INTERNATIONAL MEDICAL JOURNAL ON DOWN … · •Double nondisjunction ... A second purpose is to address psycho-educational issues with medical implications ... papers dealing with

volume 7 number 2 july 2003

Contents

• Editorial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

• Cortical microarchitecture alterations in Ts65Dn mice, an animalmodel for Down syndrome: impact of environmental enrichment . 18M. DIERSSEN ET AL.

• Double nondisjunction detected in a chromosomal study to a boywith Down syndrome phenotype . . . . . . . . . . . . . . . . . . . . . . . . . 26H. PIMENTEL, E. DYCE

• Identity in individuals with disabilities . . . . . . . . . . . . . . . . . . . . 28D. IANES

• New . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

• Book selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

• Conferences & meetings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

INTERNATIONAL MEDICAL JOURNAL ON DOWN SYNDROME

President of the FCSD Board of Trustees:Montserrat Trueta

Editor: Josep Ma. CorretgerChief Editor: Agustí SerésPublication and Coordination: Katy TriasScientific Advisers:Cardiology: J. CasaldàligaDermatology: J. FerrandoDietetics and Nutrition: A. GutiérrezEndocrinology: A. GodayOral and Maxillofacial Surgery:A. MonnerGenetics: A. SerésGynaecology: J. CararachInternal Medicine: A. GarnachoPediatric Neurology: R. GassióAdult Neurology: J. RoquerPediatric Dentistry: M.E. AlariOrthodontics: M.A. MayoralPediatric Ophthalmology: A. GalánAdult Ophthalmology: J.M. Simón, J. PuigEar, Nose and Throat: J. DomènechPediatrics: J.M. CorretgerPsychology: B. GarvíaPsychiatry: J. BarbaOrthopaedic Surgery: J.C. GonzàlezMedical Consultants:F. Ballesta Martínez, M. Cruz HernándezJ. Moreno Hernando, C.J. Epstein (USA)and S.M. Pueschel (USA)Psychology and Education Consultants:FCSD Team: R. Borbonès, M. Casellas,A. Domènech, M. Golanó, J.M. Gracia, A. deGrecia, I. Jover, M. J. Miquel, M. Peralta, M.Roura, J. Ruf, J. Sanhueza, M. Torres, D.Torres and T. VallsT. VilàL. Brown (USA)Published by:FUNDACIÓ CATALANA SÍNDROME DEDOWN (FCSD)Editorial Address:FCSDValència, 229, pral. 08007 BarcelonaPhone: 93 215 74 23 - Fax 93 215 76 99e-mail: [email protected]: http://www.fcsd.orgEditorial Secretary: Joan C. Villalonga

The purpose of DS. International Medical Review of Down Syndrome is to collect present knowledge of medical aspects of Down syndrometo review and update it on a permanent basis in every sphere, from promising developments in basic science, such as molecular biology orgenetics, to daily practice. A second purpose is to address psycho-educational issues with medical implications that may be of practicalinterest for pediatricians and pediatric specialists dealing with Down syndrome. DS will consider for publication any clinical or researchpapers dealing with Down syndrome in any of its aspects.

Thanks to LABORATORIOS DR.ESTEVE, S.A. for making this issuepossible.

© Fundació Catalana Síndrome de DownISSN: 1138-011X D.L. B-40257-1986Printed by Elite GraficPonts de Can Baruta, 2 , parc. 11- Molins deReiThis review is published in Spanish andCatalan.

RULES FOR CONTRIBUTIONS

Original papers or reviews

Reports of preferably prospective research onepidemiology, etiology, pathophysiology,pathology, clinical aspects, and diagnostic ortreatment methods. Analytical study designs arerecommended, in the form of cross-sectionalsurveys, case-control studies, cohort studies, andcontrolled trials. Alternately, reviews ordissemination paper on various aspects.Maximum length: 25,000 characters countingspaces (including abstract), and a maximum of 10tables and/or figures. Six or fewer listed authorsrecommended, and no more than 20 references.Case reports. Maximum length: 8,000 characters(including abstract) and up to 4 tables and/orfigures. Six or fewer listed authors and no morethan 8 references.Psychoeducational developments. Contributionsfrom an educational perspective which may, inconjunction with medical aspects; enhance thequality of life of people with Down Syndromeand provide an anthropologic view of the person.Maximum length 12,000 characters (includingabstract) and up to 4 tables and/or figures. Six orfewer listed authors and no more than 10references.

Presentation and arrangement

Papers should be in accordance with theUniform Requirements for ManuscriptsSubmitted to Biomedical Journals recommendedby the International Committee of MedicalJournal Editors (Vancouver style).

Consecutively numbered, double-spacedsheets of ISO A4 paper with adequate margins.Inclusion of a copy in electronic form is highlyrecommended.

The following must be stated: title of thearticle; name and complete address of the workcentre; address for correspondence. Explicitmention should be made if part of the work hasbeen presented at any meeting, symposium, orconference, if it has earned any awards or if it hasreceived any form of subsidy.Abstract. Papers to be published in sections fororiginal work, reviews, case reports andpsychopedagogical advances must carry anabstract of no more than 250 words in thelanguage of the paper and in English, precededby the title of the article in the same languages.Up to 5 Index Medicus keywords should beprovided.Text. Impersonal forms are advisable. Papersshould be clearly divided into sections. Articlesshould comprise the following sections:Original articles: Introduction, Materials orPatients and Methods, Results and Discussion.

Case reports: Introduction, Clinical Observation,and Discussion.

Reviews: after the Introduction, heading theauthor may arrange text freely.

Psychoeducational developments: after theAbstract, the author may arrange text freely. Acknowledgements. Contributions meritingacknowledgement should be specified briefly,including mention of whether support providedwas technical or material.References. References should be numberedconsecutively in the order in which they are firstmentioned in the text, using numerals inparentheses. They should be listed in a separatesheet in the Vancouver style.Tables. Tables should be typed on separatesheets of paper and numbered in Romannumerals. Tables must be cited in the text.Heading must include a title. Any abbreviationsshould be explained in a footnote to the table.Tables, figures and text should not repeat thesame information.Figures. Illustrations should be included only ifessential for a correct understanding of the text.Figures should be numbered consecutively byorder of appearance in Arabic numerals. Legendsshould be typed on a separate sheet. Charts anddrawings should be high-quality paper prints; thefirst author’s name, the top of the figure and itsnumber should be written on the back of theprint. Photographs of people should eitherpreclude identification of the subject or else beaccompanied by written permission to use thephotograph.Acronyms, abbreviations, symbols, and units.Use of acronyms should be minimal. The fullterm should be defined upon first appearance.Hematologic and biochemical measurementsshould be reported in the metric system, in termsof the International System of Units (SI).

Manuscript submission

Manuscripts should be sent to the FCSDSecretariat with a cover letter signed by allcoauthors along with a statement of authorshipand ownership. Receipt of manuscripts will beacknowledged. Acceptance and possible date ofpublication will be notified. When the article isin press, the corresponding author shall receivethe proofs for proofreading, which should bereturned within 48 hours of receipt.

The Editorial Board may suggest changes tothe text where it deems necessary and turn downany articles it considers unsuitable.

Indexed in EMBASE/Excerpta Medica and Indice Médico Español (IME)

FCSD may not be held responsible foropinions expressed by the authors ofarticles nor does it necessarily identifywith them.

Moving Steadily Ahead

The size of organizations of any kind, social orbusiness, is always under discussion. Any manageror board, especially when the organization has donerelatively well, must sooner or later choose whetherto continue to expand or to stay put.

Guardianship foundations, specifically thoseresponsible for the mentally disabled, have nowreached this point.

The answer to the question of size should beobvious, if the specific situation of each organizationis to be considered: it just depends. The decisionmust hinge, among other factors, on the quality ofservice achieved and on the reliability,diversification, and riskiness of present and, aboveall, future sources of funding. Basically, the answershould be «Why not expand?» when theguardianship foundation —or any other type oforganization— is providing services of anacceptable quality and has long-term realistic plansto improve them further. This is especially true whenthe service to society is delivered in a responsiblemanner and viewed as necessary, or evenindispensable, by the relevant sector.

At the Fundació Catalana Tutelar de DisminuïtsPsíquics (the Catalan Guardianship Foundation forthe Mentally Disabled), that has been our philosophyin working towards our set goals, such asdecentralizing management, an objective attained byestablishing delegations and thus achieving ouroverarching aim: to improve quality of service whilemore effectively meeting the needs of the nearly onehundred wards who live in the provinces of Girona,Lleida, and Tarragona. To bolster these measures, wehave reinforced the Pre-Guardianship Servicespecifically aimed at families who have requested ourguardianship for their children when they pass away.The importance for Catalonia of having at least oneguardianship foundation with full territorial coverageis a fact realized by all, and brought home to us dailyby the Government of Catalonia, the institution withthe greatest stake in our existence. It makes socialservices more dynamic, responsive and mobile,

though obviously this is only feasible thanks to theunconditional commitment of the ICASS (CatalanInstitute for Assistance and Social Services) team. Tomeet the challenges that lie ahead, the budding newcounty-level foundations are essential. They willultimately develop into a network of local carecenters. To address the difficulties and unknownissues that will inevitably arise, two working partieshave been recently set up. Our foundation, because ofits proven experience, will have a majorresponsibility in both of these working parties andwill serve as their link to enhance cooperation inshared programs and thus optimize the use of largelypublic resources.

The working parties I am referring to are therecently established Catalan CoordinatingAssociation of Guardianship Organizations and theSectoral Group of Guardianship Organizations ofthe APPS (Catalan Federation for People WithMental Disabilities); their existence should enableus to efficiently coordinate guardianship inCatalonia at every level: social, legal and economic.Furthermore, we shall be assisted by the Counsellingand Supervision Commission, working under theFamily Secretariat within the Department of SocialWelfare, and the Guardianship Commission, underthe General Directorate of Law and Legal Entitieswithin the Justice Department. The transition periodwe face poses serious risks we must try to overcometogether in pursuit of our common and single goal:guardianship to guarantee the protection and welfareof people with self-sufficiency issues.

We would like to take this opportunity to thankthe care centers in the provinces where we haveopened our new offices for their manifest supportand letters of congratulation. Without their tirelessefforts, our task would have been much moredifficult. This truly unexpected show of support addsto the joy of seeing the happiness of our wards,which is what we exist for.

ANTONI RODRÍGUEZ

Manager of the Catalan GuardianshipFoundation for the Mentally Disabled

SD-DS2003: vol. 7, núm. 2 INTERNATIONAL MEDICAL JOURNAL ON DOWN SYNDROME 17

Editorial

SD-DS18 INTERNATIONAL MEDICAL JOURNAL ON DOWN SYNDROME 2003: vol. 7, núm. 2, pp. 18-25

M. Dierssen1, R. Benavides-Piccione2, I. Ballesteros2, C. Martínez-Cué3,X. Estivill1,4, J. Flórez3, G. N. Elston2,5, J. De Felipe2

1Programa Gens i Malaltia, Centre de Regulació Genòmica, 08003Barcelona, Spain2 Institut Cajal, 28002 Madrid, Spain3Departament de Fisiologia i Farmacologia, Universitat de Cantàbria,39011 Santander, Spain4Departament de Ciències Experimentals i de la Salut, UniversitatPompeu Fabra, Barcelona, Spain5Vision, Touch & Hearing Research Centre, Dept. Physiology &Pharmacology, School of Biomedical Sciences, The University ofQueensland, Austràlia

Winner of the 8th Ramon Trias Fargas Award for Research on DownSyndrome

Correspondence to:Mara Dierssen, MD, PhDPrograma Gens i MalaltiaCentre de Regulació GenòmicaPasseig Marítim, 37-49 - 08003 Barcelona. SpainTel.: +34 93 2240900 - Fax:+34 93 2240899E-mail: [email protected]

Abstract

Down syndrome (DS) is the most common geneticdisorder associated with mental retardation, affecting 1 in1,000 newborn children in Europe. Studies of the DSpopulation provide a rare opportunity to examinerelationships between cognition, genotype, and brainneurobiology, allowing comparisons across thesedifferent levels of analysis. The crucial question is todefine how an excess of normal gene products, ininteraction with the environment, directs and constrainsneural maturation, and how this maldevelopmenttranslates into mind and behaviour. Although mentalretardation most likely involves anatomical, chemical andneurophysiological brain abnormalities, the mechanismsby which subnormal intelligence arises from theseabnormalities during development are difficult to discern.Dendritic abnormalities are the most consistentanatomical correlates of mental retardation. The earliestdescriptions of dendritic pathology in DS includeddendritic spine dysgenesis, and dendritic anomaliesinvolving branches. Dendritic abnormalities appear tohave specific consequences in the pathogenesis and

evolution of DS brains, which correlate to some extentwith the cognitive profile. This paper analyzes the corticalmicroarchitecture of animal models and the impact ofenvironmental enrichment on the phenotype, focusing ondendritic abnormalities and plasticity.

Keywords: Down Syndrome. Mice models. Dendriticspines. Environmental enrichment. Ts65Dn.

Introduction

Down Syndrome (DS) is the most common geneticdefect associated with mental retardation, with anincidence rate of about 1 per thousand live births inEurope [1]. Individuals with DS have a complexphenotype with a number of traits of variable depth andexpression. In addition to certain body and facial traits,DS is clinically associated with a large number ofabnormalities, only two of which are invariably present:learning disability and Alzheimer-like neuropathologicalfeatures.

Some described structural and functional changes in

Original

Cortical microarchitecture alterations in Ts65Dn mice,an animal model for Down syndrome:impact of environmental enrichment

the central nervous system might give rise to differenttypes and degrees of cognitive and neurologicdysfunction. Macroscopically, brain size is often small, inaddition to hypoplasia of the frontal and occipital lobesand, in 50% of cases, smaller-sized temporal lobes,hippocampus, and cerebellum; the number and depth offissures is also diminished. White-substance neuronalheterotopias have been described in the cerebellum andvermis and attributed to delayed cell migration duringembryo development. Neuronal density is diminished asa result of having fewer granular neurons in the cortex [2]and fewer neurons in the hypothalamus. Several authorsreport abnormal neural differentiation and cell migrationduring embryonal CNS development in people with DS.Moreover, a number of primary culture studies of DSbrains show changes in cell proliferation and inneurodegenerative-related processes. Fetal brains in DSthus feature a characteristically thinner brain cortex dueto lamination changes and reduced synaptic density. Inaddition to this, there is dendritic spine dysgenesis,characterized by abnormal cell membrane morphologyand properties [3], [4], [5]. Two explanations are usuallygiven to account for abnormal brain development andmaturation in DS. One assumes a nonspecific effect ofexcess genetic material; the other assumes a gene-doseeffect whereby the abnormal phenotype is the result of theunregulated expression of genes on chromosome 21(HSA21), the chief suspects being those located withinthe Down syndrome minimal region.

Dendritic changes associated withDown syndrome

Preliminary studies showed that the motor cortex of an18-month-old child with DS had sparse dendritic spinesthat were altered in shape and size. A more systematicstudy showed that the changes were associated with brainvacuolization and necrosis, which led us to suspect aneurodegenerative process [3]. Subsequently, a reducednumber of spines was also detected in other regions, suchas the cingular cortex or hippocampus. Lower spinedensity chiefly concerned the distal and middle segmentsof apical dendrites; this was found to be a DS-specificphenotype rather than a non-specific pathological trait ofmental retardation [4]. Throughout pre- and post-nataldevelopment, apical and basal dendrite length was foundto be shorter than normal. This effect was particularlystriking in the case of the apical dendrites of neurons inlayer III of the frontal cortex[6]. However, the changesare progressive, so the suspicion arose that dendritic spinedysgenesis might have been caused by a postnataldegenerative process. Older patients with DS display thesame kind of changes, usually in association with aneurodegenerative process [6]. The pyramidal and non-pyramidal neurons of the parietal and motor cortices arethe ones most concerned. Ferrer and Guillotta [5] note inone study that, for certain pyramidal neurons in areas

CA1-CA3 of the hippocampus, there is a significantreduction in the number of dendritic spines, mostmarkedly in those patients with DS who also haveAlzheimer’s disease, especially involving area CA1.

Mice models for Down syndrome

Three strategies have been employed to study thegenotype/phenotype relationship of HSA21 genes inmice. I) overexpression of a single gene or combinationof genes on this chromosome; II) the introduction of largeDNA fragments (YAC/BAC chromosomes) in the mousegenome: III) the generation of mice with an extra copy,complete or partial, of mouse chromosome 16 (MMU16),which shares certain regions of conserved synteny withHSA21. The model most often studied following the thirdtype of strategy is Ts65Dn [7], which has trisomy of thedistal segment of MMU16, from Gabpa to Tmprss2. Thisis a 15.6 Mb region in HSA21 containing half the genesdescribed for this chromosome. While this mouse doesnot display some of the changes often seen in DS, such ascongenital heart malformations, other phenotypical traitssimilar to those of DS are indeed identifiable (e.g., maleinfertility, craniofacial skeletal abnormalities, metabolicand behavioral changes) [8]. This mouse model hascognitive impairment, both in terms of long-term spatialmemory and in terms of working memory and recentmemory [9], [10], [11], all of which rely on the functionalintegrity of the hippocampus. While no major brain-structure morphological changes have been described forthese mice, specific phenotypes have been noted, such asreduced CA2 volume and lower cellularity in the dentategyrus of the hippocampus [12], [13], with functionalconsequences reflected in deteriorated LTP induction.The internal granular layer and molecular layer of thebrain are also significantly lower in volume andcellularity [14]. Moreover, this model displays some ofthe characteristic phenotypical traits of Alzheimer’sdisease, including premature loss of basal forebraincholinergic neurons and moderate astroglyosis.Immunohistochemistry shows no changes in theneuroanatomical organization of differentneurotransmission systems, such as the cholinergic,noradrenergic, serotoninergic and dopaminergic systems.However, functional studies of cell effector systems bearout significant changes in production of cyclic AMP andPCL in several areas of the brain [15], [16]. An alteredsystem of second messengers is a key factor inintercellular communication dynamics.

Cortical functionin Down syndrome

There is increasing evidence showing that thefunctions associated with the prefrontal cortex, termedexecutive functions, play a key role in both normal and

SD-DS2003: vol. 7, núm. 2, pp. 18-25 INTERNATIONAL MEDICAL JOURNAL ON DOWN SYNDROME 19

abnormal cognitive development. Executive functionshave to do with individual differences and withdifferences in cognition development; executivefunctional deficiency has thus been hypothesized as theorigin of a number of different forms of learningdisability. Some of the changes found in people with DS,such as smaller brain size, abnormal dendriticmorphology, and reduced spine number, may have anegative effect on prefrontal cortex function. Childrenwith DS have more trouble inhibiting their behavior thangenetically normal children; they also have trouble withmaintaining attention and planning actions. Hyperactivityand uninhibited response in rodents is largely determinedby deficient functioning of the prefrontal cortex. Ts65Dnmice are not totally incapable of inhibiting their behavior,a fact borne out by their performance of certainbehavioral tasks; therefore, they probably do not lackprefrontal function but rather have specific functionaldeficiencies in the prefrontal cortex. The hyperactivityand lack of flexible behavior observed in these trisomicmice may originate in their inability to inhibit activity,which is one of the executive functions controlled by theprefrontal cortex: they become hyperactive in situationswhere normal mice become vigilant, such as open fieldlighting or the open arms of the raised cross-shapedmaze; they are also hyperactive when there are plenty ofnew stimuli, as with environmental enrichment.

Environmental enrichment

Mental age increases at a slower pace in children withDS, unlike normally developing children. This entails agradual reduction of the development quotient from birthonwards during the first year of life, followed by loweredIQ subsequently, although the mental age/chronologicalage ratio is not constant. Adult IQ falls within themoderate-to-severe mental retardation range (IQ = 25-55); the highest mental age achieved is that of a 7- or 8-year-old. However, some people with DS have IQs withinthe normal range (IQ = 70-80). Low IQ levels correlatewith general mental retardation and with delayed speechand language development (articulation, phonology,expressive syntax, etc.). Early intervention programs havebeen shown to have a positive short-term influence onchildren with DS [17]. However, long-term outcomes areless consistent and more open to challenge. Furthermore,the biology underlying improvements achieved throughearly intervention programs is not known. The possibilityof applying this type of treatment approach to Ts65Dn,recently discussed by Martínez-Cué et al. [18], enabledus to look at the consequences of environmentalenrichment on the organization of brain circuits in thefrontal cortex of Ts65Dn mice. Early exposure to anenriched environment is known to bring about certainchanges in rodent behavior, morphology andneurochemistry. Structural changes concern both corticaland non-cortical areas; they consist of increased dendritic

arborization and a greater number of dendritic spines[19]. However, this is the very first in vivo study of theconsequences of environmental enrichment usingexperimental models of DS, a brain disorder that entails aserious lack of neuronal plasticity.

Materials and Methods

Animals

The mice used in this study were obtained throughsuccessive backcrossing of Ts65Dn females with hybridF1 C57/6Ei x C3H/HeSnJ (B6EiC3) males. The parentalgeneration was from Jackson Laboratory (Bar Harbor,USA); the Ts65Dn mice were cross-bred in theDevelopmental Biology Laboratory at the University ofCantabria (Santander, Spain). Non-trisomic littermateswere used as controls. All experiments were carried out incompliance with Spanish and European legislation for thehandling of laboratory animals. All procedures werepreviously approved by the Animal ExperimentationCommittee.

Environmental enrichment

After weaning (postnatal day 21) the animals wereseparated by sex and randomly assigned in equal numbersof Ts65Dn mice and normal mice to environmentalenrichment (EE) or standard environment (NE). The micein the NE arm were housed 2 or 3 per cage (20x12x12 cmPlexiglas; 20 � 2ºC; 12-hour light/dark cycle) with freeaccess to food and drink. The mice in the environmentalenrichment arm were housed 8 per cage in large(42x50x20 cm) multilevel cages with ladders and smoothside and rear walls at standard environmental conditions(20 � 2ºC; 12-hour light/dark cycle). Cages contained anactivity wheel, a swing, wooden dowels, and plastic toysproviding different types of sensory stimulation; the latterwere changed every other day. EE mice received differentkinds of food, but had to learn new behaviors in order toobtain them. Litter material was also changed weekly.The EE animals were kept in this environment from age3 weeks to 10 weeks; they were subsequently housed innormal conditions until the experiment was carried out.The effect of enrichment was observed for a number ofbehavioral tasks [18].

Tissue processing

Neuromorphologic experiments were performed atone year of age, as the success of the environmentaltreatment had to be ascertained previously in behavioralexperiments. Only the females were studied, as positiveeffects had only been found in this sex [18]. The micewere killed with a lethal sodium pentobarbitol injectionand perfused with paraformaldehyde (PF) at 4% (0.1 M,


pH 7.4, PF). The brain was extracted and the cortex of theleft hemisphere was flattened and postfixed between twoglass slides, weighed, and left overnight in PF at 4ºC.Slices were cut tangential to the cortical surface with theaid of a vibratome (150 �m) and preincubated with 10–5

M 4,6 diamidino-2-phenylindole (Sigma D9542). Cross-sections enabled identification of cell architecturaldifferences between cortical layers; the sectioncontaining layer III was thus identified and its pyramidalcells injected. The cell injection method has been amplydescribed [20]. Briefly, individual cells were injectedwith Lucifer Yellow (8% in 0.1 M Tris buffer, pH 7.4) byapplying an electric current until fluorescence wasachieved at the tips of each cell’s dendrites. Followinginjection, sections were processed with an anti-LuciferYellow antibody (1:400000 in a stock solution [2%bovine seroalbumen (Sigma A3425), 1% Triton X-100(BDH 30632), 5% sacarose in a 0.1 mol/l phosphatebuffer]), and subsequently with a specific biotinylatedsecondary antibody solution (Amersham RPN 1004;1:200 in stock), followed by a biotin—horseradish-peroxidase complex (Amersham RPN1051; 1:200 inphosphate buffer). The chromogen used was DAB (3,3’-diaminobenzidine; Sigma D 8001) (Fig 1). Slices werephotographed before and after immunohistochemistry tocontrol for tissue shrinkage and apply a correction factorif necessary.

Morphologic analysis

Cells were included in the analysis only if they had adistinct apical dendrite, a complete basal dendritic arborincluded within the section, and dendrites completelyfilled with contrast agent. As pyramidal cell structurevaries among cortical regions, only pyramidal cellsinjected within the same area of the frontal cortex wereincluded in this analysis. The cells were drawn with acamera lucida attachment and the size of the basaldendritic arbor was determined by calculating the area ofa polygon joining the outermost distal tips of thedendrites. The branching pattern was determined bycounting the number of dendrite intersections in a soma-centered template consisting of circles with anincrementally increasing radius (25-�m increments).Total dendrite length for each cell was determined withthe aid of a digital measuring system (SummaSketch III)and image analysis software (NIH Research Services,Bethesda, MD). Dendritic spine density was determinedby counting the number of spines in 10-�m segments on20 horizontally projecting dendrites on different,randomly selected cells. All spine types were includedwithout distinction in the spine counts. The total spinecount was obtained by multiplying the mean number ofspines in a given dendrite portion by the mean number ofbranches found in that region. The same operation wasapplied to all segments of the dendritic arbor.

Results

Control mice and Ts65Dn mice in standardenvironmental conditions (NE)

(a) Dendritic arbor size

The number of pyramidal neurons included in thisanalysis was 180. On first inspection, the basal dendriticarbors in layer-III pyramidal cells appeared clearlydifferent in Ts65Dn mice compared to controls (Fig. 2).Arbor size quantification (Fig. 3A) showed a clear sizereduction in trisomic versus control mice (3.0 ± 0.6 x104

�m2 vs 5.05 ± 1.1 x104 �m2, respectively; t(81) = 9.9; P <0.001).

(b) Branching pattern and dendrite length

Quantification of dendritic intersections (Fig. 3B)showed that the point of greatest dendritic arborcomplexity in Ts65Dn mice (23.25 ± 4.23) was lowerthan that in non-trisomic mice (25.19 ± 5.9), withstatistically significant differences (F(1.81) = 14.5, P <0.001). Dendrite length analysis (Fig 3C) revealedsignificantly shorter dendrites in Ts65Dn mice asopposed to controls (1.92 ± 0.31 x103 �m and 3.35 ± 0.73x103 �m, respectively; t(81) = 11.2; p < 0.001).

(c) Spine density and distribution

The maximum number of spines in 10 �m was 19.1 ±4.12 in Ts65Dn mice versus 18.1 ± 5.49 in controlanimals (Fig. 3D). Variance analysis of repeatedmeasurements of spine distribution along the dendrite asa function of distance to the soma showed that thedifferences between the two groups were statisticallysignificant (F(1.78) = 81.6, P = 0.001). These Sholl analysisdata combined with spine density information made itpossible to estimate the total number of spines on atypical cell. Trisomic animals were shown to have 24%


Fig. 1. A, B Microphotographs of layer III pyramidal cells injected with Lucifer Yellow in 150 µm sections sliced parallel to the brain cortex surface. C Microphotograph of a horizontally projecting dendrite to illustrate dendritic spines. Scale: 150 µm in figure A; 34 µm in figure B; 10 µm in figure C.

fewer spines (Fig. 3E) in their basal dendritic arbors(2603) than the control mice (3447).

Control mice and Ts65Dn mice in enrichedenvironmental conditions (EE)

(a) Dendritic arbor size

As in the case of animals reared in NE standardconditions, the pyramidal cell basal dendritic arbor size(Fig. 3A) of EE Ts65Dn mice (3.25 ± 0.6 x104 �m2) wassignificantly lower than that of EE controls (5.05 ± 1.1x104 �m2; t(94) = 13.6; P < 0.001). Environmentalenrichment produced no significant effect on this variableon either control mice (t(74) = 1.6, P = 0.053) or Ts65Dnmice (t(101) = 1.8, P = 0.064).

(b) Branching pattern and dendrite length

Quantification of dendritic intersections (Fig. 3B)showed that the point of greatest dendritic arborcomplexity in enriched Ts65Dn mice (23.8 ± 4.58) waslower than that of controls (28.5 ± 6.1). Full dendriticarbor analysis showed statistically significant differencesin branching patterns between the two genotypes (F(1.94)

= 109.8, P < 0.001). Environmental enrichmentsignificantly increased dendritic intersections in thecontrol mice (F(1.74) = 43.3, P < 0.001), but not in thetrisomic mice (F(1.101) = 3.8, P = 0.052). Dendrite lengthof EE trisomic mice was significantly lower than in EEcontrols (2.02 ± 0.44 x103 �m and 3.14 ± 0.61 x103 �m,respectively; t(94) = 9.8, P < 0.001) (Fig. 3C), but this didnot change with environmental enrichment in eithertrisomic or non-trisomic mice (t(74) = 1.3, P = 0.2; t(101) =1.2, P = 0.24, respectively).

(c) Spine density and distribution

Basal dendrite spine count (Fig. 3D) showed that thehighest density level in EE Ts65Dn mice (20.4 ± 4.4) waslower than for EE controls (25.7 ± 6.4), with statisticallysignificant differences (F(1.58) = 78.4, P < 0.001).Environmental enrichment had a dramatic impact ondendritic spine density in control mice (F(1.58) = 14.9, P <0.001), but not in Ts65Dn mice (F(1.78) = 2.6, P = 0.11).Environmental enrichment increased the total number ofspines by (>32%) in control mice, but only 3% in Ts65Dnmice (Fig 3E). As a result, the pyramidal cells of Ts65Dnmice raised in EE conditions had significantly fewerspines (2683) than the EE controls (5050).

Discussion

Many studies have shown beneficial effects of enrichedenvironments on normal mice. However, for functionalrehabilitation purposes it is important to assess whetherbrain disorders caused by genetic conditions which mayseverely impair neuronal plasticity mechanisms mayimpact the ability to respond to environmental stimulation.An earlier study showed that the Ts65Dn mouse was ableto improve cognitive function as a result of environmentalenrichment [18]. The present study focused on assessingwhether cognitive improvement was the result of plasticchanges in the pyramidal cells of frontal cortical layer III.Our paper shows considerable differences between the cellphenotypes of trisomic and control mice; trisomicphenotypes are smaller and have less complex branchingpatterns. The most salient finding of this experiment is,beyond doubt, the fact that while environmentalenrichment achieved a strong effect on the pyramidal cellsof control animals, it failed to modify the neuronalphenotype of trisomic mice. This leads us to suspect thatthe Ts65Dn mouse has an altered mechanism forregulation and maturation of cortical circuitry. Thus,trisomy appears also to affect the neuroplastic capacity ofthe trisomic brain.

The Ts65Dn mouse: an experimental model of Downsyndrome

Most of the genetic, behavioral and anatomical traitsof Ts65Dn mice are also found in people with DS [21],


Fig. 2. Camera lucida drawings of layer III pyramidal cells, as seen on theplane of a slice tangential to the cortical layers of non-trisomic and Ts65Dnmice. Scale = 100 µm.

[8]: the trisomy region is homologous, they both haveimpaired learning capacity and memory, and a number ofbrain-structure abnormalities [9], [10], [11] . Moreover,the Ts65Dn changes in behavioral patterns are compatiblewith a prefrontal cortex dysfunction [9]. Of particularinterest in this context is the study of the morphology ofpyramidal cells, the type of cell most ubiquitously presentin the neocortex. Our findings show that trisomic micehave pyramidal-neuron phenotype changes similar to

those described for people with DS. Autopsy studies haveshown dendritic changes in their brains, specifically alower number of spines that chiefly emerges in the latepostnatal period [3], [4], [5]. We found, on average, thatthe pyramidal cells of our Ts65Dn mice had 24 % fewerspines than their non-trisomic counterparts. Twoscenarios may therefore be considered: either there arefundamental differences in cortical development,meaning that trisomic mice never achieve spine densitylevels as high as those of control mice, or else they losetheir spines faster with age due to a neurodegenerativeprocess. In view of the underlying chromosomalaberration present in humans with DS and in Ts65Dnmice, a connection between the two phenotypes may behypothesized. The mouse model therefore provides anexperimental medium for the study of brain disordersand, specifically, the dendritic impairment observed inpeople with DS. Moreover, this provides an opportunityto analyze changes that may be achieved through drugand non-drug rehabilitation treatment for dendriticimpairment, which has even been posited as one of themicroanatomical substrates of learning disability [21].

The effects of environmental enrichment on Ts65Dnmice

In normal animals, environmental enrichment has anumber of behavioral, physiologic, neurochemical andneuromorphologic effects. Mice subjected to enrichedenvironments show substantial improvement in tasks thatinvolve memory, learning, and visual acuity. Thesecognitive-behavioral improvements are thought to ensuefrom changes in connectivity, that is, in the distribution ofneural connections. Improved performance of certainbehavioral tasks, learning tasks and memory tasks hasbeen linked with increased branching complexity ofpyramidal cells and elevated synapse/neuron ratios. Theenvironmental enrichment approach employed was foundto have a dramatic impact on pyramidal cell structure innon-trisomic animals. After only three weeks of exposureto an enriched environment in the late post-natal stage,these mice had a significantly higher number of dendriticspines: 32% more than the non-trisomic mice reared in astandard laboratory environment (see Methods). In thecase of trisomic mice, however, the number of spines onlyincreased by 3%, hardly significant. The figures may beinterpreted as a failure of trisomic mice to respond toenvironmental enrichment. Such a failure may be causedby the genetic changes that set it apart from controlanimals from the same stock or by the instability of theobtained response obtained, as trisomic mice lose theirspines much faster than non-trisomic ones, a factconsistent with impaired neuroplasticity. Every dendriticspine receives at least one asymmetrical glutamatergicsynapse; neurons with more spinous dendrites oughttherefore to be able to integrate more information thanneurons with fewer spines. Branching pattern differencesbetween the dendritic arbors of pyramidal cells have been


non-enriched

enriched

Control Ts65Dn

non-enriched: controlenriched: controlnon-enriched trisomic enriched trisomic

Control Ts65Dn

Distance to soma (µm)

Control Ts65Dn

Distance to soma (µm)

N. o

f sp

ines

(x1

03 )N

. of

spin

esL

eng

th(x

103µ

m)

N. o

f b

ran

chin

gs

Are

a (x

103

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)

Fig. 3. Charts depicting the basal dendritic arbor area(A), number of dendriticarbor intersections(B), dendrite length (C), dendritic spine density (D) numberof spines (E) in the layer III pyramidal cells of trisomic and non-trisomic miceraised in standard (NE) conditions and under environmentally enriched (EE)conditions.

shown to play a key role in compartmentalizinginformation and in the representational power of corticalneurons. The differences uncovered in this study thereforeprobably affect cortical function at both the cellular leveland the systems level [22]. Studies of the cerebral cortexof simians, for instance, show that prefrontal cortexpyramidal cells have more complex branching and morespinous dendrites than the cells in the sensory associativecortex which, in turn, are more complex and endowedwith more spines than those in the primary sensory cortex[22], [23]. Thus, available data allow a relationship to bemade between information processing power, which isfundamental in setting cognitive functions, and the cell-level architecture of the cerebral cortex.

Our earlier studies had shown that the Ts65Dn wasable to improve cognitive function with environmentalenrichment [18]. However, no neuromorphologicalchanges are associated with this improvement, whereas innon-trisomic mice the same kind of environmentalenrichment produces dramatic change as described inearlier literature [24]. Offhand, it might be assumed thatthe behavioral changes observed in trisomic mice are notthe result of plastic changes in the dendritic arbor. Twolines of reasoning may be followed to explain thesefindings: I) the changes produced by environmentalenrichment in trisomic mice may be less stable and maybe lost over time; or else, II) the enrichment may notbring about neuromorphological change at all, so thebehavioral effects would be the result of certain changesin cell signalling systems that cannot be observed in thephenotype of cortical pyramidal cells. In order todetermine the impact of a changed environment on cellarchitecture and on synaptic structure and function in DSbrains, as well as the durability of such effects, asystematic study of presynaptic and postsynapticcomponents of multiple corticle regions at differentstages will be required.

Conclusions

Observed changes in dendritic structure have beenlinked with several forms of mental retardation in humanbeings; in some cases they are the only physical evidenceof pathology. Dendritic structures to changes in theenvironment; in fact, they are considered theneuroanatomical substrate of cognitive-behavioralchanges achieved through environmental intervention.The paper presented here establishes strong parallelsbetween the frontal brain cortex pyramidal cell phenotypeof Ts65Dn mice and people with DS. This may be due tothe fact that they have trisomy of an analogouschromosomal region which contains genes that justpossibly may have preserved their evolutionary function.In the case of the Ts65Dn mouse, trisomy of the regionbetween App and Mx1 plays a strong role in themicroorganization of neocortical circuits. The datapresented here cannot solve the question as to whether this

effect is the result of maldevelopment or degeneration.They do bear out impaired neuroplasticity, which in turnimpairs the brain’s mechanisms for adapting to theenvironment and to environmental change. In order toidentify the molecular dysfunction underlying cellchanges observed in DS, studies of mouse models withsingle-gene overexpression will have to be undertaken.

Acknowledgements

The authors would like to thank the Jerôme LejeuneFoundation, DURSI, CEC/BIOMED2 (BMH4-CT98-3039), CICYT (SAF99-0450-C02, SAF2001-1231),DGCYT (PM99-0105), de FIS (00/0795), FundacióMarcelino Botín, the Australian National Health andMedical Research Council (GNE), the AutonomousCommunity of Madrid (RB-P, 01/0782/2000) and theReal Patronato de Atención a Minusvalías (CM-C) fortheir support.

References

1. Mastroiacovo, P. Epidemiology of Down syndrome inthe third millenium. 2nd International conferenceEDSA ‘The Adult with Down Syndrome. A newChallenge for Society’, San Marino 2002.

2. Dierssen M, Fillat C, Crnic L, Arbones M, Flórez J,Estivill X. Murine models for Down syndrome.Physiol Behav 2000; 73: 859-71.

3. Marin-Padilla M. Pyramidal cell abnormalities in themotor cortex of a child with Down’s syndrome: AGolgi study. J Comp Neurol 1976;167: 63-81.

4. Suetsugu M, Mehraein P. Spine distribution along theapical dendrites of the pyramidal neurons in Down’ssyndrome. A quantitative Golgi study. ActaNeuropathol (Berl), 1980; 50: 207-10.

5. Ferrer I, Gullotta F. Down’s syndrome andAlzheimer’s disease: dendritic spine counts in thehippocampus. Acta Neuropathol (Berl) 1990; 79:680-5.

6. Becker LE, Armstrong DL, Chan F. Dendritic atrophyin children with Down’s syndrome. Ann Neurol 2000;20:520-6.

7. Davisson MT, Schmidt C, Akeson EC. Segmentaltrisomy for murine chromosome 16: a new system forstudying Down syndrome, A: Molecular Genetics ofChromosome 21 and Down syndrome (Patterson D,Epstein CJ, eds). New York: Wiley-Liss, 1990: 263-80.

8. Dierssen M, Marti E, Pucharcos C, Fotaki V, AltafajX, Casas K, Solans A, Arbones ML, Fillat C, EstivillX. Functional genomics of Down syndrome: amultidisciplinary approach. J Neural Transm 2001;Suppl 61:131-48

9. Escorihuela RM, Fernández-Teruel A, Vallina IF,Baamonde C, Lumbreras MA, Dierssen M, TobeñaA, Flórez J. Behavioral assessment of Ts65Dn mice:


a putative DS model. Neurosci Lett 1995; 199: 143-6.

10. Escorihuela RM, Vallina IF, Martínez-Cué C,Baamonde C, Dierssen M, Tobeña A, Flórez J,Fernández-Teruel A. Impaired short- and long-termmemory in Ts65Dn mice, a model for DS. NeurosciLett 1998; 247: 171-4.

11. Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE, Johnson RM,Chen K, Sun, Y, Carlson E, Alleva E, Epstein CJ,Mobley WC. Developmental abnormalities andagerelated neurodegeneration in a mouse model ofDown syndrome. Proc Natl Acad Sci USA 1996; 93:13333-8

12. Insausti AM, Megías M, Crespo D, Cruz-Orive LM,Dierssen M, Vallina IF, Insausti R, Flórez, J.Hippocampal volume and neuronal number inTs65Dn mice: a murine model of Down syndrome.Neurosci Lett 1998; 253: 1-4.

13. Kurt MA, Davies DC, Kidd M, Dierssen M, Flórez J.Synaptic deficit in the temporal cortex of partialtrisomy 16 (Ts65Dn) mice. Brain Res 2000; 858:191-7.

14. Baxter LL, Moran TH, Richtsmeier JT, Troncoso J,Reeves RH Discovery and genetic localization ofDown syndrome cerebellar phenotypes using theTs65Dn mouse. Hum Mol Genet 2000; 9: 195-202.

15. Dierssen M, Vallina IF, Baamonde C, LumbrerasMA, Martinez-Cue C, Calatayud SG, Flórez J.Impaired cyclic AMP production in the hippocampusof a Down syndrome murine model. Brain Res DevBrain Res 1996; 95: 122-4.

16. Dierssen M, Vallina IF, Baamonde C, Garcia-Calatayud S, Lumbreras MA, Flórez J. Alterations ofcentral noradrenergic transmission in Ts65Dn mouse,

a model for Down syndrome. Brain Res 1997; 749:238-44.

17. Connolly BH, Morgan SB, Russell FF, Fulliton WL.A longitudinal study of children with Downsyndrome who experienced early interventionprogramming. Phys Ther 1993; 73: 170-9.

18. Martínez-Cué C, Baamonde C, Lumbreras M, Paz J,Davisson MT, Dierssen M, Flórez J. Differentialeffects of environmental enrichment on behavior andlearning of male and female Ts65Dn mice, a modelfor Down syndrome. Behav Brain Res 2002;134:185-200.

19. Globus A, Rosenzweig MR, Bennett EL, DiamondMC. Effects of differential experience on dendriticspine counts in rat cerebral cortex. J Comp PhysiolPsychol 1973; 82: 175-81

20. Buhl EH, Schlote W. Intracellular Lucifer yellowstaining and electronmicroscopy of neurons in slicesof fixed epitumourous human cortical tissue. ActaNeuropathol 1987; 75: 140-6.

21. Kaufmann WE, Moser HW. Dendritic anomalies indisorders associated with mental retardation. CerebCortex 2000; 10: 981-91.

22. Jacobs B, Schall M, Prather M, Kapler L, Driscoll L,Baca S, Jacobs J, Ford K, Wainwright M, Treml M.Regional dendritic and spine variation in humancerebral cortex: a quantitative study. Cereb Cortex2001; 11:558-71.

23. Elston GN, Tweedale R, Rosa MGP. Corticalintegration in the visual system of the macaquemonkey: large scale morphological differences ofpyramidal neurones in the occipital, parietal andtemporal lobes. Proc R Soc Lond Ser B 1999; 266:1367-74.

24. Diamond MC. Response of the brain to enrichment.An Acad Bras Cienc 2001; 73: 211-20


Poster produced by the FCSD for the European Year for People With Disabilities.


autosomal chromosomes, with a chromosomal pattern of48,XXY+21.

This is so infrequent, and detection so important forgenetic counselling purposes, that it was decided to publishthis case to contribute to knowledge of this matter.

Case report

Patient was a two-month-old white male born of non-consanguineous young and healthy parents with no familyhistory of genetic disease. Pregnancy and birth wereuncomplicated. Physical examination found DownSyndrome traits.

A peripheral blood chromosomal study was undertakenusing RPMI-1640 culture medium. Chromosomes wereobtained according to the procedure employed by Vermaand Babú in 1995 (protocol 2.5) [5]; GTG chromosomebanding was obtained and 50 metaphases were analyzed.The presence of two supernumerary chromosomes wasdetected in 100% of the metaphases, with a chromosomalpattern of 48,XXY+21 (Fig.1). A cytogenetic study of theparents came out normal.

Discussion

Anomalous chromosome counts usually arise duringmeiotic division, although post-zygotic changes may lead tomosaicism. This was ruled out in the present case, wheredouble non-disjunction occurred producing KS and a DSphenotype. Klinefelter syndrome was an unexpectedfinding, as the child was only two months old. Phenotypesigns of this syndrome usually emerge during adolescence.Patients display hipogenitalism and hipogonadism;secondary sex traits are generally undeveloped;

Case report

Double nondisjunction detected in a chromosomal studyof a boy with Down syndrome phenotype

Héctor Pimentel Benítez, Elisa Dyce GordonHospital Pediátrico Universitario Dr. Eduardo Agramonte Piña.Centro Provincial de Genética Médica. Camagüey, Cuba.

Correspondence to:Héctor Pimentel Benítez.Calle 2 # 6 e/ A y FinalRpto Las Mercedes. CamagüeyCP: 71200. CUBA.E-mail: [email protected]

Artícle received: 09-Dec-02

Abstract

The case presented is one of double chromosomalnondisjunction detected in a chromosomal study of a boywith clinical signs of Down syndrome, at the CytogeneticsProvincial Laboratory of Camagüey.

The cytogenetic study was carried out employing routinetechniques (GTG). The diagnosis was that there were 2supernumerary chromosomes with a chromosomal patternof 48, XXY+ 21.

The origin of this rare biological accident is discussed.

Keywords: Non-disjunction. Chromosomal syndrome.Down syndrome. Klinefelter syndrome.

Introduction

Chromosomal non-disjunction, the failed segregation ofpaired chromosomes, which may take place in the first orsecond meiotic division or in both, is the chief cause ofaneuploidy. The result is an imbalance of genetic material,where the individual will have too many or too fewchromosomes in relation to the constant species-specificnumber [1].

Chromosomal non-disjunction is the direct cause of 95%of Down syndrome cases, as well as other chromosomalconditions such as Klinefelter syndrome (KS) [2.3].

The incidence of DS in Cuba is 9.8 per thousand livebirths [4]. It is the most frequently diagnosed type ofaneuploidy at the Laboratorio de Citogenética de Camagüey.Association with other types of aneuploidy is possible butvery rare.

So far, out of 190 DS cases diagnosed at the Laboratorysince 1986, only one case (1.9%) of double non-disjunctionhas ever been found. This case involves both sexual and

gynecomastia is a possibility; tallness is very likely; there isa variable degree of intelligence and, sometimes, behavioraldisorders [6].

Chromosomal aneuploidy is usually caused by meioticnon-disjunction [6], which in the case of DS appears tooccur most frequently during maternal meiosis I [7].Klinefelter syndrome is caused in 60% of cases by non-disjunction of the maternal X chromosome (maternal X,maternal X , paternal Y), and in 40% of cases by non-disjunction during the first meiotic division inspermatogenesis [2] (maternal X, paternal X , paternal Y).

The chromosomal non-disjunction that gives rise thesecomplex cases may occur at different times. A number offactors are thought to influence the process, such aspredisposing genes, interchromosomal effects, parentalmosaicism, alpha1-antitripsin deficiency, maternalantithyroid antibodies, preovulatory hypermaturation,delayed fertilization, and changes in the physiology of thefemale reproductive tract, among others [8]. Most of these

factors are linked to the mother. However, the parentalorigin of supernumerary chromosomes can only bedetermined using molecular techniques.

Though DS has a characteristic phenotype that makes iteasy to diagnose clinically, chromosomal studies areimportant in order to identify the cause, reach a prognosis,assess the risk of recurrence, and detect other associatedchromosomal abnormalities, thus contributing to bettergenetic counselling for parents.

References

1. Lacadena JR. Genética. Madrid, A.G.E.S.A., 1981: 608-132. Thompsom-Thompson. Genética Médica . 4ª ed.

Barcelona, Masson, 1996: 201-46.3. Pimentel BHI, Dyce GE. Hallazgos cromosómicos en el

Laboratorio de Citogenética del Hospital Pediátrico Dr.Eduardo Agramonte Piña. Rev Electrónica. ArchivoMédico de Camagüey 1995.

4. Ferrero Oteiza ME. Tendencias del síndrome de Down enCuba. Su relación con la edad materna y tasa defecundidad, Rev Cubana Pediatr 1998; 70:141-44.

5. Verma RS, Babú A. Human Chromosomes. Principlesand techniques. 2 ed, New York, McGraw-Hill, 1995: 9-29.

6. Jones KL. XXY Syndrome, Klinefelter Syndrome. A:Smith´s Recognizable Patterns of Human Malformation.5ª ed. Philadelphia, W.B. Saunders Company, 1997: 72-75.

7. Petersen MB, Mikkelsen M. Nondisjunction in trisomy21: origin and mechanisms. Cytogenet Cell Genet 2000;91:199-203.

8. Magenis RE. Invited editorial: On the origin ofChromosome anomaly. Am J Hum Genet; 1988; 42:529-33.


Fig. 1. 48,XXY+21 karyotype due to double non-disjunction.

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I wish to receive SD-DS INTERNATIONAL MEDICAL JOURNAL ON DOWN SYNDROME on a four-monthly, free basis, ONLYBY E-MAIL.

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Dario IanesPsychologist.Co-Editor-in-Chief, Edizioni Centro Studi Erickson, Trento(Italy)

Correspondence to: Centro Studi EricksonLoc. Spini di Gardolo, 38014 Gardolo - Trento (Italy)e-mail: [email protected]

Article received: 16-May-03

Abstract

On the basis of the International Classification of theFunctioning of Disability and Health (ICF) (WHO 2002),which offers a clear map of the basic concepts of thefunctioning and the health of a person, the author tries todefine the structure of identity in persons with disability.Identity is the result of different relations among a numberof elements (biological, physical, environmental, social,family, etc.).

The person with a disability must be helped to avoidrestriction of identity to a limited set of elements (bodyappearance, capabilities, and family). A well-developedidentity includes relationships, interconnections, andreciprocal influences among the different aspects.

A postive environment and a family that is supportive ofautonomy encourage a child’s skill development, socialparticipation, and the emergence of positive personal factors(self-image, confidence, autonomy), which in turn foster thedevelopment of other contextual personal factors. The textanalyses the psychological functioning of identity and itsdevelopment, emphasizing the need for boundaries toseparate and protect: boundaries in body space, in personalspace, in decision-making, and in relationships. Many parentsand professionals find it difficult to respect these boundariesin persons with mental retardation, because their needs aregreat and territorial invasions ensue. This should not occur.

Keywords: Disability. Identity. Self-image. Autonomy.

Identity may be said to be a conscious, historical,planning-enabling reflection on our many traits viewed as awhole; a reflection that gives meaning to actions future andpast.

At different stages in life, individuals need to considertheir continuity in time and the fact that they are differentfrom others. In the course of life, identity growth is felt atcertain times of crisis (which is why we often speak of«identity crises»). This happens especially at crucial

developmental periods (such as adolescence, when theindividual moves beyond parentally defined identity [«I amwhat my parents want me to be»] toward an identity definedon the basis of independent choices).

Here we will especially be addressing subjective identity,that is, the whole of a person’s traits as viewed and describedby that person to him- or herself. Logically, there may be ahuge discrepancy between the way I see and define myselfand the way I am perceived by others. In many cases, theway I see myself largely depends on how I am viewed byothers and on how I know myself to be viewed by them.

From a psychological and educational standpoint,whenever we consider identity we are asking a number ofkey questions: Who am I? How do I view myself? Howwould I describe myself? What do I think of myself? Howwould I like to be? What did I use to be like? Why do I thinkof myself in this way or that? – and so forth. I use thesequestions to seek the meaning of my existence: a meaningthat must be fully my own, different from the meaning foundby others, valuable because it is individual, unrepeatable,stamped by my uniqueness.

These are tough questions, exhausting to ask and workthrough; psychological assistance for the person with mentalretardation who is developing his or her identity is also atough and exhausting undertaking. Let us then seek somereinforcement strategy for the working out of a stronger,more independent identity in persons with mentalretardation.

How can we organize such a complex psychologicalreality meaningfully? A conceptual pattern now widelydebated in many countries is the International Classificationof Functioning, Disability, and Health (ICF) (World HealthOrganization, 2002), which clearly maps out basic conceptsof individual health and functioning. Its ultimate aim is toprovide a standard, unified language and framework todescribe health and health-related states.

The words «disability» and «handicap» are no longerincluded; they have been replaced with «personal activity»and «social participation». Terms which had a negative spinnow have positive connotations, and the considered

Advances in psychology and education

Identity in individuals with disabilities

interactions among health- or disability-related factors aremore complex, to account for even the most peculiar ofsituations and properly address contextual factors, bothenvironmental and personal. Health status can no longer beassessed while ignoring the complex relations of body,mind, environment, context, and culture. Human health andfunctioning are the result of a complex, global,multidirectional interaction of all the above-mentionedaspects (Fig. 1).

Health condition is a generic term which refers todisease (whether acute or chronic), disorder, injury, ortrauma. It may also refer to other circumstances, such aspregnancy, aging, stress, congenital anomaly, or geneticpredisposition.

Body functions are the physiological functions of bodysystems (including psychological functions).

Body structures are the anatomical parts of the body,such as organs, limbs, and their components.

Activity is the execution of a task or action by anindividual; examples include communication, mobility, self-care, domestic life, or interpersonal relationships.

Participation is involvement in a life situation withinsocial integration (inclusive schooling, work andemployment, economic life, community life, and civic life).

Environmental factors make up the physical, social andattitudinal environment in which people live and conducttheir lives (including technology, the natural environment,relationships, attitudes, standards, services, systems, andpolicies).

Personal factors are a person’s individual background.They may include individual psychological factors such asself-esteem, self-efficacy, or identity.

Within this diagram, an individual’s specific functioningin a specific domain is a complex interaction betweenbiological health conditions and contextual factors. They allinteract dynamically: acting upon one of them maypotentially change some or all of the rest. The interactionsare specific and not always predictably bilateral. Interactionworks both ways: the presence of disability may evenmodify the individual’s biological status. It may often seemreasonable to ascribe an activity limitation to one or severalimpairments, or a participation restriction to one or severallimitations. However, it is important to gather independent

data about these constructs and then explore theirassociations and causal links. All components are relevant toa complete description of the health experience. Forinstance, a person can

• have an impairment without any activity limitation(e.g., a disfigurement caused by a burn may have no effecton a person’s capabilities).

• have participation issues without an impairment or anactivity limitation (e.g., a person who is HIV-positive or arecovered former mental patient may face stigmatization ordiscrimination in interpersonal relationships or jobinteractions).

• have activity limitations if unassisted yet have noparticipation problems in the current environment (e.g.,society may provide a person with restricted mobility withassistive technology that enables movement).

• experience a degree of influence in the oppositedirection (e.g., failure to use limbs may cause muscles toatrophy, or institutionalization may result in loss of socialskills).

Many people mistakenly believe that the ICF is onlyabout people with disabilities, when in fact it applies toeverybody. Health and health-related states associated withany health condition can always be described with the ICF.In other words, the ICF is universally applicable.

The ICF affords a description of situations related tohuman functioning and its restrictions and affords areference framework to organize this information,structuring it in a way that is meaningful, interrelated andeasily accessible.

«Disability» and «handicap», as pointed out above, areterms no longer employed to describe personalfunctioning. Moreover, much stress is laid on socialparticipation and school integration as key elements ofboth health and functioning, and a prominent role isassigned to contextual factors, both environmental andpersonal (which is where a person’s identity and lifeproject lie, as we have seen). How can the ICF be used tosupport the development of identity?

It reminds us constantly that the individual (and,therefore, individual identity) is the result of all theinteractions among all the different elements. A well-developed identity is very comprehensive, so all aspectsmust be taken into account; identity should be partlybiological, partly physical, connected to capacities,activities, and social participation and to environmental,social, familial, personal, and psychological factors. Peoplewith mental retardation require help to avoid confining theiridentity to just a few elements: functional or structural bodyaspects, skills (or, worse, impairments), and family. Weought to help them view themselves from every perspectivedescribed in the ICF, leaving out none. A well-developed,integrated identity must consider the relationships,interconnections and mutual influences among differentaspects. None of these aspects exists in isolation; they allinteract. A positive environmental contextual factor, such asa family that is supportive of the child’s autonomy, willreinforce skill development, social participation, and thedevelopment of positive personal contextual factors (self-


ESTADO DE SALUD(TRASTORNO O ENFERMEDAD)

ESTRUCTURAS YFUNCIONES

CORPORALES

ACTIVIDADES PARTICIPACIÓN

FACTORESCONTEXTUALES

FACTORESAMBIENTALES

FACTORESPERSONALES

HEALTH STATUS

(DISORDER OR DISEASE)

CONTEXTUALFACTORS

BODY FUNCTIONS& STRUCTURE

ACTIVITY PARTICIPATION

ENVIRONMENTALFACTORS

PERSONALFACTORS

Figure 1. Interactions among ICF components.

image, confidence, autonomous identity), which in turnreinforce the development of other factors.

The ICF teaches us to think of ourselvesinterconnectedly, linking all the different factors. Identityand self-conception are listed in the ICF as personalcontextual factors. Identity thus has a bearing on many otherpoints. For instance, I recall a boy with mild mentalretardation who was unable to learn certain household skills,such as doing the laundry and hanging it up, because withinhis gender identity (i.e., what it meant for him to be a man)these were female activities. That was his point of view; hisopinion as to what was a proper activity for a man wasconditioning his learning ability. Clearly, this belief sprangfrom cultural environmental contextual factors. Identity hasa role in many other aspects and is also influenced by them:failure and success in some capacities, functional/structuralbody limitations, issues with social participation, familyattitudes and social attitudes, are all significant parts ofindividual self-conception and identity.

But let us take a closer look at the psychologicalfunctioning of identity. Identity is developed and modifiedas a result of action over four dimensions that meritparticular attention (Fig. 2).

Under motivation we find things with a positive value(aims to be attained) or a negative value (things to beavoided): wishes, expectations, needs, models, sources ofsuccess and reward. This dimension encourages us to act, todo what it takes to achieve the desired outcome. Maslow wasone of the most influential proponents of motivation theory.Human beings, according to his view, respond to a specifichierarchy of needs with their behavior. A pyramid is a goodrepresentation: physiological needs are on the lowest tier,followed by safety needs, belonging needs, esteem needsand, at the top, self-actualization.

Two other dimensions of identity, however, passjudgment on our actions: self-efficacy («Can I actually dothe thing I would like to do?») and attributions («Are thesethe actions that truly bring about those outcomes, or are theoutcomes in my case the product of something else, such asassistance received or the indulgence of others, rather thanwhat I am able to do?»). We agree that individuals ought tohave an identity that reaffirms their ability to perform anaction («I can do it!») and the causal efficacy of their actionsin terms of achieving concrete results («Doing this leads tocertain outcomes»). Self-efficacy and attributions areimportant mediators of action and learning.

A sense of self-efficacy, according to Albert Bandura’smany studies, is a person’s perception of his or her chancesof success at performing a certain task; in other words, theperson’s sense of competence, of capability. The positiveeffects of a good sense of self-efficacy even comprisecontinuity of effort, perseverance over time, creativity, andfreedom to reach one’s own decisions independently. Thus,self-efficacy is linked with believing oneself capable oforganizing and carrying out the necessary actions to copewith future situations in order to obtain desired outcomes.Bandura states that self-efficacy beliefs strongly influencethe way individuals think, feel, find personal sources ofmotivation, and act.

Attributional style, on the other hand, is linked to theperson’s attitudes and beliefs regarding the utility of his orher commitment, active efforts, and use of strategies andactions. Attributions may be viewed as the result ofspontaneous assessments made by individuals as to who orwhat is responsible for events. All individuals have anattributional pattern made up of beliefs and cognitions. Thispattern is the person’s attributional style; it is a model usedto explain reality.

The pattern is grounded in the person’s present and pastachievements and those of others; attribution plays animportant role with regard to future achievement.Attributional style is therefore a fairly stable set of causalcategories habitually employed by an individual, with greatinterpersonal variation. Thus, some people will believe thatthings work or fail to work as a result of their active efforts;others will believe it’s because they are capable orincapable; others will think it’s because the task is easy ordifficult; and yet others will attribute success or failure tochance, specific circumstances, or bad luck.

Attributions are classified along three dimensions. Thefirst dimension is locus of control (internal vs. external): thedifference between ascribing events to internal causes (suchas effort or innate ability) and external causes (such as atask’s inherent difficulty or chance). The second dimensionis stability, which has to do with duration of cause: stabilityis greater for events attributed to unchangeable causes (suchas innate ability or the inherent difficulty posed by a task)and smaller for those attributed to unstable causes (such aschance or effort). The third dimension is controllability:some attributions, such as effort, ascribe more control to theindividual, while others, such as chance, cannot becontrolled. This is an important distinction, as it highlightsthe impact of different types of attributions on individualexpectations and perseverance in undertaking some action.Self-esteem is another important psychological aspect; it isthe opinion, perception and feelings that we have of our ownvalue or satisfaction, arising from our own positive actionsand from the positive messages we receive, and acting as asource of motivation. The better we feel about ourselves, themore valuable we feel and the more things have value for us;and the more things we wish for, the greater will our


ACCIONES

AUTOESTIMA

AUTOEFICIENCIA

VALORESOBJETIVOS

MOTIVACIÓN

ATRIBUCIONES

SELF-EFFICACY

SELF-ESTEEMATTRIBUTIONS

VALUESOBJECTIVESMOTIVATION

ACTIONS

Figure 2. Four dimensions in the development of identity.

expectations be. Self-esteem, even viewed as a unitary,global «construct», comprises a number of dimensions, eachrelatively independent of the rest. Recall that self-esteem isconstructed through cognitive self-appraisal mechanisms inrelation to external events (failures or successes), acceptanceor rejection messages from other people, and more or lessconscious standards of achievement.

Thus, we will help an individual to develop a goodindependent identity by expanding that person’s wishes andmotivation, by helping them believe in their self-efficacyand the efficacy of their actions, or by reinforcing their self-esteem. As pointed out above, time is also a key variable inthe development of identity: we are what we have been,what we have done, what we have chosen, etc. Therefore,individuals with mental retardation should be assisted inremembering their personal choices, wishes, doubts,outcomes, and emotions, often by employing tangiblememories such as mementos, photographs, trips to specialplaces, etc. We are also what we would like to be: our lifeproject, what we would like to happen, our appointmentswith ourselves.

A strong identity will always have projects to pursue,objectives to attain, and a few expectations. Yet we knowhow hard this is for people with mental retardation and fortheir families. Recently, a mother was telling me about howshe was planning for the family’s future together with herchildren and said, «We feel as if they never ever change...and the future is too uncertain and anxiety-ridden.» This«project» dimension involves a strong psychologicalcommitment by the person’s family — not just socialservices and health care services, or social and culturalpublic policy. The metacognitive ability to see oneself, topractically look at oneself from outside, is an importantelement in developing identity.

We know how difficult it is for people with mentalretardation to know themselves, but this is precisely why itis so important to assist such individuals educationally andpsychologically to gain a fuller and more accurate view ofthemselves through self-description and self-narrative. TheICF and the four spheres discussed above - motivation, self-efficacy, attributions, and self-esteem - should be used as a

framework for this task, while constantly striving forbalance between what the person has been and what theperson wishes to be (or has the project to become).

Many key «actions» for the development of adultidentity are «choices», «independent decisions», even actsof rebellion that do not meet with parental approval. Identitymay thus be said to feed on choices (of clothes, friends,adults, studies, work, etc.) and also give rise to choices.Choosing is a difficult task for a person with mentalretardation; obstacles may be cognitive, emotional (havingto give up A in order to get B), or family- or environment-related, when do the choosing for them. Encouraging self-determination in the process of choosing is not just ademocratic attitude for education, but a fundamental way ofcontributing to the development of a strong identity.

In order to grow strong and independent, an identityrequires boundaries both to separate and to protect.Boundaries in body space and personal space, boundaries ofdecisions and relationships («even if you’re completelydependent upon me, I am your father and you are my son»).Often, parents and professionals find it very difficult torespect the boundaries of individuals with mentalretardation, sometimes because they are very needy orbecause their territory has to be invaded for a number ofexcellent reasons (poor skills, safety precautions, protectionfrom hazards, etc.). However, this ought to give us pause forthought: even the most restricted person is entitled to havesome inviolate boundaries, as respecting these boundariesmay feed and reinforce the person’s identity. We all ought toremember the time when we used to hang a notice outsideour bedroom doors: «Do not disturb upon pain of death!»Unfortunately, many teenagers with mental retardation areunable to put up such notices; they can, however, demandprotective boundaries in their own ways.

The development of identity always entails some pain forevery individual, so we try to protect the person with mentalretardation from what we imagine might be excessive pain,especially when they come to realize their situation; but wemust crucially try to have a little more confidence in ourchildren’s or pupils’ psychological resources and in our ownability to provide any assistance required.


NewOn 15-16 May 2003, the 8th International Symposium on

Down Syndrome was held in the Auditorium of the «LaPedrera» Caixa de Catalunya Cultural Centre, with the title«Building the future. Questions for today. Answers fortomorrow.»

The opening keynote lecture was given by Douglas Fisherof the School of Teacher Education at San Diego StateUniversity (USA), who discussed myths and realitiesconcerning the creation of inclusive opportunities for peoplewith disabilities. Mr. Fisher also spoke during the symposiumon «What we have learned from integration.»

Other foreign specialists also took part in the symposium,including:

Dario Ianes, psychologist and co-editor-in-chief of EdizioniCentro Studi Erickson in Trento (Italy), who discussed«Identity in people with disabilities»; Elsa Coriat, psychologistand psychoanalyst, currently the coordinator of Centro Dra.Lydia Coriat in Buenos Aires (Argentina), who discussed «Therelationship between parents and professionals»; DorothyGriffiths, associated professor at the Child and Youth StudiesDepartament, Brock University, Ontario (Canada), whodiscussed «The establishment of personal relationships andbonds: cornerstones of mental welfare for people withdisabilities»; Jay Klein, a speaker at previous FCSD symposia,director of the National Home of Your Own Alliance Programat the University of New Hampshire (USA), who discussed«Strategies to help people to live in the community andestablish relationships»; and Carlo Lepri, psychologist anddirector of the Centro Studi USL3 at Genoa (Italy), whodiscussed «The individual with disability, fellow workers, andthe family: a few suggestions in case of need». Local specialistsalso gave presentations, including Josep Martínez, director ofEls Xiprers primary school in Barcelona, who presented «Thetestimony of a committed school», Maria Josep Delor, head ofthe Àrea de Formació i Inserció Laboral i Projectes (JobTraining, Job Placement and Projects Area) of APRODISCA inMontblanc, Tarragona, who under the title «Job integrationexperience» presented all the work carried out to comply withjob integration legislation. We also wish to highlight the effortsof professionals working for the FCSD in presenting ourservices and working philosophy: Marta Golanó, coordinator ofthe Centre de Desenvolupament Infantil i Atenció Precoç,discussed «Working alongside parents in the early years»; RosaBorbonés, coordinator of the School-age Follow-Up Service,gave a presentation on «Therapy groups for children andteenagers with Down syndrome»; Josep Ruf, coordinator of thePrograma d’Habitatge a la Pròpia Llar, discussed theFoundation’s housing programme; and Màrius Peralta,coordinator of the Naturally Supported EmploymentProgramme, discussed «Support in job placement». The lastspeaker was Alexandre Jollien, a Swiss philosopher withcerebral palsy, who shared an interesting consideration of«What is contributed to society by people with disabilities»; hewas introduced by writer Juan José Millás.

The 8th Ramon Trias Fargas Award for Research on DownSyndrome was handed to the winning team, M. Dierssen, R.Benavides-Piccione, I. Ballesteros, C. Martínez-Cué, X.Estivill, J. Flórez, G.N. Elston and J. De Felipe, for their paper«Cortical microarchitecture alterations in Ts65Dn mice, ananimal model for Down Syndrome: impact of environmentalenrichment».

Book selectionBOOKS

Síndrome de Down: hacia un futuro mejor. Guía para lospadres (2nd edition)

Sigfried M. PueschelBarcelona, Masson, 2002, 346 pp. ISBN 84-458-1167-3

2003, the European Year of People with Disabilities, ismeaningful timing for this thoroughly produced second editionof S.M. Pueschel’s famous book for parents of people withDown syndrome (DS). Its usefulness clearly extends beyondthe declared target audience: it is an excellent guide for anyonewho provides care for people with DS, whether professionallyor in other capacities, full-time or part-time. The book coversall the progress made in recent decades regarding theknowledge, supervision, and follow-up of these individualsfrom birth to adulthood, when they are able to display a panoplyof capabilities in good health.

Doctor Sigfried Pueschel is Professor of Pediatrics andDirector of the Child Development Center at Rhode IslandHospital, USA. His multidisciplinary work, tirelessly pursuedsince the 1960s, has produced a plethora of books and sciencepapers conveying his experiences and new hopes. This book isa summary of many of these other works. Pueschel and othersinvolved in the writing of this book are parents of young peoplewith DS, thus bringing special knowledge and sensitivity totheir treatment of all the issues.

Editorial Masson and Fundación Síndrome de Down deCantabria, with its director Dr. Jesús Flórez, also professor anddirector of the Department of Pharmacology at the Universidadde Cantabria School of Medicine, are responsible for this newSpanish edition, just as they oversaw the first. Theircommitment to and enthusiasm about every aspect of DS workare reflected in the additional utility-enhancing localizedmaterial and details they have compiled: an extensive updatedand adapted reading list, a list of Spanish-language books aboutDown syndrome, DS growth charts specific to Spain, and anappendix listing Spanish DS-related institutions, among others.

Josep M. Corretger

Conferences & meetings3rd Symposium Internacional sobre Síndrome de Down:«Sharing a worldwide commitment»

3, 4 y 5 de march 2004México D.F.

Informatión:Fundación John Langdon DownSelva # 4Insurgentes Cuicuilco, CoyoacánMéxico D.F. 04530 (México)Tel: (52-55) 56-66-85-80Fax: (52-55) 56-06-38-09, (52-55) 56-66-08-19E-mail: [email protected]

SD-DS32 INTERNATIONAL MEDICAL JOURNAL ON DOWN SYNDROME 2003: vol. 7, núm. 2

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INTERNATIONAL MEDICAL JOURNAL ON DOWN … · •Double nondisjunction ... A second purpose is to address psycho-educational issues with medical implications ... papers dealing with