the Vine-


land Adaptive Behavior Scales (VABS) than overall, their development was significantlydelayed, with a slope of 0.48, approximatelydid the mosaic group.half the rate expected for typically developingage-matched boys. As boys with fragile XCognition. The majority of boys with fragile

X present with significant cognitive delay grew older, more of them scored in the defi-cient range of the cognitive domain of the(Rousseau, Heitz, et al., 1994), usually by age

4 years (Bailey, Hatton, & Skinner, 1998). Battelle inventory, with all boys in the studyscoring in the deficient range by 66 monthsHowever, an early study of 221 preschool-

and school-age boys with fragile X showed of age. The developmental trajectories weresimilar in slope across all five domains thatthat 13% were classified as “high function-

ing” (IQ ≥ 70; Hagerman et al., 1994). In a were examined, indicating a stable develop-ment over time within a domain. As withstudy of preschool age (16–64 months) boys

with fragile X compared to age-matched boys male toddlers, preschool boys with fragile Xtested higher in motor and adaptive skills andwith developmental delay but without fragile

X, 44% of the boys with fragile X had overall lower in communication and cognitive skillsat every age. The level of FMRP was corre-IQs in borderline-average range, although

boys with fragile X scored lower on cognitive lated with the level of cognitive impair-ment—the less FMRP, the lower the cogni-assessments with the Stanford–Binet (4th edi-

tion) than boys with developmental delay. tive domain scores. Wright–Talamante et al.found that there was no significant IQ declineThere was no evidence in this cross-sectional

study that overall IQ declined among boys in young males with less than 50% methyla-tion of the full mutation, suggesting that awith fragile X across this developmental pe-

riod, although group size was limited (Freund small to moderate amount of FMRP produc-tion partially protects against significant IQet al., 1995). In a multicenter cross-sectional

analysis, boys with fragile X (aged 1–10), decline (Wright–Talamante, Cheema, Riddle,Luckey, Taylor, & Hagerman, 1996).particularly preschool boys, showed age-

related increases in adaptive skills (Vineland In contrast to boys, the developmental tra-jectory of cognition in girls with fragile X iscomposite scores), reaching levels that often

exceeded IQ expectations. IQ and adaptive more variable, with about one-half of the pre-school- and school-age girls with the full mu-behavior were highly correlated in this study,

suggesting that, like typically developing chil- tation presenting with mental retardation (fullscale IQ < 70; Rousseau, Heitz, et al., 1994).dren, their courses of development may be in

synchrony (Dykens, Ort, Cohen, Finucane, Although remarkably little is known aboutlongitudinal changes in IQ scores among pre-Spiridigliozzi, Lachiewicz, Reiss, Freund,

Hagerman, & O’Connor, 1996). The trajec- school girls with fragile X (Fisch, Simensen,Arinami, Borghgraef, & Fryns, 1994), as wetory of cognitive development in preschool-

age children with fragile X shows relatively discuss for school-age girls, several specificweaknesses characterize the cognitive profilesmild to moderate reduction in IQ compared

with typically developing children; this is in of young females with this condition, includ-ing deficits in mathematical reasoning, re-contrast to that observed in school-age chil-

dren and early adolescents with this disorder, duced attention, and decreases in short-termmemory while verbal skills remain relativelyfor which several investigators have observed

a decline in IQ scores (see below). preserved (Dykens et al., 1994).In a longitudinal prospective study of 46

boys with fragile X aged 24–66 months (aver- Behavior and emotion. Although behavioralstyles are variable, boys with fragile X be-age, 44 months), Bailey, Hatton, and Skinner

(1998) evaluated five domains, cognition, tween the ages of 2 and 5 years of age areat risk for manifesting problems with motoriccommunication, adaptive, motor, and per-

sonal–social, using the Battelle Development hyperactivity, hyperarousal, inattention, gazeavoidance, unusual speech (echolalia, persev-Inventory. The boys with fragile X varied

widely in rate and level of performance, but eration), stereotypies (hand flapping), exces-


sive mouthing behavior, self-injury (e.g., hand preschool boys (Freund et al., 1995). In a studyof preschool boys with fragile X and age- andbiting), and tactile defensiveness (Bailey, Hat-

ton, et al., 1998; Borghgraef, Fryns, Dielkens, IQ-matched control boys (Kau et al., 2000),children were rated by their mothers on the Di-Pyck, & Van den Berghe, 1987; Cohen,

Vietze, Sudhalter, Jenkins, & Brown, 1989; mensions of Temperament Scale—Revised, theChild Behavior Checklist, and the Aberrant Be-Freund et al., 1995; Fryns, 1984; Hagerman,

Amiri, & Cronister, 1991; Kau et al., 2000; havior Checklist—Community. Compared toage-, IQ-, and language-level matched boysLachiewicz, Dawson, & Spiridigliozzi, 2000;

Lachiewicz, Spiridigliozzi, Gullion, Rans- with idiopathic developmental delay, thosewith fragile X showed increased initial avoid-ford, & Rao, 1994; Maes, Fryns, Ghesquiere,

& Borghgraef, 2000; Simko et al., 1989). The ance and decreased social withdrawal.Young girls with fragile X also exhibitbehavioral style or temperament of 45 pre-

school boys with fragile X (ages 47–88 higher rates of emotional disturbance and mal-adaptive behaviors, including problems withmonths, average = 64 months) evaluated on

the Behavioral Style Questionnaire (McDevitt depression, social anxiety and withdrawal,and attention deficit (Freund et al., 1993;& Carey, 1978) showed that, compared to

typically developing boys, those with fragile Hagerman et al., 1992; Lachiewicz, 1992;Lachiewicz & Dawson, 1994a; Mazzocco,X were more active yet less intense, approach-

able, adaptable, and persistent, although there Baumgardner, Freund, & Reiss, 1998; Maz-zocco, Kates, Baumgardner, Freund, & Reiss,was considerable variability in temperament

profiles at this stage of development (Hatton 1997). By using a behavioral screening ques-tionnaire for parents of preschool boys andet al., 1999). Over the 6- to 18-month period

of this study, boys’ scores on temperament di- girls with fragile X, it was found that consid-ering the behavioral features of the child aremensions were stable and there was no link

between the severity of overall developmental useful diagnostic indicators of fragile X syn-drome, particularly in the absence of a recog-disability and behavior or temperament, sug-

gesting that IQ and temperament are separate nizable physical phenotype (Reiss et al.,1992; Teisl et al., 1999).constructs.

In the social domain, young boys withfragile X often appear excessively shy and Autistic behaviors. The topography of behav-

ioral, social, and developmental abnormalitiesanxious (Baumgardner, Reiss, Freund, & Ab-rams, 1995); they typically avoid unfamiliar that emerges in the preschool years has led

some investigators to suggest that fragile Xpeople (Cohen, Sudhalter, Pfadt, Jenkins,Brown, & Vietze, 1991), develop poor eye con- is a genetic risk factor for autism or autistic

behavior. Compared with non-fragile X malestact (Cohen, Fisch, Sudhalter, Wolf–Schein,Hanson, Hagerman, Jenkins, & Brown, 1988; who have comparable cognitive disability,

boys with fragile X are at increased risk, start-Hagerman et al., 1992; Payton, Steele, Wenger,& Minshew, 1989; Teisl, Reiss, & Mazzocco, ing at a young age, for manifesting a profile

of maladaptive behaviors that overlaps with1999; Wolff, Gardner, Paccla, & Lappen,1989), and begin to demonstrate stereotypic the phenomenologically defined DSM-IV cat-

egory of Pervasive Developmental Disordermovements and qualitative abnormalities ofspeech, such as cluttering and echolalia (Bailey, Hatton, et al., 2000; Bailey, Hatton,

Skinner, & Mesibov, 2001; Bailey, Mesibov,(Baumgardner et al., 1995; Lachiewicz et al.,1994; Sudhalter, Cohen, Silverman, & Wolf– Hatton, Clark, Roberts, & Mayhew, 1998;

Baumgardner, Reiss, Freund, & Abrams,Schein, 1990; Teisl et al., 1999). In preschoolboys with fragile X, this behavioral profile is 1995; Cohen et al., 1988; Cohen, Sudhalter,

et al., 1991a; Feinstein & Reiss, 1998; Harris,seen as early as 3–5 years of age, commensu-rate with the slowing of adaptive behavior de- 1999; Lachiewicz et al., 1994; Rogers,

Wehner, & Hagerman, 2001). Approximatelyvelopment during this age period. Amongmaladaptive behaviors, social reticence or 15 to 30% of males with fragile X fulfill DSM

criteria for autism, although a much higherwithdrawal is often the most problematic for


percentage show one or more components of with teachers and schoolmates, present signif-icant challenges to the child with fragile X.behavior from the autistic domain (Baumgar-

dner et al., 1995; Reiss & Freund, 1992). Although development progresses at half orless the normal rate in preschool-age boysThe findings suggest that young children

with fragile X demonstrate a pattern of devel- with fragile X (up to age 8), the trajectory ofdevelopment does not appear to plateau oropment that includes more autistic behaviors

than children with developmental delay but level off until later, usually during the schoolyears and into preadolescence (9–11 years).has a unique trajectory compared to that for

children with idiopathic autism (Rogers et al.,2001). Specifically, in a study of autistic be- Cognition. Although typically developing pre-

school- and school-age children and mosthaviors using DSM-III-R criteria for autism,compared with IQ- and age-matched typical groups of children with mental retardation of

mixed etiologies demonstrate a stable IQ, sev-boys, young boys with fragile X (mean age =8.7 years) showed increased dysfunction in eral cross-sectional and longitudinal investi-

gations in school-age children with fragile Xpeer social play, nonverbal communication(gaze aversion, gesturing), verbal communica- indicate that development of cognitive abili-

ties may follow an abnormal trajectory. Slow-tion (cluttered speech, echolalia, word/phraseperseveration), and repetitive motor behaviors ing or early plateauing of development (as op-

posed to a loss of skills) leads to declining(handflapping, rocking; Reiss & Freund, 1992).By using the Childhood Autism Rating Scale standardized scores in school-age children

with fragile X, perhaps beginning as young as(CARS), Bailey, Mesibov, et al. (1998) showedthat 25% of 57 young boys with fragile X 5 years of age (Bailey, Hatton, et al., 1998;

Dykens et al., 1996; Dykens, Hodapp, Ort, Fi-(mean age = 5.5 years) scored above the cut-off for autism, suggesting a relatively high in- nucane, Shapiro, & Leckman, 1989; Dykens,

Hodapp, Ort, & Leckman, 1993; Fisch, Car-cidence of autistic behaviors. In this study, theseverity of behavioral delay in boys with frag- penter, Holden, Simensen, Howard–Peebles,

Maddalena, Pandya, & Nance, 1999; Fisch,ile X was related to scores on the CARS: themore severely delayed children scored higher Carpenter, Simensen, Smits, van Roosma-

len, & Hamel, 1999; Fisch, Simensen, Tar-(more autistic) on the CARS. Compared witha control group of typically developing boys, leton, Chalifoux, Holden, Carpenter, How-

ard–Peebles, & Maddalena, 1996; Freund &those boys with fragile X (aged 3–8 years)and age-matched boys with autism were Reiss, 1991; Hagerman, Schreiner, Kemper,

Wittenberger, Zahn, & Habicht, 1989; Ho-slower to adapt, less persistent, and morewithdrawing than controls; boys with fragile dapp, Dykens, Hagerman, Schreiner, Lachie-

wicz, & Leckman, 1990; Lachiewicz, Gullion,X had a relatively flat profile of behavioraldevelopment, whereas autistic boys had sig- Spiridigliozzi, & Aylsworth, 1987). As more

demands are placed on reasoning and cogni-nificantly greater delays in social and commu-nication skills (Bailey, Hatton, et al., 2000). tion in school, the IQ of the child with fragile

X begins to decline (Hagerman et al., 1989;In terms of genetic risk factors, recent re-search suggests that autistic behaviors in chil- Hodapp et al., 1990; Lachiewicz et al., 1987).

Compared with school-aged boys with a fulldren with fragile X may be influenced by ad-ditional background genes whose own protein mutation, age-matched girls with the full mu-

tation show a wider range in IQ scores, butproduction is influenced by FMRP (see be-low; Feinstein & Reiss, 1998; Rogers et al., test–retest IQ scores also may decrease (Fisch,

Carpenter, Holden, Howard–Peebles, Madda-2001).lena, Borghgraef, Steyaert, & Fryns, 1999).

In both school-age girls and boys withSchool-age children

fragile X, the speech and language domain areparticularly affected. Compared with girls,During the school-age period of development,

increased demands on cognition and speech, boys with fragile X have significantly lowerage-equivalent language skills (Fisch, Holden,as well as new and variable social experiences


Carpenter, Howard–Peebles, Maddalena, Pan- Porter, Hull, & Hagerman, 1994; Theobald,Hay, & Judge, 1987). Relative to intellectualdya, & Nance, 1999). In a longitudinal analy-

sis of 28 male children with fragile X (aged potential, math achievement is particularly de-ficient in girls with fragile X beginning in the4–14 years) examining three domains of

adaptive behavior (Vineland Scales), Fisch, early school years. In a comparison of 5- and6-year-old school girls with and without frag-Carpenter, Holden, Howard–Peebles, et al.

(1999) found that, compared with socializa- ile X matched for age, full-scale IQ score, andgrade in school, verbal scores were compara-tion or daily living skills, communication was

the most severely affected skill, which ap- ble but math ability scores for girls with frag-ile X were significantly lower than the aver-peared to plateau early. Furthermore, there is

some evidence that delays in communication age scores for typically developing girls(Mazzoccco, 2001). As we examine later, theskills are age related. Communication skills

age equivalents are about half the chronologi- neural underpinnings of this deficit in girlswith fragile X are beginning to emerge.cal age of preteen children with fragile X, a

delay that increases for children aged 11 yearsor older (Dykens et al., 1996). This finding Behavior and emotion. In the behavioral do-

main, prospective studies of small groups ofwas confirmed in longitudinal studies show-ing a decline in speech and language skills in school-age boys with fragile X show that

whereas cognitive abilities decline in a non-children over 10 years of age, with speech andlanguage development at approximately 50% linear manner, adaptive behaviors (scored by

the Vineland Adaptive Behavior Scales) de-of typically developing children (Bailey, Hat-ton, et al., 1998; Dykens et al., 1993). cline steeply and linearly (Fisch et al., 1996).

Whereas Vineland domain scores did not re-The profile of school-age girls (mean =11.3 years) and boys (mean = 10 years) with veal a specific profile of adaptive skills devel-

opment, Abberrant Behavior Checklist scoresfragile X on the Stanford–Binet IntelligenceScale shows distinct patterns of weaknesses in in school-age boys with fragile X (average =

8.7 years) revealed high levels of hyperactiv-visual–motor coordination, spatial memory,and arithmetic, but strengths in verbal label- ity, stereotypic movements, and unusual speech

(Baumgardner et al., 1995) compared to boysing and comprehension (Freund & Reiss,1991). Girls with fragile X (7–14 years) with a comparable level of cognitive disabil-

ity not due to fragile X. Compared with typi-show significant relative weaknesses on visuo-construction tasks such as block assembly and cally developing boys (mean = 10.3 years),

age-matched boys with fragile X were lessdrawing (Cornish, Munir, & Cross, 1998). Thisprofile of weaknesses in visual memory and emotionally stable and less open to new expe-

riences; particularly boys with parents whoperception, mental manipulation of visual–spatial relationships among objects, visual– were less angry and more consistent in plan-

ning with the child were more agreeable,motor coordination, processing of sequentialinformation and arithmetical stimuli, and at- open, and less irritable than boys with parents

who openly displayed anger and were incon-tentional/executive function has been welldocumented in both male and female children sistent in their planning (van Lieshout, De

Meyer, Curfs, & Fryns, 1998). As we discusswith fragile X (Freund & Rice, 1996; Freund& Reiss, 1991; Hagerman et al., 1992; Hin- in a later section, parental psychological sta-

tus and quality of home environments are im-ton, Halperin, Dobkin, Ding, Brown, & Mie-zejeski, 1995; Mazzocco, Hagerman, Cronis- portant correlates of behavior in both boys

and girls with fragile X.ter–Silverman, & Pennington, 1992; Mazzocco,Pennington, & Hagerman, 1993; Miezejeski, Social behaviors begin to become more

problematic as boys enter the school-age pe-Jenkins, Hill, Wisniewski, French, & Brown,1986; Munir, Cornish, & Wilding, 2000a, riod (Freund, 1995), and school-age boys with

fragile X syndrome demonstrate deficits with2000b; Riddle, Cheema, Sobesky, Gardner,Taylor, Pennington, & Hagerman, 1998; peers, social avoidance, avoidance of eye con-

tact, and gaze aversion, as well as inattention,Schapiro et al., 1995; Sobesky, Pennington,


impulsivity, and hyperactivity in school and symptoms were more variable and less severethan in boys with fragile X. Cohen et al.social situations (Bailey et al., 1998a, 2001a;

Baumgardner et al., 1995; Bregman, Leck- found only 1.7% of 33 school girls with frag-ile X were autistic (Cohen, Brown, Jenkins,man, & Ort, 1988; Einfeld, Tonge, & Turner,

1999; Lachiewicz et al., 1994; Reiss & Krawczun, French, Raguthu, Wolf–Schein,Sudhalter, Fisch, & Wisniewski, 1989). ThisFreund, 1990, 1992). As in preschool boys,

school-age boys with fragile X also exhibit low rate is consistent with the 4:1 predomi-nance of males to females with autism and theautistic behaviors and boys with fragile X and

autistic behaviors demonstrate slower growth limited number of clinical case descriptionsof autistic, fragile X females (Bolton, Rutter,in developmental age than boys without autis-

tic behaviors (Bailey, Hatton, et al., 2001). Butler, & Summers, 1989; Gillberg, Ohlson,Wahlstrom, Steffenburg, & Blix, 1988; Hag-Behavioral symptoms in school-age girls

with fragile X particularly include shyness erman, Chudley, Knoll, Jackson, Kemper, &Ahmad, 1986).and social avoidance, mild to moderate symp-

toms of ADHD, and anxiety and depression(Freund et al., 1993; Hagerman et al., 1992; Hyperarousal. A particularly notable behav-

ioral characteristic in children with fragile XLachiewicz, 1992; Mazzocco, Kates, et al.,1997). In school-age girls with fragile X, is a strong propensity for hyperarousal. In par-

ticular, boys with fragile X are predisposed toprevalence of significant anxiety symptomsvaried from 23 (Lachiewicz & Dawson, hyperarousal, which is signaled by behaviors

such as poor eye contact, tactile defensive-1994a) to 50% (Freund et al., 1993; Maz-zocco, Baumgardner, et al., 1998). Although ness, hyperactivity, hand flapping, nail biting,

and tantrums (Bailey, Hatton, et al., 1998;girls and boys with fragile X show deficits insocial interactions with their peers, this typi- Borghgraef et al., 1987; Cohen, Vietze, et al.,

1989; Freund et al., 1995; Fryns, 1984; Hag-cally does not extend to relationships withtheir parents or caregivers, with whom they erman et al., 1991; Kau et al., 2000; Lachie-

wicz et al., 1994, 2000; Maes et al., 2000;are generally able to establish strong and de-velopmentally appropriate attachments (Reiss Simko et al., 1989). Most boys with fragile X

are highly sensitive to auditory, tactile, visual,& Freund, 1992). Relative to their own sisterswithout fragile X, girls with fragile X aged and olfactory stimuli (Cronister & Hagerman,

1989) and may overreact in highly stimulating6–14 years had higher ratings of withdrawnbehaviors (Mazzocco, Baumgardner, et al., environments such as a supermarket or mall

(Besler & Sudhalter, 1995; Cohen, 1995). Re-1998). Young girls with fragile X were oftenrated by their parents and teachers as signifi- cent studies of heartbeat irregularities showed

that, compared with typically developingcantly more withdrawn and depressed whencompared with control girls, and 38% of the boys, those with fragile X had higher heart

rates during passive phases, as reflected ingirls with fragile X were diagnosed withmood disorders in a structured interview shorter heart periods, which was a result of

increased sympathetic and reduced parasym-(Freund et al., 1993). In one study, 47% ofgirls with fragile X aged 4–11 years demon- pathetic nervous system activity (Boccia &

Roberts, 2000; Roberts, Boccia, Bailey, Hat-strated high Child Behavior Checklist Tscores (>70) for social withdrawal, and 26% ton, & Skinner, 2001). In addition, children

with fragile X also showed greater magnitude,also had high T scores on the depression scale(Lachiewicz, 1992). more responses, and lower rates of habitua-

tion to skin stimulation, suggesting an abnor-The social avoidance and anxiety seen ingirls with fragile X qualitatively overlaps with mal overreaction in the sympathetic nervous

system (Miller, McIntosh, McGrath, Shyu,that associated with pervasive developmentaldisorders. Although autistic behaviors were Lampe, Taylor, Tassone, Neitzel, Stack-

house, & Hagerman, 1999). Along with thereported more frequently for 6- to 16-year-oldgirls with fragile X compared to girls without findings of increased cortisol levels in boys

with fragile X discussed later in this reviewfragile X (Mazzocco, Kates, et al., 1997), the


(Hessl, Glaser, Dyer–Friedman, Blasey, Has- fragile X were able to learn simple tasks butshowed impairment on more complex tasks re-tie, Gunnar, & Reiss, 2002; Wisbeck, Huff-

man, Freund, Gunnar, Davis, & Reiss, 2000), quiring memorization (Kaufmann et al., 1990),suggesting that more difficult tasks requiringthese findings support the neural and physio-

logical basis of hyperarousal in boys with the use of working memory to guide behaviormay be difficult for males with fragile X.fragile X.

Executive function. One of the most consistentAdolescents

neuropsychological findings in school-agechildren with fragile X is a deficit in execu- An early study of adolescent and adult women

with the fragile X premutation showed no dif-tive functioning, involving goal-directed, fu-ture-oriented behaviors involving working ferences from control subjects with respect to

cognitive abilities or profile, neuropsycholog-memory, planning, and inhibition (Hagermanet al., 1992; Mazzocco, Hagerman, Cronister– ical function, psychiatric diagnoses or symp-

toms, and self-rated personality profiles (Re-Silverman, & Pennington, 1992; Mazzocco,Hagerman, & Pennington, 1992; Sobesky et iss, Freund, Abrams, Boehm, & Kazazian,

1993). However, this issue has recently re-al., 1994; Thompson, Gulley, Rogeness, Clay-ton, Johnson, Hazelton, Cho, & Zellmer, gained attention, as evidence indicating that

individuals with large premutations may man-1994). In studies of high-functioning girlswith fragile X (IQ > 70), the largest group ifest some of the signs and symptoms of frag-

ile X (Johnston, Eliez, Dyer–Friedman, Hessl,differences from control girls involved tasksof executive function, which are conceptual Glaser, Blasey, Taylor, & Reiss, 2001). In

males and females with the fragile X full mu-problem solving, flexibility in thinking, inhi-bition, and concept formation (Mazzocco et tation, however, there appears to be steady

cognitive growth until late childhood andal., 1993). These group differences remainedsignificant even when statistically accounting early adolescence (10–15 years of age), at

which point mental age plateaus and IQ de-for the effects of IQ. In a study of molecularand phenotypic correlations in females with clines (Dykens, Hodapp, Ort, et al., 1989).fragile X, it was found that the X inactivationratio (a metric that parallels FMRP levels) Cognition. IQs of children with fragile X that

initially begin to decline in middle childhoodwas strongly and positively correlated withexecutive function (Sobesky, Taylor, Pen- continue to decline through adolescence (Hag-

erman et al., 1989; Lachiewicz et al., 1987),nington, Bennetto, Porter, Riddle, & Hager-man, 1996), suggesting that executive func- and adolescent males with higher initial IQ

scores are more likely to manifest IQ declinetioning is sensitive to levels of FMRP. Thedefects in executive functioning may help to than those with initial lower levels of intelli-

gence (Dykens, Hodapp, Ort, et al., 1989). Itexplain some of the other weaknesses in fe-males with fragile X—problems in attentional was suggested that the decline in IQ in fragile

X might be explained by inherent propertiesfunction, organization, and memory and be-havioral problems such as hyperactivity or of cognitive tests, which for older children

may place greater emphasis on skills that areimpulsivity.Boys with fragile X also show a deficit in known to be specific weaknesses in this disor-

der (Hagerman et al., 1989). However, find-executive functioning, which may help ex-plain some cognitive and behavioral prob- ings from studies of adaptive behavior devel-

opment in fragile X, which rely on informantlems. As in girls, deficits in executive func-tion in boys with fragile X are consistent with (usually parent) report, also indicate atypical

developmental trajectory. Particular weak-problems in attentional control and impulsiv-ity, difficulty with maintaining one topic and nesses are seen in communication skills in ad-

olescents with fragile X. From the preschoola tangential conversational style, and deficitsin memory. In a study of working-memory to adolescent years and into adulthood, indi-

viduals with fragile X consistently show de-tasks, Kaufmann et al. found that boys with


creased trajectories in speech and language 1996). Although social anxiety and attentionaldysfunction are likely to be “core” deficits di-skills, approximately half those of normal ad-

olescents. rectly correlated with reduced FMRP in fe-males, the development of depression may bea secondary complication associated with so-Behavior and emotion. As noted above, adap-

tive behavior skills also decline as the child cial neglect or rejection by peers and increas-ing self-awareness of behavioral, emotional,enters the adolescent years. In a multicenter

study of adaptive behavior profiles in males and cognitive differences from others (Fopma–Loy, 2000).with fragile X, Dykens et al. (1993, 1996)

found that boys between 1 and 10 years old As in females with fragile X, males withfragile X are usually socially interested butshowed significant age-related gains in adap-

tive skills, but older boys between 11 and 20 avoidant and many have problems relating totheir peers. For example, adolescent boysyears old showed more variability in adaptive

skills and there was no relationship between with fragile X commonly avert their gazewhen meeting new people. Wolff et al. (1989)age and the changes in adaptive skills. As

these males with fragile X reached early adult- illustrated the unique and commonly observedpattern of gaze aversion in adolescent andhood (21–40 years), age-equivalent adaptive

scores stabilized. Relative strengths were seen adult males with fragile X. Of 18 adolescentsand adults in the study, 14 demonstrated gazein daily living skills and weaknesses in com-

munication were evident only among older aversion with avoidant behavior; in this longi-tudinal study, 6 boys with fragile X who weremales with fragile X (Dykens et al., 1993,

1996). under 8 years of age did not demonstrate gazeaversion, but nearly all the adolescent malesIn the social domain, adolescent and young

adult women with the fragile X full mutation over 12 showed this unique greeting behavior.This greeting behavior has been linked to themanifest anxiety in social interaction and are

at high risk for developing major depression excessive anxiety seen in boys with fragile Xin social situations (Kerby & Dawson, 1994).(Freund, Reiss, Hagerman, & Vinogradov,

1992; Hagerman & Sobesky, 1989; Reiss, As is discussed in a later section, recent neu-roimaging research has examined the neuralHagerman, Vinogradov, Abrams, & King,

1988; Sobesky et al., 1994, 1996; Thompson basis of gaze aversion.et al., 1994; Thompson, Rogeness, McClure,Clayton, & Johnson, 1996). The relationship Executive function. Adolescent females with

the fragile X full mutation continue to showbetween neurobehavioral functioning and CGGrepeat length was studied in female carriers significant and consistent deficits on tasks of

executive functioning, which are not totallyof the fragile X premutation (56–166 repeats;Johnston et al., 2001). Compared with those accounted for by their lower IQs. In particu-

lar, adolescent girls and young adult womenindividuals with smaller (<100 repeats) al-leles, those females with larger (>100 repeats) with fragile X are at risk for demonstrating

impulsivity and attentional inefficiency andalleles scored significantly higher on the In-terpersonal Sensitivity and Depression sub- have difficulty with the organizational aspects

of their memory. In a neurocognitive study,scales of the Symptom Checklist-90-R (Dero-gatis, 1994). The behaviors encompassing women with the fragile X full mutation per-

formed worse than those with the premutationthese dimensions include withdrawn behaviorand depressed mood. Females with a premuta- or those without fragile X on tests of execu-

tive function, spatial ability, and visual mem-tion have been reported to show schizotypaltraits, emotional difficulties, social anxiety ory, but the defects seen in executive func-

tioning were more obvious than visuospatialand increased prevalence with mood disorders(Franke, Leboyer, Gansicke, Weiffenbach, Bi- deficits (Bennetto, Pennington, Porter, Tay-

lor, & Hagerman, 2001).ancalana, Cornillet–Lefebre, Croquette, Fros-ter, Schwab, Poustka, Hautzinger, & Maier, Males in this age group also show prob-

lems in executive functioning, which may be1998; Sobesky et al., 1996; Thompson et al.,


associated with continued problems with work- 5 years of age. It reaches a plateau in middleto late childhood or early adolescence, gener-ing memory and planning activities (Hager-

man et al., 1992). Preliminary evidence from ally by age 10, as evidenced by declining IQscores and a lack of consistent gains duringour laboratory suggests that individuals with

fragile X use a cognitive strategy that relies these years. Beginning in the preschool yearsand extending into the school and adolescenton verbal working-memory processing in per-

forming a behavioral inhibition task, provid- years, boys with fragile X show pervasivedeficits in conversational language skills withing support to a hypothesis that subjects with

fragile X may have the adaptive ability to over- increasing discrepancy between language leveland chronological age. Patterns of behavioral,come some executive functioning weaknesses

through verbal mediation strategies (Freund & social, and developmental abnormalities thatemerge in preschool boys suggest that fragileReiss, 1991).X is a risk factor for autistic behavior. In par-ticular, the presence of a nervous system that

Summary and synthesisis poorly modulated (e.g., hyperarousal, prob-lems with inhibition and habituation) mayIn summary, both female and male children

and adolescents with the fragile X full muta- contribute to the development of the autistic“features” observed in children with fragile X.tion are at significant risk for developing a

characteristic profile of behavioral, cognitive, Girls with fragile X are more variable intheir development; whereas those with the fulland emotional problems beginning in infancy

that is qualitatively similar, but quantitatively mutation may show mildly to moderately se-vere quantitative and qualitative abnormali-different, in females and males with the full

mutation. In contrast, individuals with the pre- ties, those with the premutation are much morelikely to show trajectories similar to typicallymutation usually show normal functioning un-

less repeat length is greater than 100, in which developing girls. In preschool and school-agegirls, the presence of social anxiety, shyness,case manifestations may be highly variable.

As early as 9 months, mothers of children with and avoidant behavior appears to be a riskfactor for the emergence of depression in latefragile X, usually boys, may notice that their

infants show a delay in developmental mile- childhood and adolescence and beyond. In theschool environment especially, peer neglect orstones and abnormal tone and motor coordina-

tion. On average, delays are noticed in the in- rejection as well as increasing self-awarenessof differences from normal children predis-fant at 24 months, but on average, children

with fragile X are not diagnosed until a year pose girls with fragile X to poor self-esteemand various emotional problems. Our worklater, usually because as a result of persistent

speech delays or behavioral abnormalities. As and that of others leads us to believe that shy-ness and anxiety are linked and are centralboys with fragile X reach preschool age, there

is significant variability in development, but manifestations of the genetic “risk” from theFMR1 mutation in females. As children withoverall, their rate of development ranges from

one third to one half that expected for typi- fragile X reach adolescence, cognition andadaptive behavior skills continue to decline.cally developing boys. Expressive language is

more adversely affected than receptive lan- Executive functioning, particularly involvingworking memory, inhibition, and planning, alsoguage, whereas scores for motor and adaptive

function are relatively higher compared with fail to develop at expected rates during theadolescent years.communication and cognitive functioning. The

pattern of adaptive development in boys with Prospective longitudinal studies of largegroups of children with fragile X are neededfragile X shows significant growth from 1 to

10 years of age, gains that may be most robust to better understand the topography of typicaland atypical development in fragile X syn-in the toddler and preschool years and less

marked in the school-age years. Cognitive and drome. This information is vital because (a)elucidating the biological and environmentaladaptive behavioral development slows in

children with fragile X beginning as early as factors that influence cognitive and behavioral


outcomes will identify areas of function sensi- mains characteristic of RNA binding proteins,suggesting that FMRP’s function is involvedtive to intervention; (b) obtaining precise in-

formation about development will help deter- in binding mRNAs during protein synthesis(Feng, 2002); in vitro, FMRP binds mRNAmine whether specific interventions lead to

meaningful changes in functioning; and (c) selectively and is associated with polyribosomesand the rough endoplasmic reticulum (Jin &understanding specific domains of suboptimal

development may provide clues for the devel- Warren, 2000). Further, analysis of FMRPbinding sites indicates that it contains both aopment of new, early interventions.nuclear localization signal and an export sig-nal (Eberhart, Malter, Feng, & Warren, 1996),

Neurological Basis of Phenotype,suggesting FMRP shuttles between cytoplasm

Behavior, and Cognitionand nucleus, possibly to transport specificmRNAs to translating ribosomes (Feng et al.,

Neuron and synapse level1997; Tamanini, Willemsen, van Unen, Bon-tekoe, Galjaard, Oostra, & Hoogeveen, 1997).In the 10 years following the discovery of the

FMR1 gene (Verkerk et al., 1991), advances FMRP’s functional role as an mRNA bindingprotein is so critical to normal developmentin genetics and cell research have provided

scientists with a wealth of information about that a de novo point mutation in one of itsRNA binding sites leads to a severe form ofthe mechanisms of FMR1 mutation and the

functions of FMRP. Several research groups fragile X syndrome (De Boulle, Verkerk,Reyniers, Vits, Hendrickx, Van Roy, Van denhave begun to decipher the molecular signals

important for FMR1 gene expression at the Bos, de Graaff, Oostra, & Willems, 1993).FMRP is believed to regulate synaptic ac-neuronal level that begin to explain the range

of cognitive and behavioral features of fragile tivity by transporting mRNAs transcribed froma number of other genes to neuronal dendritesX (Brown, Jin, Ceman, Darnell, O’Donnell,

Tenenbaum, Jin, Feng, Wilkinson, Keene, Dar- in response to neural stimulation. In animals,behavioral and environmental stimulation pro-nell, & Warren, 2001; Darnell, Jensen, Jin,

Brown, Warren, & Darnell, 2001; Schaeffer, duces elevated FMRP expression in brainneurons (Irwin, Galvez, & Greenough, 2000;Bardoni, Mandel, Ehresmann, Ehresmann, &

Moine, 2001; Zhang, Bailey, Matthies, Renden, Irwin, Swain, Christmon, Chakravarti, Weiler,& Greenough, 2000). Further, the localizationSmith, Speese, Rubin, & Broadie, 2001).of FMRP to dendrites and dendritic spinessuggests that FMRP is involved in regulationFMRP function in neurons. In this section, we

review what is currently known about FMRP’s of proteins involved in dendritic structure orfunction (Feng et al., 1997; Weiler et al.,function at the neuronal level. How FMRP

regulates normal neuronal development and 1997); therefore, it is believed that FMRPplays an important role in regulating proteinits absence leads to the observed array of neu-

rological dysfunctions continues to be an on- translation at postsynaptic sites that are criti-cal for synaptic development and functiongoing research effort (Feng, 2002).

At the neuronal level, FMRP is found pri- during memory and learning (Worley, 1998).Evidence from animal models of fragile Xmarily in the cell body, in dendrites, and in

synapses (Devys, Lutz, Rouyer, Bellocq, & and in humans with fragile X indicates thatduring development, absent or reduced FMRPMandel, 1993; Feng, Gutekunst, Eberhart, Yi,

Warren, & Hersch, 1997; Weiler, Irwin, Klint- disrupts the normal adaptive formation andelimination (pruning) of dendritic spines, asova, Spencer, Brazelton, Miyashiro, Comery,

Patel, Eberwine, & Greenough, 1997). In neu- process known as neuronal plasticity. In nor-mal animals during early development or inrons, FMRP is predominately associated with

actively translating ribosomes during protein those reared in a sensory-deprived environ-ment, neurons exhibit abnormally long den-synthesis (Khandjian, Corbin, Woerly, & Rous-

seau, 1996). Analysis of the amino acid se- dritic spines with immature morphologies andelevated spine numbers. Post mortem studiesquence of FMRP has revealed molecular do-


in subjects with fragile X show cortical neu- tic binding structures in mRNA (G-quartets),Darnell et al. found several mRNAs to whichrons with similar morphological abnormalities

of dendritic processes (Hinton, Brown, Wis- FMRP binds that are misregulated in neuronsof subjects with fragile X (Darnell et al., 2001).niewski, & Rudelli, 1991; Rudelli, Brown,

Wisniewski, Jenkins, Laure–Kamionowska, Independently, using microarray or “DNA chip”analysis, Brown et al. identified 432 mRNAsConnell, & Wisniewski, 1985). A recent qual-

itative examination of brain autopsy tissues in the mouse brain that were normally associ-ated with FMRP; of these, 251 mRNAs alsofrom both temporal and visual cortical areas

of individuals with fragile X revealed signifi- appeared in lymphoblast cells from fragile Xpatients (Brown et al., 2001). Of the 12 over-cantly more immature dendritic spines that

are longer and morphologically abnormal lapping FMRP-associated mRNAs found inboth experiments, 8 contained the characteris-compared with brain tissues from control sub-

jects (Irwin, Patel, Idupulapati, Harris, Crisos- tic G-quartet binding structure, and it wasshown that these mRNAs were abnormallytomo, Larsen, Kooy, Willems, Cras, Kozlow-

ski, Swain, Weiler, & Greenough, 2001). expressed and regulated in neurons of patientswith fragile X. Three mRNAs were found par-Additional clues for the role of FMRP in

neuronal development come from animal ticularly critical for normal neuronal develop-ment. One mRNA codes for microtubule-as-models of fragile X. In the fruit fly Drosoph-

ila melanogaster knockout model of the FMR1 sociated protein (MAP1B), which is involvedin synaptic maturation through the extensionhomolog (dfxr), neurons exhibit enlarged syn-

aptic terminals with structural defects and al- of axons and dendrites; another mRNA codesfor somaphorin 3F, which is critical for axontered neurotransmission (Zhang et al., 2001).

Also, neuronal tissue from the fragile X mouse path finding; and a third mRNA codes for theprotein ID3, involved in normal neuronalmodel (Fmr-1 knockout mice) shows more im-

mature dendritic spines with greater spine den- plasticity (Brown et al., 2001). It is interestingthat one mRNA codes for the protein MINT,sities and impairments in spine maturation and

pruning compared with neuronal tissue from which affects craniofacial development, theabsence of which may account for the longthe normal mouse (Comery, Harris, Willems,

Oostra, Irwin, Weiler, & Greenough, 1997). face and prominent forehead/jaw in patientswith fragile X.From the evidence in both animals and hu-

man, Feng recently suggested two roles for Thus, during normal development, FMRPis produced at synapses in response to synapticFMRP in neurons: FMRP is required for syn-

apse formation and maturation, which is un- activation and FMRP is increased in the brainundergoing active synaptogenesis in responseder the control of signals during development;

and/or FMRP, in response to neurotransmitter to motor learning or enriched environments. Inthe individual with fragile X, reductions or ab-release, controls the localization and/or trans-

lation of its bound mRNA(s) at postsynaptic sence of FMRP cause developmental changesat the neuronal level, chiefly abnormalities ofsites (Feng, 2002). Thus, structural and func-

tional abnormalities in the fragile X brain may dendritic spines, which are related by impair-ments in spine maturation and a failure of nor-result from translational misregulation of

FMRP-bound mRNAs within the synapse as mal synaptic pruning. Recent evidence hasimplicated several important mRNA targets ofwell as from structural synaptic defects ac-

quired during development. How FMRP regu- FMRP in this process, including those involvedin neuronal plasticity and development, syn-lates those neuronal functions critical for nor-

mal development has, until recently, remained aptic maturation and axon path finding. Theseneurodevelopmental processes lead to bothlargely unknown.structural and functional abnormalities thatcan be visualized with brain imaging method-FMRP targets. Discovering the specific FMRP

mRNA targets important to neuronal develop- ologies as discussed in the next section.The work on FMR1 function, FMRP, andment has been at the forefront of recent re-

search. By identifying unique and characteris- neuronal development was the subject of re-


cent reviews (Churchill, Grossman, Irwin, Gal- neuroimaging evidence shows that prefron-tal–striatal white matter connectivity is dis-vez, Klintsova, Weiler, & Greenough, 2002;

Irwin et al., 2001; Kaytor & Orr, 2001; O’Don- rupted in the brain of individuals with fragileX (Barnea–Goraly et al., 2002), and that pre-nell & Warren, 2002; Oostra, 2002; Oostra &

Chiurazzi, 2001). frontal–parietal areas show activation differ-ences during math computation (Menon, Ri-vera, White, Glover, & Reiss, 2000; Rivera,Neural systems levelMenon, White, Glaser, & Reiss, 2002), and

Over the past 15 years, a series of brain im- working memory tasks (Kwon, Menon, Eliez,aging studies in our laboratory have consis- Warsofsky, White, Dyer–Friedman, Taylor,tently established links between reduced or Glover, & Reiss, 2001; Menon, Kwon, Eliez,absent FMRP and abnormalities of specific Taylor, & Reiss, 2000). Taken together, theseneuroanatomical regions in subjects with frag- neuroimaging findings implicate disruptionsile X (primarily school-age children or older) in specific neural systems in individuals withas compared to IQ matched (non-fragile X) fragile X that are associated with the neurobe-and typically developing subjects (Eliez, Bla- havioral and neurocognitive phenotype.sey, Freund, Hastie, & Reiss, 2001; Kates,Abrams, Kaufmann, Breiter, & Reiss, 1997; Structural neuroimaging: Magnetic resonance

imaging (MRI)Mostofsky, Mazzocco, Aakalu, Warsofsky,Denckla, & Reiss, 1998; Reiss, Abrams, Caudate. Both females and males with

fragile X show highly significant increases inGreenlaw, Freund, & Denckla, 1995; Reiss,Aylward, Freund, Joshi, & Bryan, 1991; caudate nucleus volume compared to IQ and

healthy controls (Reiss, Abrams, Greenlaw,Reiss, Freund, Tseng, & Joshi, 1991; Reiss,Lee, & Freund, 1994; Reiss, Patel, Kumar, & Freund, & Denckla, 1995; Reiss, Freund, et

al., 1995). In a more recent MRI study in bothFreund, 1988). Figure 3 shows a compilationof our findings from this neuroimaging re- children and adolescents with fragile X, Eliez

also found that both males and females hadsearch. Our studies and others have describedabnormalities such as increased cerebral and significantly larger caudate volumes than con-

trols, although males with fragile X had sig-ventricular volumes (Eliez et al., 2001; Reiss,Abrams, et al., 1995; Reiss, Abrams, Singer, nificantly larger caudate volumes than fe-

males with fragile X (Eliez et al., 2001). ThisRoss, & Denckla, 1996; Reiss, Freund, et al.,1991; Schapiro et al., 1995; Wisniewski, finding supports the hypothesis that females

represent an intermediate status of the FMR1Segan, Miezejeski, Sersen, & Rudelli, 1991),enlarged caudate nucleus (Reiss, Abrams, et gene mutation on brain development.

The caudate is a subcortical nucleus thatal., 1995; Reiss, Freund, Baumgardner, Ab-rams, & Denckla, 1995) and hippocampal vol- functions as a component of neural systems

through which the cerebral cortex affects be-umes (Kates et al., 1997; Reiss, Aylward, etal., 1991), and decreased cerebellar vermis havior. Although well known for involvement

in movement, the caudate nucleus also is be-area (Mazzocco, Kates, et al., 1997; Mostof-sky et al., 1998; Reiss, Aylward, et al., 1991; lieved to play an important role in cortical–

subcortical loops related to emotion and cog-Reiss, Freund, et al., 1991) and superior tem-poral gyrus volume (Reiss, Lee, & Freund, nition via connections with nonmotor areas of

the frontal cortex, including the dorsolateral1994). Further, diffusion tensor imaging (DTI)

Figure 3. The compilation of structural and functional MRI findings from our neuroimaging laboratory(prior to 2000) showing brain regions altered in subjects with fragile X compared with controls. DD,individuals with developmental disability comparable to fragile X (fraX); TYP, typically developingindividuals. Brain image copyright the Digital Anatomist, University of Washington. The three-dimen-sional reconstructions of the right hemisphere and deep structures are used with permission of the DigitalAnatomist Project at the University of Washington.


prefrontal, medial and lateral orbitofrontal, gion also is implicated in the interpretation offaces and gaze (Campbell, Heywood, Cowey,and anterior cingulate regions (Cummings,

1993; DeLong, 2000; Masterman & Cum- Regard, & Landis, 1990; Hoffman & Haxby,2000; Wicker, Michel, Henaff, & Decety,mings, 1997). Disturbances of these frontal–

subcortical circuits are known to produce dis- 1998), and alterations in this region and struc-tures associated with the face/gaze neural cir-turbance in attention and spatial working

memory, motor programming/movement se- cuit may be associated with the observed be-havior of gaze aversion in subjects with fragilelection, regulation of mood, social behavior,

impulse control, and flexibility in behavioral X as described below.Cerebellar vermis. An early neuroimagingresponse to environmental cues (Cummings,

1993; Masterman & Cummings, 1997). Thus, study from our laboratory (Reiss, Patel, et al.,1988) showed a significantly decreased poste-disruption of circuits involving prefrontal–

striatal connections would be consistent with rior cerebellar vermis and pons and increasedfourth ventricular area in subjects with fragilesome of the cognitive and behavioral abnor-

malities observed in fragile X: attention defi- X, compared with control subjects. We theo-rized that vermis alterations could account forcit, hyperactivity, stereotypic and perseverative

language and motor behavior, and problems some of the behavioral and cognitive abnor-malities observed in males with fragile X, par-with impulse control (Abrams, Reiss, Freund,

Baumgardner, Chase, & Denckla, 1994; Reiss, ticularly those overlapping with autism. In afurther investigation of subjects with fragileAbrams, et al., 1995). An important finding

is that in control subjects, larger caudate is X compared with males with other causes ofdevelopmental disability and normally devel-associated with higher IQ, whereas in the sub-

jects with fragile X, larger caudate is corre- oping males, the finding of a significantly de-creased posterior cerebellar vermis volumelated with lower IQ (Reiss, Abrams, et al.,

1995). This suggests that the developmental and increased fourth ventricle volume wasreplicated in subjects with fragile X comparedprocess leading to increased caudate volume

in subjects with fragile X reflects aberrant with males in the comparison groups (Reiss,Aylward, et al., 1991). This result was furtherneural organization.

Hippocampus. We previously reported in- confirmed in a study of young females withfragile X who were compared with age- andcreased hippocampal volume from two inde-

pendent investigations in our laboratory (Kates IQ-matched, typically developing females (Re-iss, Freund, et al., 1991). Results from otheret al., 1997; Reiss et al., 1994). The volume

changes were greater in subjects with fragile laboratories using smaller numbers of subjectshave replicated our findings of increased brainX than normally developing controls or con-

trol subjects with developmental delay but volumes (Schapiro et al., 1995) and decreasedcerebellar vermis size (Guerreiro, Camargo,without fragile X. The hippocampus is in-

volved in encoding and retrieving episodic Kato, Marques-de-Faria, Ciasca, Guerreiro,Netto, & Moura–Ribeiro, 1998).memories and encodes and consolidates vi-

sual and language-related associations. The The cerebellar vermis is normally involvedin processing sensory information (Rao, Mayer,hippocampus also is used in spatial problem

solving and movement-related cues to guide & Harrington, 2001) and modulating atten-tion, emotion, and coodinating movement; itspatial behavior. Further, this structure is in-

volved in the detection of novel stimuli in a also may play a role in language (Bobee, Ma-riette, Tremblay–Leveau, & Caston, 2000;developing child.

Superior temporal gyrus. Age-related de- Critchley, Corfield, Chandler, Mathias, & Do-lan, 2000; Levisohn, Cronin–Golomb, &creases in superior temporal gyrus volume

have been reported in individuals with fragile Schmahmann, 2000; Mostofsky et al., 1998;Parsons, Denton, Egan, McKinley, Shade,X (Reiss, Aylward, et al., 1991), an area im-

portant in processing complex auditory and Lancaster, & Fox, 2000; Richter, Lee, &Pardo, 2000; Riva & Giorgi, 2000).language stimuli. The superior temporal re-


White matter connectivity in fragile X—DTI. 1997), longitudinal DTI and MRI studies ininfants and young children with fragile X willGiven its role in the regulation of multiple

brain proteins, reduction in FMRP is likely to be critical in helping us elucidate the plastic-ity and development of frontal–striatal andinfluence brain structure and function via dif-

ferent mechanisms. For example, recent evi- parietal networks in fragile X syndrome.dence has shown that one of the proteins thatis regulated by FMRP is involved in axon Functional neuroimaging with fMRI. Al-

though we can offer hypotheses implicatingpath finding (Brown et al., 2001; Darnell etal., 2001), a process that has direct influences dysfunction of brain regions seen from these

structural studies to account for the pathogen-on axonal directionality, cohesiveness, andconnectivity. To study the integrity of white esis of neurobehavioral abnormalities in indi-

viduals with fragile X, we must confirm thematter tracts in subjects with fragile X, weused DTI, a recently developed MRI tech- link between neuroanatomy and neurobehav-

ior with studies of brain function. Becausenique enabling us to visualize and measurethe orientation of white matter tracts in vivo fragile X is a disorder whose initial manifesta-

tions are observed in infancy, knowledge of(Basser & Pierpaoli, 1996; Pierpaoli, Jezzard,Basser, Barnett, & Di Chiro, 1996). Using this early variation in functional neuroanatomy is

critical to improve our knowledge of specifictechnique, we studied 10 females with fragileX and 10 age-matched healthy females (Bar- gene–brain–behavior linkages in this condi-

tion. Yet, as of 1995, only one functional (posi-nea–Goraly et al., 2002).Compared with controls, subjects with tron emission tomography) brain study had

been carried out in fragile X using a limitedfragile X showed lower fractional anisotropy(FA) values, mostly in frontal–striatal and pa- sample (Schapiro et al., 1995). In the inter-

vening years, we have published results fromrietal sensorimotor tracts. FA is a commonlyemployed metric in DTI studies as it is corre- several studies in fragile X using fMRI

(Kwon et al., 2001; Menon, Kwon, et al.,lated with the directional coherence of whitematter fiber tracts. In conjunction with our 2000; Rivera et al., 2002; Tamm, Menon,

Johnston, Hessl, & Reiss, 2002) and severalMRI findings of abnormal caudate volumes infragile X and functional MRI (fMRI) studies others are currently in process. These studies

are described below and summarized in Tableshowing abnormalities in prefrontal areas(discussed below), these DTI findings support 1. The data from these fMRI studies and pre-

liminary results from our laboratory havea hypothesis that dysfunctional prefrontal–striatal (caudate) networks underlie some of been invaluable in helping us elucidate the

neurodevelopmental pathways that underliethe neurocognitive and neurobehavioral defi-cits in fragile X syndrome. The finding of ab- disruption of brain function in fragile X.

Arithmetic reasoning/computation. Amongnormal white matter tracts leading to the pari-etal lobes is relevant to the observed cognitive the fundamental cognitive deficits seen in

children with fragile X, problems in arithme-weaknesses in arithmetic reasoning and visuo-spatial processing in subjects with fragile X. tic reasoning and computation are well docu-

mented (Bennetto et al., 2001; Curfs, Borgh-Thus, aberrations in white matter in subjectswith fragile X as detected with DTI suggests graef, Wiegers, Schreppers–Tijdink, & Fryns,

1989; Dykens, Hodapp, & Leckman, 1989;that reduced or absent FMRP disrupts axondirectionality and coherence, possibly due to Kemper, Hagerman, Ahmad, & Mariner, 1986;

Kemper, Hagerman, & Altshul–Stark, 1988).misregulation of protein(s) by FMRP in neu-rons (e.g., MAP 1B, related to axon extension Accordingly, brain activation during arithme-

tic processing in subjects with fragile X wasand semaphorin 3F, related to axon path find-ing) as well as by disruption of dendrite matu- studied using fMRI (Rivera et al., 2002). Fe-

males with fragile X were compared with nor-ration. Because synapse formation is concur-rent with dendrite and axon growth beginning mally developing control females who at-

tempted to solve arithmetic equations within early infancy (Huttenlocher & Dabholkar,


Table 1. Summary of functional MRI studies in fragile X (FX)

Brain Function Principal Findings/Conclusions References

Arithmetic Unlike controls, subjects with FX could not modulate Menon, Rivera, et al.processing brain activation in response to increasing difficulty of (2000); Rivera et al.

the math task. (2002)In the control group, brain activation increased in parietal,

prefrontal, and cerebellar regions as a function of taskdifficulty. (FX increased only in prefrontal regions.)

In the FX group, FMR1 protein (FMRP) level waspositively correlated with brain activation for the three-operand task in (math-related) prefrontal and parietalregions.

Working Typical controls subjects show activation of the prefrontal Kwon et al. (2001);memory, cortex with additional regions recruited for the two- Menon, Kwon, etvisuospatial back condition. FX subjects show scattered prefrontal al. (2000)

and parietal cortex activation in the one-back task;activation is not increased during the two-backcondition.

Correlation between FMRP levels and brain activationprovides direct evidence between gene expression andcognition.

Executive In performing cognitive interference tasks, females with Tamm et al. (2002)function FX demonstrate a markedly different pattern of

activation than controls.Compared with controls, FX subjects have longer reaction

times and adopt a strategy trading speed for accuracy.Females with FX had reduced activation in brainregions important for modulating goal-directedbehavior.

Deficits in cognitive interference processing duringcognitive interference may arise from inability torecruit and modulate lateral prefrontal and parietalresources.

two (1 + 3 = 4) or three (2 + 3 − 1 = 4) sion underlies deficits in math performance inpersons with fragile X and that reduction inoperands. Subjects with fragile X showed sig-

nificant impairment in behavioral perfor- this critical neuronal protein impedes the nor-mal process of neural recruitment associatedmance on the three-operand but not the two-

operand arithmetic equations. Significant brain with tasks of increasingly difficulty.Working memory. As we have seen, prob-activation was observed bilaterally in the pre-

frontal and parietal cortices for unaffected lems with working memory have been re-ported to be an important component of cog-subjects and in the bilateral prefrontal and left

angular gyrus for subjects with fragile X, for nitive dysfunction in fragile X syndrome(Cornish, Munir, & Cross, 2001; Munir et al.,both trial types. Subjects with fragile X exhib-

ited less overall activation than did unaffected 2000a). To understand the neurological foun-dations of working memory in fragile X, wesubjects in both types of trials; and, unlike the

unaffected group, they did not show increased used fMRI to study females with fragile Xand typically developing females who per-extent of activation in association with greater

task difficulty. During the three-operand trials, formed standard one-back and two-back work-ing memory tasks (Kwon et al., 2001; Menon,activation in bilateral prefrontal and motor/pre-

motor, and left supramarginal and angular gyri Kwon, et al., 2000). Compared with controls,subjects with fragile X showed significantlywere positively correlated with FMRP, sug-

gesting that decreased FMR1 protein expres- reduced performance on the two-back test but


not the one-back test. Whereas control sub- adults with fragile X syndrome (Bregman,Leckman, & Ort, 1988; Cohen, Vietze, et al.,jects showed increased brain activation be-

tween the two working memory tasks, sub- 1989; Cohen, Vietze, Sudhalter, Jenkins, &Brown, 1991; de Vries, van den Ouweland,jects with fragile X showed no change in

activation between the two tasks. Significant Mohkamsing, Duivenvoorden, Mol, Gelsema,van Rijn, Halley, Sandkuijl, Oostra, Tibben,positive correlations were found in control

subjects between frontal and parietal activa- & Niermeijer, 1997; Einfeld, Molony, & Hall,1989; Wolff et al., 1989). Although manytion and performance (as percent correct) on

the two-back task but not on the one-back hypotheses have been suggested to explainwhy subjects with fragile X avoid eye contacttask. However, in subjects with fragile X, sig-

nificant positive correlations were found dur- (e.g., hyperarousal, anxiety, shyness), the neu-ral basis of this behavior has not been studied.ing the two-back task between FMRP expres-

sion and activation in prefrontal and Preliminary evidence from our laboratory re-sults suggest that gaze aversion may be partlysupramarginal gyri (Table 2). Thus, subjects

with fragile X syndrome are unable to modu- related to reduced brain activation in subjectswith fragile X. In response to face and gazelate activation in prefrontal and parietal cortex

in response to an increasing working memory information, individuals with fragile X havenormal or slightly increased levels of activa-load, and these deficits are related to a lower

level of FMRP expression. tion in brain regions involved in interpretinggaze direction in a social context but deficientExecutive function: Cognitive interference.

To study functional neuroanatomical changes activation in brain areas associated with gazeprocessing, chiefly the superior temporal sul-during cognitive intereference, we used a vari-

ant of the Stroop interference task, in which cus, an area involved in interpreting gaze di-rection in a social context.processing of one stimulus interferes with the

simultaneous processing of another (e.g., theword BLUE printed in red ink; Tamm et al.,

Summary and synthesis2002). Compared with controls, females withfragile X had longer reaction times during the Converging evidence from molecular studies

with subjects with fragile X and from fragileinterference condition of this task, and adopteda strategy trading speed for accuracy. Com- X animal models has shown how reductions

in FMRP lead to the complex sequences ofpared to females with fragile X, controlsshowed more activation in the anterior cingu- molecular events resulting in suboptimal cog-

nitive performance. FMRP functions an mRNAlate gyrus, frontal–striatal circuits, left andright supramarginal gyri, left and right poste- binding protein, transporting messenger ribo-

nucleoprotein complexes between nucleus andrior hippocampus, and cerebellar vermis. How-ever, subjects with fragile X showed more ac- cytoplasm of the neuron. These FMRP-associ-

ated mRNAs, which have been identified astivation in the left middle and inferior frontalgyri as well as the right angular gyrus. Fur- important to neuronal plasticity and develop-

ment, synaptic maturation, and axon pathfind-ther, between-group analyses revealed that fe-males with fragile X had reduced activation ing, translate ribosomes in dendrites during

critical developmental periods of activity-in the left orbitofrontal gyrus, thought to beinvolved in modulating goal-directed behav- dependent synaptic function, maturation, and

plasticity. When FMRP levels are reduced orior. Overall, these findings suggest that defi-cits in cognitive interference processing dur- absent, as occurs in fragile X or the mouse

and fruit fly knockout models of this condi-ing a Stroop-like task in females with fragileX may arise from their inability to appropri- tion, abnormal morphologies of cortical den-

dritic processes are observed. The resultantately recruit and modulate prefrontal and pari-etal resources. disorganization in neuronal circuitry of sub-

jects with fragile X produces the observableGaze aversion. As we have seen, sociallymediated gaze aversion is one of the more profile of cognitive, emotional, and behav-

ioral abnormalities in this disorder. Determin-common behavioral features in children and

Table 2. Correlations between genetic, environmental, and neurobiological functions in fragile X (FX) syndrome

Variable IQ Measures Brain Volume Brain Function Behavior

FMRP levels ⇓ FMRP, ⇓ IQ in M and F (fM) ⇓ FMRP, ⇓ cerebellar Math processing: ⇓ FMRP, ⇓ FMRP, ⇑ social withdrawal, anxious/with FXa–d vermis in M and F ⇓ activation of bilateral depressed behavior in F with fMj

(fM) with fMe prefrontal cortex and L ⇓ FMRP, ⇑ distractibility in F with fMb

⇓ FMRP, ⇑ caudate supramarginal + angular No correlations with adaptive behavior in M,nucleus in M and F gyri in F with fMg F with fMk

with fM and ⇑ lateral Working memory tests:ventricle in M with ⇓ FMRP, ⇓ activation RfM; caudate and lateral inferior and bilateral middleventricle volumes frontal gyri + bilateralcorrelate negatively supramarginal gyri in Fwith IQ f with fMh,i

CGG repeat length No correlations in M or F with ⇑ >100 RL, ⇑ scores on Interpersonal(RL) fMd,l,m Sensitivity and Depression Subscales

(SCL-90-R) in F with pM: no correlationfor ≤100 RL in F with pMl

⇑ RL, ⇑ attention problems, anxiety/withdrawal in F with fMn

Mean parent IQ ⇑ MPIQ, ⇑ IQ in F with fMd

(MPIQ) ⇑ MPIQ, ⇑ performance IQ in Mwith fM, and IQ index scoresin F with fMb

Quality of home ⇑ QH, ⇑ in F with fM and ⇑ QH, ⇓ autistic behaviors in M with fMj

environment (QH) typically developing Fb,o ⇑ QH, ⇑ adaptive behavior in M with fMk

Note: The FMRP level is a direct measure of the peripheral FMR1 protein levels. Activation R, the proportion of active (unmethylated, FMRP producing) FMR1 genes to total FMR1genes, is highly correlated with FMRP and is combined under FMRP levels; fM, FX full mutation; pM, FX premutation; F, females; M, males; L, left; R, right; ⇑ increased;⇓ decreased.aKaufmann et al. (1999). bDyer–Friedman et al. (2002). cAbrams et al. (1994). dReiss, Freund, et al. (1995). eMostofsky et al. (1998). fReiss, Abrams, et al. (1995). gRivera et al. (2002).hMenon, Kwon, et al. (2002). iKwon et al. (2001). jHessl et al. (2002). kGlaser et al. (2002). lJohnston et al. (2001). mMazzocco et al. (1997). nFreund et al. (1993). oKuo et al. (2002).

950


ing how these changes at the neuronal and tis- Environmental and Biological InteractionsInfluencing Outcomessue level are manifested in structure and

function of the brains from subjects with frag-ile X is a major objective of our neuroimaging As we have seen, studies over the past two

decades have established that children withresearch.Structural MRI studies have begun to lo- fragile X are at increased risk for the develop-

ment of a relatively specific profile of cogni-calize neuroanatomical differences seen in in-dividuals with fragile X. Although no differ- tive, emotional, and behavioral abnormalities.

It is also recognized that considerable individ-ences have been observed in brain symmetryor in neocortical lobe volumes in subjects ual variability exists in the severity of these

abnormalities, and therefore, it is important towith fragile X, both males and females withthe disorder show anatomical abnormalities of elucidate the full range of this variability and

to identify factors, other than reduced FMRP,several brain regions. Notably, significant vol-ume increases are seen in the caudate nucleus that contribute to phenotypic variation in chil-

dren with fragile X (Finegan, 1998). FMR1 isand hippocampus, and decreases are seen insuperior temporal gyrus and cerebellar vermis. only one gene and, accordingly, the general

genetic background of the individual plays aThese structural findings, particularly thoseseen in the caudate, are robust, and suggest significant role in influencing outcomes (Re-

iss, Freund, et al., 1995). Certainly, environ-correlations with neurobehavior and neuro-cognition in fragile X. Abnormalities on DTI, mental risk factors such as home and school

environment also influence development andparticularly in prefrontal–caudate pathways,suggest developmental abnormality leading to outcomes of children with fragile X, and stud-

ies designed to elucidate how functional out-aberrant neural connectivity during develop-ment that may need to be overcome to estab- comes are moderated and mediated by risk

factors such as family and educational envi-lish “normal” function in fragile X. The ab-normalities in white matter tracts may be ronments as well as neural function are vital

to understanding and optimizing developmentrelated to FMRP’s function in regulating axo-nal path finding. in children with fragile X.

Research attempting to identify factors thatFunctional imaging results suggest that, al-though individuals with fragile X are gener- influence outcome in fragile X has been lim-

ited to examining associations between cogni-ally activating appropriate brain regions dur-ing cognitive processing, unlike controls, they tive or behavioral function and genetic vari-

ables such as mutation category or direct andcannot recruit the additional resources “on de-mand” in response to increasing task diffi- indirect measures of FMR1 expression in blood

(Abrams et al., 1994; Bailey, Hatton, Tassone,culty. The functional deficits are found to cor-relate with the level of FMRP expression et al., 2001; Kaufmann, Abrams, Chen, &

Reiss, 1999; Mazzocco, Sonna, Teisl, Pinit,(higher FMRP levels were associated withmore normal brain activation). These studies Shapiro, Shah, & Reiss, 1997; Reiss, Freund,

et al., 1995; Rousseau, Heitz, et al., 1994;may provide a metric for measuring responsesto new treatments for fragile X. Tassone, Hagerman, Ikle, Dyer, Lampe, Wil-

lemsen, Oostra, & Taylor, 1999; Tassone,Further functional and structural neuro-imaging studies from our neuroimaging labo- Hagerman, Taylor, Mills, Harris, Gane, &

Hagerman, 2000; Taylor, Safanda, Fall, Quince,ratory in subjects with fragile X are under-way; our goal is to demonstrate a statistically Lang, Hull, Carpenter, Staley, & Hagerman,

1994). Studies focused on cognitive functionsignificant association between the specificgenetic marker of fragile X and brain activa- have generally shown that a small to moderate

proportion of intellectual ability in childrention and to understand more precisely the tim-ing and nature of these neurobiological dis- with fragile X can be predicted by these ge-

netic variables. A study of the association be-ruptions during early development in childrenwith fragile X. tween FMRP and behavior in fragile X (Tas-


sone, Hagerman, Ikle, et al., 1999) showed a cluding a background genetic predispositionto learning problems or psychopathology (in-negative correlation between FMRP and 10

behaviors associated with fragile X, but only dependent of the FMR1 mutation), may con-tribute to cognitive and behavioral variationin males with mosaicism.

However, at present, it is apparent that ge- in children with fragile X (Jeffries, Reiss,Brown, Meyers, Glicksman, & Bandyopa-netic measures are necessary, but not suffi-

cient, to explain variation in cognitive, emo- dhyay, 1993; Reiss, Freund, et al., 1995). Ex-amination of the home and school environ-tional, and behavioral outcome in children

with fragile X. There are several reasons why ment also may yield important informationabout nongenetic influences on child cogni-genetic measures may be limited in predicting

outcomes in children with fragile X syndrome. tive and behavioral function and outcome. Al-though developing specific, biological treat-First, the most commonly used genetic mea-

sures are based on tissues of mesodermal ori- ments to prevent or reverse the deleteriouseffects of fragile X is a common goal in thegin (usually blood leukocytes), while rela-

tively inaccessible brain tissue is of ectodermal field, identifying and measuring environmen-tal influences (e.g., effectiveness of educa-origin (Abrams, Kaufmann, Rousseau, Oos-

tra, Wolozin, Taylor, Lishaa, Morel, Hooge- tional or therapeutic services, characteristicsof parents) will help us develop more effec-veen, & Reiss, 1999; Tassone, Hagerman,

Gane, & Taylor, 1999; Willemsen, Anar, De tive temporally proximate interventions. Evenwhen specific biological treatments becomeDiego Otero, de Vries, Hilhorst–Hofstee,

Smits, van Looveren, Willems, Galjaard, & available, reduced FMRP in the brain affectsearly development when the nervous systemOostra, 1999). Also, leukocytes rapidly and

continually turn over throughout an individu- undergoes its most rapid growth and matura-tion and therefore reduction of cognitive/al’s life span, whereas neurons do not gener-

ally turn over after birth. If having increasing behavioral symptoms may be less successfulin older individuals. Thus, knowledge of earlyFMRP production confers functional advan-

tage to leukocyte progenitors, then individuals environmental influences on outcome is likelyto have long-term benefit to individuals andwho are mosaic for different FMR1 mutation

types (e.g., premutation and full mutation families affected by fragile X.lines, varying allele sizes, and/or methylation)may manifest increasing “selection” of more

Influences on cognitive, behavioral,“fit” cell lines over time (Mornet, Jokic,

and emotional outcomesBogyo, Tejada, Deluchat, Boue, & Boue,1993; Rousseau, Heitz, Oberle, & Mandel, Cohort and methods. To study cognitive, be-

havior, and emotional outcomes, we con-1991; Rousseau, Robb, Rouillard, & DerKaloustian, 1994). In our ongoing work, we ducted in-home evaluations of 120 children

(aged 6–17 years) with fragile X (40 girls, 80are attempting to characterize this process andunderstand how it relates to age and mutation boys; mean age = 10.7 years), their unaffected

siblings (62 girls, 58 boys; mean age = 11.2type.It also is highly likely that a significant years), and their parents. Independent predic-

tor values were (a) biological/demographicproportion of the variance in cognitive, emo-tional, and behavioral function in children variables, including age, gender, FMRP levels,

and mean parental IQ; and (b) environmentalwith fragile X is attributable to other biologi-cal influences (genes whose expression are variables, including family income, quality of

the home environment (Wechsler, 1991), pa-regulated by FMRP or the hundreds or thou-sands of other genes that regulate brain matu- rental psychopathology (Derogatis, 1994), and

effectiveness of educational and therapeutic ser-ration and function) or environmental influ-ences such as the prenatal and postnatal vices (Dyer–Friedman, Glaser, Hessl, John-

ston, Huffman, Taylor, Wisbeck, & Reiss,environment. For example, as with most neu-ropsychiatric or developmental disorders, psy- 2002). The principal dependent variables in-

cluded WISC-III IQ and index scores (Wech-chological characteristics of the parents, in-


sler, 1991), Vineland Adaptive Behavior Scale the moderately low to low range. For boyswith fragile X, older age and lower IQ pre-(Sparrow, 1984), domain scores and scores

from the CBCL checklist (Achenbach, 1991), dicted decreased Composite, Communication,and Socialization (standardized) Vineland do-and the Autism Behavior Checklist (Krug et

al., 1993). The results from the studies using main scores, supporting the hypothesis thatthe rate of growth of adaptive behavior skillsthis cohort are described below (Dyer–Fried-

man et al., 2002; Glaser et al., 2002; Hessl, declines in school-age boys with fragile X. Aswas found in cognitive outcome factors, theDyer-Friedman, Glaser, Wisbeck, Barajas,

Taylor, & Reiss, 2001; Kuo, Reiss, Freund, & quality of the home environment also was re-lated to increased domain scores in boys withHuffman, 2002).fragile X: a better quality of home environ-ment translated to higher scores on adaptiveCognitive outcome. Using this cohort of 120

families, Dyer–Friedman et al. (2002) mea- behavior testing. For girls with fragile X,adaptive behavior was most strongly associ-sured the genetic and environmental factors

influencing the cognitive outcomes in chil- ated with IQ. Adaptive behavior was not sig-nificantly associated with FMRP in eitherdren with fragile X. Girls with fragile X, on

average, performed in the borderline intellec- boys or girls with fragile X (see Table 2).These results provide the first evidence thattual functioning range for full scale IQ (M =

75.48), whereas boys with fragile X performed both biological and environmental factorscontribute significantly to adaptive behaviorsin the moderate mental retardation range (M =

46.35, floor effect in 43%). Girls with fragile development in typically developing siblingcontrols and boys with fragile X.X in this study demonstrated relative strengths

in verbal domains. However, there was evi-dence of an age-related decline in FSIQ and Emotional and behavioral outcome. Hessl et

al. measured the influence of environmentalverbal skills for boys with fragile X in thiscross-sectional sample. Multiple regression and genetic factors on behavior problems and

autistic symptoms in boys and girls with frag-analyses showed that the cognitive outcomesfor girls with fragile X were most strongly ile X syndrome with this cohort (Hessl et al.,

2001). Generally, both boys and girls withpredicted by the mean IQ of their parents witha small proportion of the variance accounted fragile X exhibited social, attention, and

thought problems in the borderline to clinicalfor by the quality of their home environment.FMRP was associated with girls’ levels of range on the CBCL. Boys with fragile X had

moderate levels of autistic behavior similar todistractibility. Mean parental IQ was asso-ciated with boys’ performance IQs, whereas those of a sample of children with severe

mental retardation but well below that of chil-FMRP was associated with boys’ full scaleIQs. The quality of boys’ home environments dren diagnosed with autism. Mild levels of

autistic behavior were seen in girls with frag-accounted for more of the variance in theircognitive outcomes than it did for girls. Thus, ile X with as much variability as boys.

In this study, behavior problems in boysboth biological/genetic factors and environ-mental factors were significant predictors of with fragile X were consistently associated

with environmental factors, but not with FMRPIQ in children with fragile X syndrome; how-ever, the influence of specific factors differed or IQ. Specifically, maternal reports of more

effective educational and therapeutic servicesbetween girls and boys.were associated with fewer behavioral prob-lems and autistic symptoms, whereas parentalAdaptive behavior outcome. Using the cohort

described above, Glaser et al. (2002) studied psychopathology was significantly associatedonly with internalizing problems. Autistic be-how biological and environmental factors in-

fluenced the development of adaptive behav- haviors increased linearly in boys with fragileX as the quality of their home environmentior in children with fragile X. Boys with frag-

ile X had Vineland domain scores in the low decreased.In contrast to boys with fragile X, genetic,range whereas girls with fragile X scored in


rather than environmental, factors were asso- siblings, so counseling may be useful. Third,home and educational environment stronglyciated with behavior problems in girls with

fragile X. Although FMRP was more strongly influence autistic behaviors in boys with frag-ile X such that a more structured, enrichedassociated with internalizing types of prob-

lems, IQ was more strongly associated with home environment and targeted behavioral in-tervention may reduce these behaviors.externalizing behavioral problems, which de-

creased linearly as levels of FMRP decreased.Overall, IQ and FMRP accounted for 34% of Cortisol and behavior. Despite the relatively

consistent links between FMR1 gene functionthe variance in total behavior problems amonggirls with fragile X. In contrast to boys with and outcomes in children with fragile X, there

is still considerable variability in stress-re-fragile X, for the most part, genetic ratherthan environmental factors were associated lated behavioral problems, ranging from high

levels of distress, often in novel social situa-with behavior problems in girls. AlthoughFMRP was more strongly associated with in- tions, to normal functioning. As we have

seen, this variability can be partly explainedternalizing types of problems, IQ was morestrongly associated with externalizing prob- by nongenetic factors, such as characteristics

of the home environment and the effective-lems. Finally, IQ was the only significant pre-dictor of autistic behavior in girls with fragile ness of educational and therapeutic services

(Hessl et al., 2001). However, other individualX, accounting for approximately 33% of thevariance. characteristics of children or the environments

in which they live may help to better accountIn girls with fragile X, FMRP was signifi-cantly associated with withdrawn and anx- for these individual differences, leading to

more effective methods of assessment andious/depressed behavior, but not with social,attention, or thought problems on the CBCL. treatment of stress-related symptoms.

One such characteristic, the function of theAlso, increased effectiveness of therapeuticservices was associated with girls’ decreased hypothalamic–pituitary–adrenal (HPA) axis,

may help to explain some of the variability inattention and thought problems. Boys withfragile X did not change results pertaining to stress-related symptoms among children with

fragile X. Reports of endocrine abnormalitiesFMRP such that FMRP was not associatedwith any behavioral scores. In boys, the more in children with fragile X (Bregman, Leck-

man, & Ort, 1990; Butler & Najjar, 1988;effective educational and therapeutic serviceswere significantly correlated with less with- Loesch, Huggins, & Hoang, 1995), observa-

tions of neurobehavioral features such as hy-drawn behavior, less anxious/depressed be-havior, and fewer attention and thought prob- perarousal and social anxiety, and evidence of

neuroanatomical abnormalities such as hippo-lems, a result similar to that seen in girls withfragile X. campus enlargement (Kates et al., 1997;

Reiss, Freund, et al., 1995), suggests that anThese findings are among the first to linkFMRP expression to behavior and further take abnormal HPA axis function may be a compo-

nent of the fragile X syndrome. Specifically,into consideration emphasize the importanceof home and school environments in influenc- children with fragile X have a higher inci-

dence of precocious puberty and elevated go-ing behavior in children with fragile X. Theresults highlight several points at which inter- nadotrophin levels (Butler & Najjar, 1988;

Moore, Chudley, & Winter, 1990), and expe-vention might be effective. First, the associa-tion between the effectiveness of educational rience less pubertal growth than normal chil-

dren, despite normal prepubertal growthand therapeutic services and behavioral out-come indicates that from the mother’s per- (Loesch et al., 1995). This abnormal growth

pattern may be due to a premature activationspective, the fit between the child’s develop-mental needs and the services he or she of the HPA in children with fragile X.

Based on the well-characterized profile ofreceives is important. Second, parental psy-chopathology was associated with behavior autonomic and behavioral overreactivity and

hyperarousal observed in our studies and thoseproblems in children with fragile X and their


of others, we hypothesized that children with psychopathology, the home environment, andthe effectiveness of educational and therapeu-fragile X would have higher levels of the ad-

renal hormone, cortisol, in comparison to their tic services. It is interesting that the level ofsalivary cortisol predicted as much, or moreunaffected siblings, and accordingly, we in-

vestigated the extent of abnormal activation of the variance in behavior problems as thelevel of protein expressed by the FMR1 gene.of the HPA axis in children with fragile X and

its relevance to neurobehavioral and neuroan- Thus, the results highlight many sources ofindividual differences in behavior problemsatomical abnormalities (Hessl et al., 2002). In

this study, 109 children (70 males and 39 fe- among children with fragile X, suggestingthat multidimensional assessment may be nec-males) and their unaffected siblings (51 males

and 58 females) completed an in-home evalu- essary to best predict the outcomes of individ-ual affected children. However, a large pro-ation including a cognitive assessment and

structured social challenge task. Multiple portion of the variance in behavior problemsof children with fragile X, especially boys, re-samples of salivary cortisol were collected

throughout the evaluation day (including pre- mains unexplained. Unknown characteristicsof children and their families may be influen-and postsocial challenge) and on two typical,

nonschool days. Measures of FMR1 gene, tial. The use and effectiveness of medication,parenting practices, the presence or absencechild intelligence, the quality of the home en-

vironment, parental psychopathology, and the of other siblings affected by fragile X, andother biological or genetic factors also may beeffectiveness of educational and therapeutic

services also were measured. Regression anal- associated with the frequency and severity ofbehavioral and psychiatric problems in theseyses were conducted to determine whether

adrenocortical activity was associated with children.In summary, the scope and quality of infor-behavioral problems after controlling for sig-

nificant genetic and environmental factors. mation collected in these studies provides aunique opportunity to understand the develop-Both the fragile X and sibling groups ex-

hibited the expected diurnal decline in corti- mental trajectory of cognitive, adaptive be-havior, and emotional/behavioral domains assol. On typical days, a significant main effect

of diagnosis and a diagnosis by gender inter- well as more precisely elucidate those envi-ronmental and biological factors that most in-action showed that, in comparison with their

siblings, children with fragile X, especially fluence outcomes in children with fragile X.males, have higher levels of salivary cortisol.On evaluation days, children with fragile Xshowed increased cortisol reactivity during How the Study of Fragile X Can Informcognitive evaluation and when meeting re- Developmental Theorysearch staff. We found no correlation betweencortisol level and IQ within the fragile X During the past 25 years, researchers and cli-

nicians have made dramatic gains in the fieldsgroup. Increased cortisol was significantly as-sociated with behavioral problems in boys and of neuroscience, human development, and de-

velopmental psychopathology. Despite thesegirls with fragile X but not in their unaffectedsiblings, suggesting that the HPA axis may advances, less progress has been made in un-

derstanding the relationship between neurobi-have an independent association with behav-ioral problems in children with this disorder. ological, behavioral, and cognitive develop-

ment of atypical and typical populations. ToThese findings replicate and extend previousresults from our lab obtained from a different, what extent can neurodevelopmental disorders

in childhood be interpreted within models ofsmaller sample of children (Wisbeck et al.,2000) in which highly significant family ef- normal development? How can the study of

developmental disorders inform us about typi-fects on salivary cortisol were detected.Predictors of behavior problems included cal development of the brain, cognition, and

behavior? Through our behavioral neurogene-child intelligence, FMR1 gene function, andadrenocortical activity, as well as parental tics approach to studying homogeneous popu-


lations such as fragile X syndrome, we are recent technological advances have greatlyenhanced and refined this analysis on manycloser to answering these questions today.

Certainly, the study of normal develop- levels. Particularly, in the past decade, wehave seen the development of more sophisti-ment has provided researchers with a founda-

tion that has furthered our understanding of cated imaging equipment and software forMRI and DTI, increasingly sensitive tools foranomalous growth and development, which,

for example, has helped us to determine the genetic analysis, informative fragile X animalmodels, as well as more reliable and valid be-causes of birth defects and understand the

progress of complex human disease. How- havioral and cognitive instruments.What, then, has fragile X taught us aboutever, the reverse is also true: researchers have

gained valuable information about normal de- developmental theory? At the level of thegene, studies of individuals with fragile X, asvelopment through the study of abnormal de-

velopment. By studying atypical populations, well as the mouse and fruit fly knockout mod-els of this condition, have recently provideddevelopmental theories can be affirmed, aug-

mented, and challenged. A comprehensive us with valuable new insights into the geneticcontrol of neural development. Specifically,understanding of abnormal development can

elucidate the consequences of alternate devel- we have seen that the fragile X mental retar-dation protein, FMRP, increases in those brainopmental pathways, help us define the range

and variability of responses to challenges, and regions undergoing active synaptogenesis inresponse to motor learning or being reared inspecify the limits of behavioral and biological

plasticity in affected individuals. In particular, complex and enriched environments. In nor-mal neurodevelopment, FMRP associatesstudying childhood neurodevelopmental dis-

orders at multiple levels allows us to better with several mRNAs that are integrally in-volved in critical neurodevelopmental pro-understand typical development by highlight-

ing specific developmental domains or events cesses such as neuronal plasticity and devel-opment, synapse and dendrite formation andthroughout a child’s life span, thereby helping

to delineate the boundaries of pathology. In maturation, and axon path finding. In the ab-sence of FMRP, such processes unfold in anour research approach, we have focused our

study of neurodevelopment on disorders with aberrant manner very early in neurodevelop-ment, leading to impairments in dendriticspecific genetic etiologies as a means of

developing greater insights into neurode- spine maturation and a failure of normal syn-apse pruning and axon formation. At the neu-velopmental pathways that might otherwise

be obscured or diluted by studying more be- ral systems level, such neurodevelopmentalimpairments result in specific alterations inhaviorally defined disorders. Fragile X has

proved researchers with an invaluable “exper- brain structure and function.Our structural MRI studies of individualsiment of nature” to examine developmental

processes in a more homogenous population with fragile X have revealed significant vol-ume increases in the caudate nucleus andwith respect to aberrant neurodevelopmental.

As we have seen, in fragile X, a single hippocampus, and decreases in the superiortemporal gyrus and cerebellar vermis. Thesegene defect on the X chromosome triggers a

cascade of highly complex events that leads structural findings, particularly those seen inthe caudate, are robust, and suggest correla-the neural system down a path to its ultimate

manifestations of increased risk for problems tions with neurobehavior and neurocognitionin fragile X. For example, the caudate, throughin behavior, learning, and development. Since

the discovery of the genetic basis of fragile X its connections with the frontal cortex, coordi-nates attention and working memory, regula-syndrome in 1991, researchers and clinicians

from many disciplines have had a rare oppor- tion of mood, impulse control, and flexibilityin behavioral responses to environmentaltunity to study the complex interplay between

genes, neurodevelopment, cognitive and be- cues, functions that show impairment in thechild with fragile X. Further, our recent DTIhavioral development, and environmental ef-

fects on developmental outcomes. In addition, analyses have uncovered abnormalities in


white matter tracts, particularly in prefrontal– of age, reaching a plateau in middle to latechildhood or early adolescence, generally bycaudate pathways, suggesting aberrant neural

tracts and connectivity that may need to be age 10, as evidenced by declining IQ scoresand a lack of consistent gains during theseeventually overcome to establish “normal”

function in individuals with fragile X. These years. Beginning in the preschool years andextending into the school and adolescentabnormalities in white matter tracts may be

related to FMRP’s function in regulating axon years, boys show pervasive deficits in conver-sational language skills with increasing dis-extension and path finding during neural de-

velopment. crepancy between language level and chrono-logical age. We have seen that the patterns ofIn our fMRI studies, we have seen distinct

alterations in brain activation patterns from behavioral, social, and developmental abnor-malities that emerge in preschool boys sug-children with fragile X compared with typi-

cally developing children in tasks of executive gests that fragile X is a risk factor for autisticbehavior. In particular, the presence of a ner-functioning, visuospatial processing, and math

ability. While individuals with fragile X are vous system that is poorly modulated (e.g.,hyperarousal, problems with inhibition andgenerally activating appropriate brain regions

during cognitive processing, unlike typically habituation) may contribute to the developmentof the autistic “features” observed in childrendeveloping subjects, they cannot recruit the

additional resources “on demand” in response with fragile X.Girls with fragile X are more variable into increasing task difficulty. These functional

deficits correlate with the level of FMRP ex- their development: whereas those with the fullmutation may show mildly to moderately se-pression: higher FMRP levels are associated

with more normal brain activation. By identi- vere quantitative and qualitative abnormali-ties, those with the premutation are muchfying specific regions involved in these cogni-

tive tasks, we can more clearly understand more likely to show trajectories similar to typ-ically developing girls.how neurodevelopmental changes in fragile X

are manifested in cognitive functioning and, The trajectories of these impairments frominfancy through adolescence and adulthoodmost importantly, our results provide an im-

portant metric for directing and following the are complex and variable due to variability inthe interplay between complex genetic, envi-responses to new treatments for fragile X.

In terms of neurocognitive and neuro- ronmental, and biological risk factors. The re-sulting heterogeneity in individual patterns ofbehavioral development, we observe that,

compared with typically developing children, development and symptom manifestations infragile X underscore that both genetic expres-those with fragile X show early delays in

functioning. These delays are characterized sion and environmental factors influence ex-pression in this disorder. Differences in FMRPparticularly by age-related declines in IQ, dis-

turbance in language and communication, re- localization among females and FMRP levelsin both males and females due to polymor-duced trajectory in the development of adap-

tive behaviors, cognitive abnormalities within phisms in genes whose mRNAs are bound byFMRP likely contribute to this heterogeneity.the domains of executive function and visual-

spatial cognition, hyperactivity, and signifi- As we have seen, the child’s environmentstrongly influences the expression of problemcant problems with hyperarousal and anxiety.

Boys are less variable than girls in expressing behaviors (including autistic symptoms) andcognitive ability. Recently, Grossman et al re-such cognitive and behavioral symptoms. On

average, delays are noticed in the infant at 24 viewed the contributions that environmentand experience has made on psychopathologymonths. As boys with fragile X reach pre-

school age, their rate of development ranges in fragile X and other disorders, suggestingthat there may be multiple genetically or envi-from one-third to one-half that expected for

typically developing boys. Cognitive and adap- ronmentally influenced routes to commondevelopmental outcomes as well as multipletive behavioral development slows in boys

with fragile X beginning as early as 5 years outcomes in a common genetic syndrome


(Grossman, Churchill, McKinney, Kodish, Otte, Interrelationships between cognition and be-havior are seen in females with fragile X in& Greenough, 2003).

Thus, we can appreciate how behavioral which an increase in anxiety is associatedwith lower math ability and decreases in at-neurogenetics, as a multilevel systems ap-

proach, has led us to an improved understand- tention are associated with decreased socialskills. Finally, outcomes of children with fragileing of the complex linkages among genetic,

neurobiological, cognitive, and behavioral vari- X are strongly influenced by their environment.For example, increased mean parental IQ andables that contribute to neurodevelopmental

dysfunction. According to such an integrated socioeconomic status correlate with increasedIQ of the child. Particularly in males with frag-“systems neuroscience” (Cicchetti & Dawson,

2002) approach, the brain can be conceptual- ile X, we see a significant interplay betweenbrain, behavior, and environment through a pre-ized as developing and operating in a highly

plastic, self-organizing environment, which is mature activation of the HPA axis and cortisolproduction, expressed in boys as hyperarousal.less constrained by predetermined boundaries

than previously thought (Posner, Rothbard, Ultimately, however, to better understandthe topography of typical and atypical devel-Farah, & Bruer, 2001). In this scheme, distrib-

uted groups of neurons maintain functional opment in fragile X syndrome, we need pro-spective longitudinal studies of large groupsinterconnections based on experience in addi-

tion to a genetically predetermined scheme of children with fragile X. This research isvital because (a) elucidating the biological(Courchesne, Chisum, & Townsend, 1994;

Gottlieb, Wahlsten, & Lickliter, 1998; John- and environmental factors that influence cog-nitive and behavioral outcomes will identifyson, 1998; Thelen & Smith, 1998). Thus, in

addition to genotypic variability influencing areas of function sensitive to intervention, (b)obtaining precise information about develop-behavior and cognition, social experiences

also significantly affect neural structure and ment will help determine whether specific in-terventions lead to meaningful changes infunction throughout development (Cicchetti

& Tucker, 1994; Dawson, Hessl, & Frey, functioning, and (c) understanding specificdomains of suboptimal development may pro-1994; Francis, Diorio, Liu, & Meaney, 1999;

Gottlieb, 1992; Kandel, 1998; Meaney, Di- vide clues for us to formulate early interven-tions in children with fragile X.orio, Francis, Widdowson, LaPlante, Caldji,

Sharma, Seckl, & Plotsky, 1996). Our studies In summary, we have today a clearer un-derstanding of atypical development in fragileof individuals with fragile X have partly af-

firmed this. We have seen the complex inter- X and how the perturbations in a specific ge-netic locus alters brain development andplay between genetic events, brain activation

and structure, and behavior and cognition, as thereby alters the development of psychologi-cal functions. This study has begun to provideshown in Table 2. For example, decreases in

FMRP are associated with decreases in brain us with an integrated scientific explanationfor the disorder, and achieving such explana-activation during math processing, working

memory tasks, and cognitive processes as well tions has important consequences for both ba-sic developmental science and clinical prac-as changes in specific brain structures, partic-

ularly caudate. Other molecular/genetic changes tice. Understanding how language and speechdevelops abnormally in fragile X syndromesuch as increased CGG amplification size and

decreased FMRP levels are associated with de- (as with other neurogenetic disorders like Turn-er syndrome, VCFS, and Williams syndrome)creases in a child’s IQ; increased FMR1 meth-

ylation is associated with brain structural will help us understand how it develops nor-mally in typically developing children. Thechanges. Further, decreases in FMRP also

correlate with an increase in stereotypy, com- same is true for other domains such as execu-tive function, social cognition, and emotionmunication, and attention problems and a de-

crease in peer socialization. Decreases in ver- regulation. In clinical practice, having an inte-grated scientific explanation of a disordermis and increases in caudate are linked with

decreases in IQ and increases in stereotypy. such as fragile X inevitably leads to improve-


ments in diagnosis and early detection as well and cognition accumulate through a progres-sion of worsening anatomic and functionalas new treatments.connectivity in key pathways in the brain? Doparticular genetic and environmental influ-

Implications for Future Researchences accumulate during development thatfurther alter brain function later in life? WhenProgress in fragile X research over the last

decade—from the detailed characterization of are children with fragile X most likely to de-velop maladaptive behaviors or plateau inthe FMR1 gene and FMRP function at the

neuronal level to the characterization of brain their cognitive trajectory? What factors have apositive influence on cognitive and behavioraland behavioral abnormalities—truly has been

dramatic and exciting for the field of develop- development? What factors other than re-duced FMRP contribute to the severity ofmental psychopathology. The capability of uti-

lizing behavioral neurogenetics research strat- maladaptive behaviors and cognitive impair-ment? When is intervention most needed andegies has required technical advances that have

only recently become available. In particular, most effective? What are the best cognitive,behavioral, and functional metrics for follow-recent advances in molecular genetics and

brain imaging have greatly facilitated our ing response to interventions?Answering these questions will be key inknowledge of abnormal and normal brain–

behavior development in genetic disorders developing a more complete framework fromwhich to design and implement biological andsuch as fragile X, and today a more profound

understanding of the developmental psycho- environmental interventions for children withfragile X. In developing such a framework,pathology of fragile X is within our grasp.

Fragile X also serves as an important re- we must first characterize the complex devel-opmental trajectories in infants and youngminder of the complexities involved in eluci-

dating the pathogenesis of neurogenetic and children with fragile X. Although most inves-tigators agree that IQ and adaptive behaviorneurodevelopmental disorders. Despite the

clearly identified genetic cause and well-char- scores decline in young children with fragileX, the precise timing and neurobiologicalacterized neuropsychological, molecular, cel-

lular, and neuroanatomic features, the disor- basis of this important clinical feature areunknown. Particularly, our research mustder is far from being completely understood.

Gaps remain in our understanding of the de- have a focus on infants and young preschoolchildren for whom dynamic changes in brainvelopmental relationships between FMR1 gene

function and the complex patterns of cogni- development and organization are takingplace.tive and behavioral abnormalities and abnor-

malities in brain structure and function in Our ongoing studies using longitudinal,prospective designs with multiple time assess-fragile X. In particular, we still do not under-

stand the precise timing and nature of gene– ments are designed to elucidate the early signsof aberrant brain development in infant andbrain–behavior disruptions in children with

fragile X. Likewise, although it is clear that preschools with fragile X. Our goals are tounderstand the developmental trajectories ofmutations of the FMR1 gene, in general, in-

crease risk for cognitive, behavioral and emo- (a) brain structure and function, specificallypatterns of brain size and shape and whitetional dysfunction, knowledge of how func-

tional outcome is moderated and mediated by matter connectivity; (b) cognitive, behavioral,and emotional development as they relatefactors such as age, the family and educa-

tional environments, and neural function has to morphological brain characteristics; (c)HPA function; and (d) FMR1 gene expres-only recently begun to emerge. Information of

this nature is vital to understanding and opti- sion (FMRP) in relation to brain–behaviorchanges. In assessing such developmentalmizing development in children with fragile

X. For example, are infants and preschoolers trajectories, we must compare developingchildren with fragile X with age- and gender-with fragile X born with the “full measure” of

the genetic risk, or do problems in behavior matched controls, children with idiopathic de-


velopmental disability, and those with devel- By measuring and accounting for these ge-netic influences, we are, therefore, better ableopment disabilities with specific etiologies

and with non-fragile X, autistic children. to begin to understand the roles of other fac-tors such as the environment, and neuroendo-This research will provide new and much-

needed information to help us characterize the crine function in the outcomes of childrenwith fragile X. The answers to the questionspattern and timing of changes in brain size,

shape, and connectivity during early brain de- posed here will provide us with the informa-tion necessary to construct well-informedvelopment in children with fragile X. A more

complete picture of these developmental pat- clinical trials in the near future, in which theimportant biological and environmental influ-terns will help us see the cross-sectional and

longitudinal relationships between specific ences can be assigned etiological significancewith confidence. In our ongoing and future re-brain characteristics and the pattern of se-

lected cognitive characteristics and behavioral search, elucidating how the brain is structur-ally and functionally different in children withabnormalities known to be abnormal in young

children with fragile X. fragile X and how the children with this disor-der behave, learn, and experience emotionsFurther study of fragile X as a model sys-

tem will likely provide us with important new differently will help us determine specific treat-ments and predict outcomes in these children.insights into the pathogenesis of related devel-

opmental disorders and abnormalities of be- Our ultimate goal is to improve the lives ofthose affected by fragile X syndrome and gainhavior and cognition in young children. By

studying individuals with fragile X, we can deeper insights into the causes of other behav-ioral, developmental, and learning problemstrace the pathway that begins with the single

genetic mutation out to its ultimate manifesta- that occur in children.tions in behavior, learning, and development.

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