trends and challenges in behavioural phenotype research

Editorial

Trends and challenges in behavioural phenotyperesearch

The 10th International Symposium of the Societyfor the Study of Behavioural Phenotypes (SSBP)takes place in Sacramento this year. This meetingwill feature the first Tom Oppe Keynote Lecture inrecognition of the work of the Society’s first Presi-dent, who died this year. The theme of the meetingis commonalities across rare genetic disorders at themolecular and neurobiological level and the way inwhich these commonalities lead to new avenues oftranslational research. This edition of JIDR featuresabstracts from this meeting and empirical studiesthat seek to extend our understanding of the effectsof genetic disorders on the cognitive profiles andbehaviour of people with intellectual disability (ID).Papers in this edition demonstrate the diverseeffects of genetic disorders, both within andbetween syndromes, and add to the increasinglyrobust evidence for an association between geneticdisorders and behavioural difference. The impor-tance of this association for social, educational andclinical services is becoming more apparent, but issometimes negated by either a reluctance to acceptindividual difference as a key component of person-environment fit or rigid adherence to genetic deter-minism. A significant challenge for those involvedwith people with ID caused by a genetic disorder isthe integration of value-driven support and serviceprovision with knowledge about the effects of com-paratively rare genetically determined syndromes.

There is slow growing recognition that whilsteach genetic syndrome might only affect a relatively

small number of people, the total number of peopleaffected is substantial. If lowest estimates are used,then for profound/severe ID (3.8/1000; 50% geneticcause) and moderate/mild ID (25/1000; 13% geneticcause), approximately 370 000 people in the UKare affected. Using estimates in the midrange, thefigure is closer to half a million in the UK. A world-wide estimate is likely to approach 10 millionpeople. The rarity of each syndrome means thatpractitioners often have limited experience andknowledge of any given syndrome, and it is this thathas motivated parents to create increasingly influen-tial and well-organized syndrome support groupsthat provide a service to families and professionalsin the absence of statutory provision.

This combination of the rarity of individual syn-dromes and the large number of individual syn-dromes (estimated at 1500) is at the heart of adifference in research paradigms and assumptionsthat underpin service delivery. If there are demon-strable differences between syndrome groups, thenis there merit in describing psychopathology inpeople with ID of differing aetiologies at grouplevel? If the needs of service users are shared anduniform, then is there merit in identifying aetiology?Responses to these questions need to be supportedby data rather than dogma, and one source of thatdata is high-quality behavioural phenotype research.Should that research show that identifying geneticaetiology can be useful in predicting and designingaspects of service need or effective intervention,

Journal of Intellectual Disability Research doi: 10.1111/j.1365-2788.2007.00987.x

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© 2007 The Authors. Journal Compilation © 2007 Blackwell Publishing Ltd

then the question is can services respond to thisevidence given the diversity of identified need andthe scale of specific needs? Clearly, there is a poten-tial role here for informed and effective person-centred planning, and there may be good reason forthis process to draw on behavioural phenotyperesearch.

At a more fundamental level, the growth ofbehavioural phenotype research stems, in part, fromthe realization that paths from gene to protein tocentral nervous system structure and function tocognitive endophenotype to behaviour can be tracedby identifying the genetic disorder as the definingcriterion for a group for research purposes, and oneor more aspects of development and behaviour asthe outcome. This strategy is in stark contrast tothat often seen in the study of autistic spectrumdisorder and attention deficit hyperactivity disorder(ADHD) where groups are typically defined bybehavioural, social and cognitive impairments andgenetic disorder is sought as the research outcome.Points of overlap for these strategies are emergingas cognitive correlates of shared behavioural phe-nomena are described with increasing specificityand seem set to displace behaviour as the mostrobust focus of assessment for the purpose ofresearch (see Morton (2004) for a discussion of thisissue). This shift in emphasis in behavioural pheno-type studies is evident in many of the studiesdescribed in this edition which, when consideredalongside the work on imaging, hold much promisefor providing more complete accounts of the asso-ciations between genetic disorders and behaviour inpeople with an ID.

The focus on the cognitive endophenotype ismost evident in contemporary work on Down, Will-iams and fragile X syndromes. Research on thesesyndromes has demonstrated the use of methodsand designs that can be emulated for other groups.As the most pressing clinical problems in other syn-dromes are addressed, such as self-injury in Corne-lia de Lange syndrome and hyperphagia in Prader–Willi syndrome, so attention is turning to the moresubtle cognitive and social impairments that can behypothesized to be present, on the basis of behav-ioural presentation, and that have been exploredpreviously in other groups. This process of transfer-ring methods and pathways across groups hasrecently been complemented by a developmental

perspective, most notably applied to Williams syn-drome (e.g. Karmiloff-Smith et al. 2004), andexamination of change with age beyond adolescencein Down syndrome and fragile X syndrome. Forthese three syndromes, the delineation of the pathfrom gene to behaviour is progressing well, andthere is much to be learned from the way in whichresearch evolved in these syndromes.

The story of fragile X is a useful model for howknowledge of the gene can dramatically enhanceour understanding of phenotypic variation anduncover new disorders associated with the samegene. Sixteen years ago, the FMR1 gene wassequenced and soon thereafter high-functioning(normal IQ) males with fragile X syndrome wereshown to have a lack of methylation of the fullmutation leading to a greater production of FMR1

protein (FMRP). Recent studies of individuals withfragile X syndrome and a phenotype of hyperph-agia, obesity and small genitalia coupled with themolecular finding that Cytoplasmic FMRP-interacting protein (CYFIP), located in the 15qregion important for Prader–Willi syndrome, led tothe discovery that CYFIP is dramatically downregu-lated in this subgroup (Nowicki et al. 2007). More-over, the majority of this subgroup also has autism,so the downregulation of CYFIP may explain whyautism occurs in this subgroup and perhaps inothers without fragile X syndrome.

There are likely to be many more examples ofmolecular overlap that will be important for transla-tional treatment issues. Studies of the fragile Xknockout mouse have demonstrated up-regulationof the metabotropic glutamate 5 (mGluR5) pathwayleading to long-term depression and weakening ofsynaptic connections (Bear et al. 2004) and down-regulation of the GABAA system leading to poorinhibition (D’Hulst et al. 2006; Selby et al. 2007).These abnormalities can be reversed with pharma-cological agents leading to targeted treatments forfragile X that will hopefully lead to significant clini-cal differences in behaviour, seizures and, perhaps,cognition. Clinical trials are beginning for fenobam,an mGluR5 antagonist (Porter et al. 2005; Hager-man 2006), and also ganaxolone, a GABAA agonist,in individuals with fragile X syndrome. However,these agents may turn out to be important forothers with autism who have similar glutamate orGABA abnormalities.

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Editorial


Although carriers with premutation fragile X werepreviously considered unaffected, the consistentphenotype seen in older male carriers of tremor andataxia was associated with the finding at the molecu-lar level of elevated FMR1 mRNA in carriers(Tassone et al. 2000). Further research demonstrateda new mechanism of disease in carriers, RNA toxic-ity, that leads to neuronal cell death and whitematter disease that eventually culminates in thefragile X-associated tremor ataxia syndrome(FXTAS) (Hagerman & Hagerman 2004).There isnow evidence that RNA toxicity may occur in child-hood causing mild neurodevelopmental problemssuch as ADHD and social deficits including autismspectrum disorders (ASD) in a subgroup of boysand men with the premutation (Farzin et al. 2006).Therefore, a single gene has two different mecha-nisms for causing ASD, lack of FMRP and elevatedmRNA. It is likely that RNA toxicity may be occur-ring in many other disorders including myotonicdystrophy, spinocerebellar ataxias and some demen-tias (Ranum & Day 2004). Autoimmune diseaseincluding hypothyroidism and fibromyalgia are alsocommon in older female carriers with the premuta-tion and the mechanism of this involvement is likelyrelated to the up-regulation of alpha B crystallin andother proteins important to immune function withthe elevation of mRNA in the premutation (Coffeyet al. in press; Arocena et al. 2005).Therefore, thepremutation may have an important additive effectacross a number of adult and childhood disorderswith a complex genetic aetiology including autism,cerebellar tremor, ataxia, parkinsonism, psychiatricdisorders, dementia and even autoimmune disease.It is also not surprising that FMRP also regulatesamyloid precursor protein, which is implicated inAlzhemier’s disease (Westmark & Malter 2007).

This sequence of findings in the fragile Xresearch story demonstrates how tracking the pathfrom gene to behaviour in one syndrome has pro-vided a rationale for pharmacological intervention,identified a process that might account for variabil-ity in ASD within a syndrome, shown novel associa-tions at a genetic level between fragile X andPrader–Willi syndrome and identified neuronalchanges with age that are associated with loss offunction. There is, of course, no reason why theresearch story in each syndrome should not beequally interesting.

As behavioural phenotype research continues togrow, there are new challenges to address. Differ-ences in change with age beyond adolescence are apressing issue given the interaction betweenincreases in life expectancy and the increase in thenumber of genetically determined syndromes thathave been identified in the last 30 years. Translatingbasic research into clinical intervention is, perhaps,the greatest challenge and there are early signs thatthis is becoming increasingly possible. Perhaps themost immediate challenge is for researchers in thefield to open a constructive dialogue with cliniciansand service providers, hence the inclusion of theabstracts from the 12th Annual Scientific Meetingof the SSBP in this edition of JIDR.

Chris Oliver

School of Psychology, University of Birmingham, UK

Randi Hagerman

MIND Institute and Department of Pediatrics, University of

California, Davis, USA

References

Arocena D. G., Iwahashi C. K., Won N., Beilina A.,Ludwig A. L., Tassone F., Schwartz P. H. & HagermanP. J. (2005) Induction of inclusion formation and dis-ruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells. HumanMolecular Genetics 14, 3661–71.

Bear M. F., Huber K. M. & Warren S. T. (2004) ThemGluR theory of fragile X mental retardation. Trends inNeurosciences 27, 370–7.

Coffey S. M., Cook K., Tartaglia N., Tassone F., NguyenD. V., Pan R., Bronsky H. E., Yuhas J., BorodyanskayaM., Grigsby J., Hagerman P. J. & Hagerman R. J.(0000) Expanded clinical phenotype of women with theFMR1 premutation. American Journal of Medical Genetics(in press).

D’Hulst C., De Geest N., Reeve S. P., Van Dam D.,De Deyn P. P., Hassan B. A. & Kooy R. F. (2006)Decreased expression of the GABAA receptor in fragileX syndrome. Brain Research 1121, 238–45.

Farzin F., Perry H., Hessl D., Loesch D., Cohen J., Bacal-man S., Gane L., Tassone F., Hagerman P. & Hager-man R. (2006) Autism spectrum disorders andattention-deficit/hyperactivity disorder in boys with thefragile X premutation. Journal of Developmental andBehavioral Pediatrics 27, S137–44.

Hagerman R. J. (2006) Lessons from fragile X regardingneurobiology, autism, and neurodegeneration. Journal ofDevelopmental and Behavioral Pediatrics 27, 63–74.


Editorial


Hagerman P. J. & Hagerman R. J. (2004) The fragile-Xpremutation: a maturing perspective. American Journalof Human Genetics 74, 805–16.

Karmiloff-Smith A., Thomas M. S. C., Annaz D., Hum-phreys K., Ewing S., Grice S., Brace N., Van DuurenM., Pike G. & Campbell R. (2004) Exploring theWilliams syndrome face processing debate: the impor-tance of building developmental trajectories. Journal ofChild Psychology and Psychiatry and Allied Disciplines 45,1258–74.

Morton (2004) Understanding Developmental Disorders: ACausal Modelling Approach. Blackwell, Oxford.

Nowicki S. T., Tassone F., Ono M. Y., Ferranti J., Cro-quette M. F., Goodlin-Jones B. & Hagerman R. J.(2007) The Prader-Willi phenotype of fragile X syn-drome. Journal of Developmental and Behavioral Pediatrics28, 133–8.

Porter R. H., Jaeschke G., Spooren W., Ballard T. M.,Buttelmann B., Kolczewski S., Peters J. U., PrinssenE., Wichmann J., Vieira E., Muhlemann A., Gatti S.,

Mutel V. & Malherbe P. (2005) Fenobam: a clinicallyvalidated nonbenzodiazepine anxiolytic is a potent,selective, and noncompetitive mGlu5 receptorantagonist with inverse agonist activity. Journal ofPharmacology and Experimental Therapeutics 315,711–21.

Ranum L. P. & Day J. W. (2004) Myotonic Dystrophy:RNA pathogensis comes into focus. American Journal ofHuman Genetics 74, 793–804.

Selby L., Zhang C. & Sun Q. Q. (2007) Major defects inneocortical GABAergic inhibitory circuits in micelacking the fragile X mental retardation protein. Neuro-science Letters 412, 227–32.

Tassone F., Hagerman R. J., Taylor A. K., Gane L. W.,Godfrey T. E. & Hagerman P. J. (2000) Elevated levelsof FMR1 mRNA in carrier males: a new mechanism ofinvolvement in fragile X syndrome. American Journal ofHuman Genetics 66, 6–15.

Westmark C. J. & Malter J. S. (2007) FMRP MediatesmGluR5-Dependent Translation of Amyloid PrecursorProtein. PLoS Biology 5, e52.


Editorial


trends and challenges in behavioural phenotype research

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