A Cohort Study of Intellectual Disability Focusing on Fragile X Syndrome in Indonesia

*Tri Indah Winarni -  Faculty of Medicine Diponegoro University, Indonesia
Farmaditya EP Mundhofir -  Faculty of Medicine Diponegoro University, Indonesia
Sultana MH Faradz -  Faculty of Medicine Diponegoro University, Indonesia
Received: 8 Jun 2016; Published: 31 Jul 2016.
Open Access
Citation Format:
Article Info
Section: Original Research Articles
Language: EN
Full Text:
Supp. File(s):
Cover Letter
Subject
Type Research Instrument
  Download (12KB)    Indexing metadata
Statistics: 501 153
Abstract

Background: Intellectual disability (ID) is a major public health problem because the defect, treatment and rehabilitation require long life both medical and socio-economic assessment. Fragile X syndrome (FXS) is the most common cause of inherited X-linked intellectual disabilities (ID) with reduced penetrance. With regards to behavioral and emotional phenotype, FXS commonly mixed up with idiopathic autism. The prevalence is found higher in males compared to females. In accordance with rapid development of diagnosis technique, the prevalence of FXS is defining worldwide including Indonesia using, currently, simple molecular method.

Objectives: This study was aimed to diagnose genetic cause of ID and to establish the prevalence of FXS among ID population in Central Java, and Yogyakarta Province.

Method: Screening has been performed since 1994 continuously in high risk population (special school with and without autism) using clinical, cytogenetic, and FMR1 gene PCR-based molecular approach. Cascade testing was subjected to the family members with positive result of FXS and many new cases were disclosed in our cohort study.

Results: The prevalence of FXS among ID population was calculated to be 1.9% (5/262) in 1994 and 1.7% (9/527) in 2011. Among autism population it was determined to be 6.15% (4/65). Trisomy 21 was found in 14% (74/527) as a major cause of ID.

Conclusion: The prevalence of FXS among screened ID population overtime is comparable.

 

Note: This article has supplementary file(s).

Keywords
intellectual disability; cohort study; fragile X syndrome; Indonesia

Article Metrics:

  1. van Schrojenstein Lantman-de Valk HM, van den Akker M, Maaskant MA, et al. Prevalence and incidence of health problems in people with intellectual disability. J Intellect Disabil Res. 1997;41 ( Pt 1):42-51.
  2. Durkin MS, Schneider H, Pathania VS, et al. Learning and Developmental Disabilities. In: Jamison DT, Breman JG, Measham AR, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington (DC)2006.
  3. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: A meta-analysis of population-based studies. Research in developmental disabilities. 2011;32(2):419-436.
  4. Garber KB, Visootsak J, Warren ST. Fragile X syndrome. Eur J Hum Genet. 2008;16(6):666-672.
  5. Reddy KS. Cytogenetic abnormalities and fragile-X syndrome in Autism Spectrum Disorder. BMC Med Genet. 2005;6(1):3.
  6. Raymond FL. X linked mental retardation: a clinical guide. Journal of medical genetics. 2006;43(3):193-200.
  7. Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A. Screening for fragile X syndrome: a literature review and modelling study. Health Technol Assess. 2003;7(16):1-106.
  8. Hagerman PJ. The fragile X prevalence paradox. J Med Genet. 2008;45(8):498-499.
  9. Mundhofir FE, Winarni TI, Nillesen W, et al. Prevalence of fragile X syndrome in males and females in Indonesia. World J Med Genet. 2012;2(3):15-22.
  10. Paluszkiewicz SM, Martin BS, Huntsman MM. Fragile X syndrome: the GABAergic system and circuit dysfunction. Developmental neuroscience. 2011;33(5):349-364.
  11. Coffee B, Zhang F, Warren ST, Reines D. Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells. Nature Genetics. 1999;22:98-101.
  12. 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.
  13. Cummings CJ, Zoghbi HY. Trinucleotide repeats: mechanisms and pathophysiology. Annual review of genomics and human genetics. 2000;1:281-328.
  14. Wang Q, Green E, Barnicoat A, et al. Cytogenetic versus DNA diagnosis in routine referrals for fragile X syndrome [see comments]. Lancet. 1993;342(8878):1025-1026.
  15. Bhowmik DA, Dutta A, Chatterjee A, Sinha AK, Chattopadhyay A, Mukhopadhyay K. Screening for fragile X syndrome among neurobehavioral patients from Kolkata, Eastern India. J Clin Diagnostic Res. 2009;3(1):1266-1273.
  16. Crawford DC, Meadows KL, Newman JL, et al. Prevalence of the fragile X syndrome in African-Americans. Am J Med Genet. 2002;110(3):226-233.
  17. Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K. Prevalence of carriers of premutation-size alleles of the FMRI gene--and implications for the population genetics of the fragile X syndrome. American journal of human genetics. 1995;57(5):1006-1018.
  18. Hantash FM, Goos DM, Crossley B, et al. FMR1 premutation carrier frequency in patients undergoing routine population-based carrier screening: insights into the prevalence of fragile X syndrome, fragile X-associated tremor/ataxia syndrome, and fragile X-associated primary ovarian insufficiency in the United States. Genetics in medicine : official journal of the American College of Medical Genetics. 2011;13(1):39-45.
  19. Dombrowski C, Levesque ML, Morel ML, Rouillard P, Morgan K, Rousseau F. 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. 2002;11(4):371-378.
  20. Toledano-Alhadef H, Basel-Vanagaite L, Magal N, et al. Fragile-X Carrier Screening and the Prevalence of Premutation and Full-Mutation Carriers in Israel. American journal of human genetics. 2001;69:351-360.
  21. Coffee B, Keith K, Albizua I, et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. American journal of human genetics. 2009;85(4):503-514.
  22. Faradz SMH, Buckley M, Tang L-P, Leigh D, Holden JJA. Molecular screening for fragile X syndrome among Indonesian children with developmental disability. American journal of medical genetics. Part A. 1999;83(4):350-351.
  23. Li SY, Chen YC, Lai TJ, Hsu CY, Wang YC. Molecular and cytogenetic analyses of autism in Taiwan. Hum Genet. 1993;92(5):441-445.
  24. Estecio M, Fett-Conte AC, Varella-Garcia M, Fridman C, Silva AE. Molecular and cytogenetic analyses on Brazilian youths with pervasive developmental disorders. J Autism Dev Disord. 2002;32(1):35-41.
  25. Elias MH, Ankathil R, Salmi AR, Sudhikaran W, Limprasert P, Zilfalil BA. A new method for FMR1 gene methylation screening by multiplex methylation-specific real-time polymerase chain reaction. Genetic testing and molecular biomarkers. 2011;15(6):387-393.
  26. Rajan-Babu IS, Law HY, Yoon CS, Lee CG, Chong SS. Simplified strategy for rapid first-line screening of fragile X syndrome: closed-tube triplet-primed PCR and amplicon melt peak analysis. Expert reviews in molecular medicine. 2015;17:e7.
  27. Teo CR, Law HY, Lee CG, Chong SS. Screening for CGG repeat expansion in the FMR1 gene by melting curve analysis of combined 5' and 3' direct triplet-primed PCRs. Clinical chemistry. 2012;58(3):568-579.
  28. Lyons JI, Kerr GR, Mueller PW. Fragile X Syndrome: Scientific Background and Screening Technologies. The Journal of molecular diagnostics : JMD. 2015;17(5):463-471.
  29. Chandrasekara CH, Wijesundera WS, Perera HN, Chong SS, Rajan-Babu IS. Cascade Screening for Fragile X Syndrome/CGG Repeat Expansions in Children Attending Special Education in Sri Lanka. PloS one. 2015;10(12):e0145537.
  30. Chaudhary AG, Hussein IR, Abuzenadah A, et al. Molecular diagnosis of fragile X syndrome using methylation sensitive techniques in a cohort of patients with intellectual disability. Pediatric neurology. 2014;50(4):368-376.
  31. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revised. Washington DC: American Psychiatric Association; 2000.
  32. Sutherland GR. Heritable fragile sites on human chromosomes I. Factors affecting expression in lymphocyte culture. American journal of human genetics. 1979;31(2):125-135.
  33. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research. 1988;16:1215.
  34. Fu Y-H, Kuhl DPA, Pizzuti A, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox. Cell. 1991;67(6):1047-1058.
  35. Mundhofir FE, Winarni TI, van Bon BW, et al. A cytogenetic study in a large population of intellectually disabled Indonesians. Genetic testing and molecular biomarkers. 2012;16(5):412-417.
  36. Winarni TI, Utari A, Mundhofir FE, Hagerman RJ, Faradz SM. Fragile X syndrome: clinical, cytogenetic and molecular screening among autism spectrum disorder children in Indonesia. Clinical genetics. 2013;84(6):577-580.
  37. Kaufmann WE, Abrams MT, Chen W, Reiss AL. Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome. Am J Med Genet. 1999;83(4):286-295.
  38. Hagerman RJ, Amiri K, Cronister A. Fragile X checklist. Am J Med Genet. 1991;38(2-3):283-287.
  39. Symons FJ, Clark RD, Hatton DD, Skinner M, Bailey DB, Jr. Self-injurious behavior in young boys with fragile X syndrome. American journal of medical genetics. Part A. 2003;118(2):115-121.
  40. Wisbeck JM, Huffman LC, Freund L, Gunnar M, Davis EP, Reiss AL. Cortisol and social stressors in children with fragile X: A pilot study. Journal of developmental and behavioral pediatrics : JDBP. 2000;21:278-282.
  41. Hessl D, Glaser B, Dyer-Friedman J, Reiss AL. Social behavior and cortisol reactivity in children with fragile X syndrome. J Child Psychol Psychiatry. 2006;47(6):602-610.
  42. Budimirovic DB, Bukelis, I., Cox, C., Gray, R.M., Tierney, E., Kaufmann, W.E. Autism spectrum disorder in Fragile X syndrome: Differential contribution of adaptive socialization and social withdrawal. American Journal of Medical Genetics Part A. 2006;140A(17):1814-1826.
  43. Roberts JE, Weisenfeld LA, Hatton DD, Heath M, Kaufmann WE. Social approach and autistic behavior in children with fragile X syndrome. J Autism Dev Disord. 2007;37(9):1748-1760.
  44. Hagerman RJ, Rathmell B, Wang P, et al. Treatment of Fragile X Syndrome with STX209 (arbaclofen): Open-Label Extension Experience. Paper presented at: International Society for Autism Research2012; Toronto, Canada.
  45. Hagerman R, Lauterborn J, Au J, Berry-Kravis E. Fragile X Syndrome and Targeted Treatment Trials. In: Denman RB, ed. Modeling Fragile X
  46. Syndrome. Vol 54. Berlin Heidelberg: Springer-Verlag; 2012:297-335.
  47. Hagerman R, Hoem G, Hagerman P. Fragile X and autism: Intertwined at the molecular level leading to targeted treatments. Mol Autism. 2010;1(1):12.
  48. Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics. 2010;7(3):264-274.
  49. Winarni TI, Utari A, Mundhofir FE, Hagerman RJ, Faradz SM. Fragile X Syndrome: Clinical, Cytogenetics and Molecular Screening among Autism Spectrum Disorder Children in Indonesia. Clinical genetics. 2013.
  50. Mundhofir FEP, Winarni TI, Nillesen W, et al. Prevalence of fragile X syndrome in males and females in Indonesia. World Journal of Medical Genetics. 2012;2(3):15.
  51. Crawford DC, Acuna JM, Sherman SL. FMR1 and the fragile X syndrome: human genome epidemiology review. Genetics in medicine : official journal of the American College of Medical Genetics. 2001;3(5):359-371.
  52. Sherman SL, Jacobs PA, Morton NE, et al. Further segregation analysis of the fragile X syndrome with special reference to transmitting males. Hum Genet. 1985;69(4):289-299.
  53. Biancalana V, Glaeser D, McQuaid S, Steinbach P. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. European journal of human genetics : EJHG. 2015;23(4):417-425.
  54. Monaghan KG, Lyon E, Spector EB, erican College of Medical G, Genomics. ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genetics in medicine : official journal of the American College of Medical Genetics. 2013;15(7):575-586.