Skip to main content
SpringerLink
Log in

Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co-morbid autism spectrum disorder

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Seizures are a common co-occurring condition in those with fragile X syndrome (FXS), and in those with idiopathic autism spectrum disorder (ASD). Seizures are also associated with ASD in those with FXS. However, little is known about the rate of seizures and how commonly these problems co-occur with ASD in boys with the FMR1 premutation. We, therefore, determined the prevalence of seizures and ASD in boys with the FMR1 premutation compared with their sibling counterparts and population prevalence estimates. Fifty premutation boys who presented as clinical probands (N = 25), or non-probands (identified by cascade testing after the proband was found) (N = 25), and 32 non-carrier controls were enrolled. History of seizures was documented and ASD was diagnosed by standardized measures followed by a team consensus of ASD diagnosis. Seizures (28%) and ASD (68%) were more prevalent in probands compared with non-probands (0 and 28%), controls (0 and 0%), and population estimates (1 and 1.7%). Seizures occurred more frequently in those with the premutation and co-morbid ASD particularly in probands compared with those with the premutation alone (25 vs. 3.85%, p = 0.045). Although cognitive and adaptive functioning in non-probands were similar to controls, non-probands were more likely to meet the diagnosis of ASD than controls (28 vs. 0%, p < 0.0001). In conclusion, seizures were relatively more common in premutation carriers who presented clinically as probands of the family and seizures were commonly associated with ASD in these boys. Therefore, boys with the premutation, particularly if they are probands should be assessed carefully for both ASD and seizures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, text revised, 4th edn. American Psychiatric Association, Washington, DC

  • Aziz M, Stathopulu E, Callias M, Taylor C, Turk J, Oostra B, Willemsen R, Patton M (2003) Clinical features of boys with fragile X premutations and intermediate alleles. Am J Med Genet 121B:119–127

    Article  PubMed  Google Scholar 

  • Bailey DB Jr, Raspa M, Olmsted M, Holiday DB (2008) Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A 146A:2060–2069

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Berry-Kravis E (2002) Epilepsy in fragile X syndrome. Dev Med Child Neurol 44:724–728

    Article  PubMed  Google Scholar 

  • Berry-Kravis E, Raspa M, Loggin-Hester L, Bishop E, Holiday D, Bailey DB (2010) Seizures in fragile X syndrome: characteristics and comorbid diagnoses. Am J Intellect Dev Disabil 115:461–472

    Article  PubMed  Google Scholar 

  • Brooks-Kayal A (2010) Epilepsy and autism spectrum disorders: are there common developmental mechanisms? Brain Dev 32:731–738

    Article  PubMed  Google Scholar 

  • Brouwer JR, Huizer K, Severijnen LA, Hukema RK, Berman RF, Oostra BA, Willemsen R (2008) CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome. J Neurochem 107:1671–1682

    Article  PubMed  CAS  Google Scholar 

  • Centers for Disease Control and Prevention (2009) Prevalence of autism spectrum disorders—autism and developmental disabilities monitoring network, United States, 2006. MMWR Surveill Summ 58:1–20

    Google Scholar 

  • Chen Y, Tassone F, Berman RF, Hagerman PJ, Hagerman RJ, Willemsen R, Pessah IN (2010) Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet 19:196–208

    Article  PubMed  CAS  Google Scholar 

  • Chonchaiya W, Schneider A, Hagerman RJ (2009a) Fragile X: a family of disorders. Adv Pediatr 56:165–186

    Article  PubMed  Google Scholar 

  • Chonchaiya W, Utari A, Pereira GM, Tassone F, Hessl D, Hagerman RJ (2009b) Broad clinical involvement in a family affected by the fragile X premutation. J Dev Behav Pediatr 30:544–551

    Article  PubMed  Google Scholar 

  • Chonchaiya W, Tassone F, Ashwood P, Hessl D, Schneider A, Campos L, Nguyen DV, Hagerman RJ (2010) Autoimmune disease in mothers with the FMR1 premutation is associated with seizures in their children with fragile X syndrome. Hum Genet 128:539–548

    Article  PubMed  CAS  Google Scholar 

  • Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ (2007) Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J Autism Dev Disord 37:738–747

    Article  PubMed  Google Scholar 

  • Constantino JN, Gruber CP (2005) The social responsiveness scale (SRS) manual. Western Psychological Services, Los Angeles

    Google Scholar 

  • Cowan LD, Bodensteiner JB, Leviton A, Doherty L (1989) Prevalence of the epilepsies in children and adolescents. Epilepsia 30:94–106

    Article  PubMed  CAS  Google Scholar 

  • Dombrowski C, Levesque ML, Morel ML, Rouillard P, Morgan K, Rousseau F (2002) Premutation and intermediate-size FMR1 alleles in 10 572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet 11:371–378

    Article  PubMed  CAS  Google Scholar 

  • Farzin F, Perry H, Hessl D, Loesch D, Cohen J, Bacalman S, Gane L, Tassone F, Hagerman P, Hagerman R (2006) Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation. J Dev Behav Pediatr 27:S137–S144

    Article  PubMed  Google Scholar 

  • Fatemi SH, Folsom TD (2011) The role of fragile X mental retardation protein in major mental disorders. Neuropharmacology 60:1221–1226

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Carvajal I, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ, Tassone F (2009) Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn 11:324–329

    Article  PubMed  CAS  Google Scholar 

  • Garcia-Nonell C, Ratera ER, Harris S, Hessl D, Ono MY, Tartaglia N, Marvin E, Tassone F, Hagerman RJ (2008) Secondary medical diagnosis in fragile X syndrome with and without autism spectrum disorder. Am J Med Genet A 146A:1911–1916

    Article  PubMed  Google Scholar 

  • Haerer AF, Anderson DW, Schoenberg BS (1986) Prevalence and clinical features of epilepsy in a biracial United States population. Epilepsia 27:66–75

    Article  PubMed  CAS  Google Scholar 

  • Hagerman PJ, Stafstrom CE (2009) Origins of epilepsy in fragile X syndrome. Epilepsy Curr 9:108–112

    Article  PubMed  Google Scholar 

  • Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M (2009) Advances in the treatment of fragile X syndrome. Pediatrics 123:378–390

    Article  PubMed  Google Scholar 

  • Hagerman R, Hoem G, Hagerman P (2010) Fragile X and autism: intertwined at the molecular level leading to targeted treatments. Mol Autism. doi:10.1186/2040-2392-1-12

  • Handa V, Goldwater D, Stiles D, Cam M, Poy G, Kumari D, Usdin K (2005) Long CGG-repeat tracts are toxic to human cells: implications for carriers of fragile X premutation alleles. FEBS Lett 579:2702–2708

    Article  PubMed  CAS  Google Scholar 

  • Harris SW, Hessl D, Goodlin-Jones B, Ferranti J, Bacalman S, Barabato I, Tassone F, Hagerman PJ, Herman K, Hagerman RJ (2008) Autism profiles of males with fragile X syndrome. Am J Ment Retard 113:427–438

    Article  PubMed  Google Scholar 

  • Hauser WA, Annegers JF, Kurland LT (1991) Prevalence of epilepsy in Rochester, Minnesota: 1940–1980. Epilepsia 32:429–445

    Article  PubMed  CAS  Google Scholar 

  • Hollander E, Dolgoff-Kaspar R, Cartwright C, Rawitt R, Novotny S (2001) An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry 62:530–534

    Article  PubMed  CAS  Google Scholar 

  • Hunsaker MR, Wenzel HJ, Willemsen R, Berman RF (2009) Progressive spatial processing deficits in a mouse model of the fragile X premutation. Behav Neurosci 123:1315–1324

    Article  PubMed  CAS  Google Scholar 

  • Hunter JE, Allen EG, Abramowitz A, Rusin M, Leslie M, Novak G, Hamilton D, Shubeck L, Charen K, Sherman SL (2008) No evidence for a difference in neuropsychological profile among carriers and noncarriers of the FMR1 premutation in adults under the age of 50. Am J Hum Genet 83:692–702

    Article  PubMed  CAS  Google Scholar 

  • Iwahashi C, Tassone F, Hagerman RJ, Yasui D, Parrott G, Nguyen D, Mayeur G, Hagerman PJ (2009) A quantitative ELISA assay for the fragile X mental retardation 1 protein. J Mol Diagn 11:281–289

    Article  PubMed  CAS  Google Scholar 

  • Kobau R, Zahran H, Thurman DJ, Zack MM, Henry TR, Schachter SC, Price PH (2008) Epilepsy surveillance among adults–19 states, behavioral risk factor surveillance system, 2005. MMWR Surveill Summ 57:1–20

    PubMed  Google Scholar 

  • Kogan MD, Blumberg SJ, Schieve LA, Boyle CA, Perrin JM, Ghandour RM, Singh GK, Strickland BB, Trevathan E, van Dyck PC (2009) Prevalence of parent-reported diagnosis of autism spectrum disorder among children in the US, 2007. Pediatrics 124:1395–1403

    Article  PubMed  Google Scholar 

  • Le Couteur A, Rutter M, Lord C, Rios P, Robertson S (1989) Autism diagnostic interview: a standardized investigator-based instrument. J Autism Dev Disord 19:363–387

    Article  PubMed  CAS  Google Scholar 

  • Loesch DZ, Bui QM, Dissanayake C, Clifford S, Gould E, Bulhak-Paterson D, Tassone F, Taylor AK, Hessl D, Hagerman R, Huggins RM (2007) Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci Biobehav Rev 31:315–326

    Article  PubMed  Google Scholar 

  • Loesch DZ, Godler DE, Khaniani M, Gould E, Gehling F, Dissanayake C, Burgess T, Tassone F, Huggins R, Slater H, Choo KH (2009) Linking the FMR1 alleles with small CGG expansions with neurodevelopmental disorders: preliminary data suggest an involvement of epigenetic mechanisms. Am J Med Genet A 149A:2306–2310

    Article  PubMed  CAS  Google Scholar 

  • Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC, Pickles A, Rutter M (2000) The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 30:205–223

    Article  PubMed  CAS  Google Scholar 

  • Matsuo M, Maeda T, Sasaki K, Ishii K, Hamasaki Y (2010) Frequent association of autism spectrum disorder in patients with childhood onset epilepsy. Brain Dev 32:759–763

    Article  PubMed  Google Scholar 

  • Mullen EM (1995) Mullen scales of early learning. American Guidance Service, Circle Pines

    Google Scholar 

  • Murphy CC, Trevathan E, Yeargin-Allsopp M (1995) Prevalence of epilepsy and epileptic seizures in 10-year-old children: results from the metropolitan Atlanta developmental disabilities study. Epilepsia 36:866–872

    Article  PubMed  CAS  Google Scholar 

  • Musumeci SA, Hagerman RJ, Ferri R, Bosco P, Dalla Bernardina B, Tassinari CA, De Sarro GB, Elia M (1999) Epilepsy and EEG findings in males with fragile X syndrome. Epilepsia 40:1092–1099

    Article  PubMed  CAS  Google Scholar 

  • Pallin DJ, Goldstein JN, Moussally JS, Pelletier AJ, Green AR, Camargo CA Jr (2008) Seizure visits in US emergency departments: epidemiology and potential disparities in care. Int J Emerg Med 1:97–105

    Article  PubMed  Google Scholar 

  • Paul R, Pessah IN, Gane L, Ono M, Hagerman PJ, Brunberg JA, Tassone F, Bourgeois JA, Adams PE, Nguyen DV, Hagerman R (2010) Early onset of neurological symptoms in fragile X premutation carriers exposed to neurotoxins. Neurotoxicology 31:399–402

    Article  PubMed  CAS  Google Scholar 

  • Qin M, Entezam A, Usdin K, Huang T, Liu ZH, Hoffman GE, Smith CB (2011) A mouse model of the fragile X premutation: effects on behavior, dendrite morphology, and regional rates of cerebral protein synthesis. Neurobiol Dis 42:85–98

    Article  PubMed  CAS  Google Scholar 

  • Roid GH (2003) Stanford-Binet intelligence scales manual, 5th edn. Riverside Publishing, Itasca

    Google Scholar 

  • Rutter M, Bailey A, Berument SK, Lord C, Pickles A (2003) Social communication questionnaire (SCQ). Western Psychological Services, Los Angeles

    Google Scholar 

  • Sherman S (2002) Epidemiology. In: Hagerman RJ, Hagerman PJ (eds) Fragile X syndrome: diagnosis, treatment and research, 3rd edn edn. The Johns Hopkins University Press, Baltimore, pp 136–168

    Google Scholar 

  • Sparrow SS, Cicchetti DV, Balla DA (2005) Vineland adaptive behavior scales, 2nd edn. AGS Publishing, Circle Pines

    Google Scholar 

  • Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TE, Hagerman PJ (2000) Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet 66:6–15

    Article  PubMed  CAS  Google Scholar 

  • Tassone F, Pan R, Amiri K, Taylor AK, Hagerman PJ (2008) A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations. J Mol Diagn 10:43–49

    Article  PubMed  CAS  Google Scholar 

  • Theodore WH, Spencer SS, Wiebe S, Langfitt JT, Ali A, Shafer PO, Berg AT, Vickrey BG (2006) Epilepsy in North America: a report prepared under the auspices of the global campaign against epilepsy, the international bureau for epilepsy, the international league against epilepsy, and the World Health Organization. Epilepsia 47:1700–1722

    Article  PubMed  Google Scholar 

  • Tuchman R, Alessandri M, Cuccaro M (2010) Autism spectrum disorders and epilepsy: moving towards a comprehensive approach to treatment. Brain Dev 32:719–730

    Article  PubMed  Google Scholar 

  • Wechsler D (1991) Wechsler intelligence scale for children, 3rd edn. The Psychological Corporation, San Antonio

    Google Scholar 

  • Wechsler D (1997) Wechsler adult intelligence scale: administration and scoring manual, 3rd edn. Harcourt Assessment Inc, San Antonio

    Google Scholar 

  • Wechsler D (1999) Wechsler abbreviated scale of intelligence (WASI). Harcourt Assessment Inc, San Antonio

    Google Scholar 

  • Wechsler D (2002) Wechsler preschool and primary scale of intelligence, 3rd edn. The Psychological Corporation, San Antonio

    Google Scholar 

  • Wechsler D (2003) Wechsler intelligence scale for children, 4th edn. Harcourt Assessment Inc, San Antonio

    Google Scholar 

Download references

Acknowledgments

We deeply thank all participants and families who participated in this study. This work was supported by National Institute of Health Grants HD036071, HD02274, DE019583, DA024854, AG032119, AG032115, MH77554; National Center for Resources UL1RR024146; Health and Human Services Administration of Developmental Disabilities Grant 90DD05969 and the Grant from King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand (Dr. Chonchaiya).

Conflict of interest

Dr. Hagerman has received funding from Seaside Therapeutics, Novartis, Roche, Forest, Neuropharm, Johnson & Johnson, and Curemark for clinical trials, but these are unrelated to this study. She also consults with Novartis and Roche regarding clinical trials in fragile X syndrome unrelated to this study. Dr. Hessl has received funding from Novartis and Roche for clinical trials and consultation unrelated to this study. Other authors have indicated they have no financial relationships relevant to this article to disclose.

Author information

Authors and Affiliations

  1. Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California Davis Health System, 2825 50th Street, Sacramento, CA, 95817, USA

    Weerasak Chonchaiya, Jacky Au, Andrea Schneider, David Hessl, Susan W. Harris, Meredith Laird, Flora Tassone & Randi J. Hagerman

  2. Division of Growth and Development, Department of Pediatrics, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand

    Weerasak Chonchaiya

  3. Department of Pediatrics, University of California Davis Health System, Sacramento, CA, USA

    Jacky Au, Susan W. Harris & Randi J. Hagerman

  4. Department of Psychiatry and Behavioral Sciences, University of California Davis Health System, Sacramento, CA, USA

    Andrea Schneider & David Hessl

  5. Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California, Davis, CA, USA

    Yi Mu & Danh V. Nguyen

  6. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA, USA

    Flora Tassone

Authors
  1. Weerasak Chonchaiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacky Au
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David Hessl
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susan W. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Meredith Laird
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yi Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Flora Tassone
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Danh V. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Randi J. Hagerman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Randi J. Hagerman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chonchaiya, W., Au, J., Schneider, A. et al. Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co-morbid autism spectrum disorder. Hum Genet 131, 581–589 (2012). https://doi.org/10.1007/s00439-011-1106-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-011-1106-6

Keywords

Search

Navigation