Brain Morphology in Autism and Fragile X Syndrome Correlates With Social IQ: First Report From the Canadian-Swiss-Egyptian Neurodevelopmental Study

Abstract

Fragile X syndrome shares most of the behavioral phenotypic similarities with autism. How are these similarities reflected in brain morphology? A total of 10 children with autism and 7 with fragile X underwent morphological (T1) 1.5-T magnetic resonance imaging (MRI). The authors found no significant difference in total brain volumes, regional volumes, gyrification index, sulcul depth, and cerebral cortical thickness. However, children with autism showed significant decrease in the medial prefrontal bilaterally and the left anterior cingulate cortices. Regression analysis revealed positive correlation between the medial prefrontal cortical thickness and the social IQ. The authors suggest that the difference between the 2 groups in the medial prefrontal and anterior cingulate cortices thickness may entail an altered social cognitive style. Functional MRI studies directly differentiating between social indifference (autism) and social avoidance (fragile X) are needed to further characterize the spectrum of social abnormalities between these 2 groups.

Keywords

autism fragile X syndrome magnetic resonance imaging cerebral cortical thickness medial prefrontal anterior cingulate

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References

Diagnostic and Statistical Manual of Mental Disorders, DSM-IV . 4th ed. Washington, DC: American Psychiatric Press; 1994.

Veenstra-Vanderweele J. , Christian SL , Cook EH Jr. Autism as a paradigmatic complex genetic disorder. Annu Rev Genomics Hum Genet. 2004 ;5:379-405.

Szatmari P. , Paterson AD , Zwaigenbaum L. , et al., and the Autism Genome Project Consortium. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007;39(3):319-328.

Sudhalter V. , Cohen IL , Silverman W. , Wolf-Schein EG. Conversational analyses of males with fragile X, Down syndrome, and autism: comparison of the emergence of deviant language. Am J Ment Retard. 1990;94(4):431-441.

Rogers SJ , Wehner DE , Hagerman R. The behavioral phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders . J Dev Behav Pediatr. 2001;22(6):409-417.

Kaufmann WE , Cortell R. , Kau AS , et al. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet A. 2004;129A(3):225-234.

Verkerk AJ , Pieretti M. , Sutcliffe JS , et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65(5):905-914.

Bailey DB Jr , Mesibov GB , Hatton DD , Clark RD , Roberts JE , Mayhew L. Autistic behavior in young boys with fragile X syndrome. J Autism Dev Disord. 1998;28(6):499-508.

Philofsky A. , Hepburn SL , Hayes A. , Hagerman R. , Rogers SJ Linguistic and cognitive functioning and autism symptoms in young children with fragile X syndrome. Am J Ment Retard. 2004; 109(3):208-218.

10.

Hagerman RJ , Chudley AE , Knoll JH , Jackson AW 3rd , Kemper M. , Ahmad R. Autism in fragile X females. Am J Med Genet. 1986;23(1-2):375-380.

11.

Demark JL , Feldman MA , Holden JJ Behavioral relationship between autism and fragile x syndrome. Am J Ment Retard. 2003;108(5):314-326.

12.

Budimirovic DB , Bukelis I. , Cox C. , Gray RM , Tierney E. , Kaufmann WE Autism spectrum disorder in fragile X syndrome: differential contribution of adaptive socialization and social withdrawal . Am J Med Genet A. 2006;140A(17):1814-1826.

13.

Kau AS , Reider EE , Payne L. , Meyer WA , Freund L. Early behavior signs of psychiatric phenotypes in fragile X syndrome. Am J Ment Retard. 2000;105(4):286-299.

14.

Sabaratnam M. , Murthy NV , Wijeratne A. , Buckingham A. , Payne S. Autistic-like behaviour profile and psychiatric morbidity in fragile X syndrome: a prospective ten-year follow-up study. Eur Child Adolesc Psychiatry. 2003;12(4):172-177.

15.

Roberts JE , Schaaf JM , Skinner M. , et al. Academic skills of boys with fragile X syndrome: profiles and predictors. Am J Ment Retard. 2005;110(2):107-120.

16.

Devys D. , Lutz Y. , Rouyer N. , Bellocq JP , Mandel JL. The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nat Genet. 1993;4(4): 335-340.

17.

Loesch DZ , Bui QM , Dissanayake C. , et al. Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci Biobehav Rev. 2007;31(3):315-326.

18.

Comery TA , Harris JB , Willems PJ , et al. Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci U S A. 1997;94(10):5401-5404.

19.

Weiler IJ , Greenough WT Synaptic synthesis of the fragile X protein: possible involvement in synapse maturation and elimination. Am J Med Genet. 1999;83(4):248-252.

20.

Belmonte MK , Bourgeron T. Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat Neurosci . 2006;9(10):1221-1225.

21.

Castellanos FX , Lee PP , Sharp W. , et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA. 2002; 288(14):1740-1748.

22.

Gottesman II , Shields J. A polygenic theory of schizophrenia. Proc Natl Acad Sci U S A. 1967;58(1):199-205.

23.

Glahn DC , Thompson PM , Blangero J. Neuroimaging endophenotypes: strategies for finding genes influencing brain structure and function. Hum Brain Map. 2007 ;28(6):488-501.

24.

Hariri AR , Weinberger DR Imaging genomics. Br Med Bull. 2003;65:259-270.

25.

Gottesman II , Gould TD The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003; 160(4):636-645.

26.

Meyer-Lindenberg A. , Weinberger DR Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev. 2006;7(10):818-827.

27.

Mostofsky SH , Mazzocco MM , Aakalu G. , Warsofsky IS , Denckla MB , Reiss AL Decreased cerebellar posterior vermis size in fragile X syndrome: correlation with neurocognitive performance. Neurology. 1998;50(1):121-130.

28.

Mazzocco MM , Pulsifer M. , Fiumara A. , et al. Brief report: autistic behaviors among children with fragile X or Rett syndrome: implications for the classification of pervasive developmental disorder. J Autism Dev Disord. 1998;28(4):321-328.

29.

Reiss AL , Lee J. , Freund L. Neuroanatomy of fragile X syndrome: the temporal lobe. Neurology . 1994;44(7):1317-1324.

30.

Kates WR , Abrams MT , Kaufmann WE , Breiter SN , Reiss AL Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome. Psychiatry Res. 1997;75(1):31-48.

31.

Reiss AL , Abrams MT , Greenlaw R. , Freund L. , Denckla MB Neurodevelopmental effects of the FMR-1 full mutation in humans. Nat Med. 1995;1(2):159-167.

32.

Eliez S. , Schmitt JE , White CD , Wellis VG , Reiss AL A quantitative MRI study of posterior fossa development in velocardiofacial syndrome. Biol psychiatry. 2001;49(6):540-546.

33.

Gothelf D. , Furfaro JA , Hoeft F. , et al. Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP). Ann Neurol. 2008;63(1): 40-51.

34.

Aylward EH , Minshew NJ , Field K. , Sparks BF , Singh N. Effects of age on brain volume and head circumference in autism. Neurology. 2002;59(2):175-183.

35.

Carper RA , Moses P. , Tigue ZD , Courchesne E. Cerebral lobes in autism: early hyperplasia and abnormal age effects. Neuroimage. 2002;16(4):1038-1051.

36.

Piven J. , Arndt S. , Bailey J. , Havercamp S. , Andreasen NC , Palmer P. An MRI study of brain size in autism. Am J Psychiatry . 1995;152(8):1145-1149.

37.

Hardan AY , Jou RJ , Keshavan MS , Varma R. , Minshew NJ Increased frontal cortical folding in autism: a preliminary MRI study. Psychiatry Res. 2004;131(3):263-268.

38.

Casanova MF , Buxhoeveden DP , Switala AE , Roy E. Neuronal density and architecture (Gray Level Index) in the brains of autistic patients. J Child Neurol. 2002;17(7):515-521.

39.

Zilbovicius M. , Garreau B. , Samson Y. , et al. Delayed maturation of the frontal cortex in childhood autism. Am J Psychiatry. 1995; 152(2):248-252.

40.

Miodonski A. The angioarchitectonics and cytoarchitectonics (impregnation modo Golgi-Cox) structure of the fissural frontal neocortex in dog. Folia Biol (Krakow). 1974;22(3):237-279.

41.

Hilgetag CC , Barbas H. Developmental mechanics of the primate cerebral cortex. Anat Embryol (Berl). 2005;210(5-6):411-417.

42.

Rakic P. Radial versus tangential migration of neuronal clones in the developing cerebral cortex. Proc Natl Acad Sci U S A. 1995; 92(25):11323-11327.

43.

Schopler E. , Reichler RJ , DeVellis RF , Daly K. Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Dev Disord. 1980;10(1):91-103.

44.

Wechsler D. Wechsler Intelligence Scale for Children-Revised Manual. New York: Psychological Corporation; 1974.

45.

Perry A. , Freeman N. Psychometric properties of the Childhood Autism Rating Scale (CARS). The Meeting of the Ontario Association on Developmental Disabilities Research Preconference; March 1996, Ontario , Canada.

46.

Sponheim E. Changing criteria of autistic disorders: a comparison of the ICD-10 research criteria and DSM-IV with DSM-III-R, CARS, and ABC. J Autism Dev Disord. 1996;26(5):513-525.

47.

Eggert D. Comparative study on the social competence of mentally retarded children and nonretarded children using the Vineland-Social-Maturity-Scale (VSMS) [in German] . Prax Kinderpsychol Kinderpsychiatr. 1974 ;23(4):139-144.

48.

MacDonald D. , Kabani N. , Avis D. , Evans AC Automated 3-D extraction of inner and outer surfaces of cerebral cortex from MRI. Neuroimage. 2000;12(3):340-356.

49.

Lewis P. , Abbeduto L. , Murphy M. , et al. Cognitive, language and social-cognitive skills of individuals with fragile X syndrome with and without autism. J Intellect Disabil Res. 2006;50(pt 7):532-545.

50.

Frith CD

The social brain?

Philos Trans R Soc Lond B Biol Sci. 2007;362(1480):671-678.

51.

Adolphs R. Cognitive neuroscience of human social behaviour. Nat Rev . 2003;4:165-178.

52.

Geday J. , Gjedde A. , Boldsen AS , Kupers R. Emotional valence modulates activity in the posterior fusiform gyrus and inferior medial prefrontal cortex in social perception. Neuroimage . 2003;18(3):675-684.

53.

Mitchell JP , Macrae CN , Banaji MR Dissociable medial prefrontal contributions to judgments of similar and dissimilar others. Neuron. 2006;50(4):655-663.

54.

Frith CD , Frith U. Social cognition in humans. Curr Biol. 2007 ; 17(16):R724-R732.

55.

Amaral DG The amygdala, social behavior, and danger detection. Ann N Y Acad Sci. 2003;1000:337-347.

56.

Kau AS , Tierney E. , Bukelis I. , et al. Social behavior profile in young males with fragile X syndrome: characteristics and specificity. Am J Med Genet A. 2004;126A(1):9-17.

57.

Cohen IL , Sudhalter V. , Pfadt A. , Jenkins EC , Brown WT , Vietze PM Why are autism and the fragile-X syndrome associated? Conceptual and methodological issues. Am J Hum Genet. 1991;48(2):195-202.

58.

Feinstein C. , Reiss AL Autism: the point of view from fragile X studies . J Autism Dev Disord. 1998;28(5):393-405.

59.

Hagerman R. The physical and behavioral phenotype. In: Hagerman R , Hagerman PJ , eds. Fragile X Syndrome: Diagnosis, Treatment, and Research. 3rd ed. Baltimore, MD: Johns Hopkins University Press; 2002:3-110.

60.

Hatton DD , Hooper SR , Bailey DB , Skinner ML , Sullivan KM , Wheeler A. Problem behavior in boys with fragile X syndrome. Am J Med Genet. 2002;108(2):105-116.

61.

Baron-Cohen S. , Belmonte MK Autism: a window onto the development of the social and the analytic brain. Annu Rev Neurosci. 2005;28:109-126.

62.

Mazzocco MM , Pennington BF , Hagerman RJ Social cognition skills among females with fragile X. J Autism Dev Disord. 1994;24(4):473-485.

63.

Simon EW , Finucane BM Facial emotion identification in males with fragile X syndrome. Am J Med Genet. 1996;67(1): 77-80.

64.

Turk J. , Cornish K. Face recognition and emotion perception in boys with fragile-X syndrome. J Intellect Disabil Res. 1998; 42(pt 6):490-499.

65.

Hagan CC , Hoeft F. , Mackey A. , Mobbs D. , Reiss AL Aberrant neural function during emotion attribution in female subjects with fragile X syndrome. J Am Acad Child Adolesc Psychiatry. 2008; 47(12):1443-2354.

66.

Freund LS , Reiss AL , Abrams MT Psychiatric disorders associated with fragile X in the young female. Pediatrics. 1993;91(2): 321-329.