Major Disorders Investigated:
Fragile X Syndrome
Rett Syndrome
Down Syndrome
X-Linked Mental Retardation
Smith-Lemli-Opitz-Syndrome
Fragile X Syndrome
Rett Syndrome
Down Syndrome
X-Linked Mental Retardation
Smith-Lemli-Opitz-Syndrome
Fragile X Syndrome Overview
Fragile X syndrome is the most common cause of inherited intellectual disability (ID) and among the more common genetic causes of autism spectrum disorders (ASD.) Fragile X Syndrome is one of a number of Fragile X-Associated Disorders (FXD). Current research suggests Fragile X Syndrome affects an estimated one in every 3,600 males and one in every 4,000-6,000 females in the general population. It is associated with a wide range of impairments, from mild learning disabilities to severe intellectual disability. Fragile X syndrome is also characterized by a number of physical and behavioral abnormalities, which include among others attentional difficulties, anxiety, and autistic behavior.
In most cases, Fragile X syndrome is associated with an unstable expansion of a CGG trinucleotide repeat within the 5’ UTR region of the translational regulator FMR1. Based on the size of this expansion, alleles are classified as normal (5-40 repeats), intermediate or gray zone (41-60 repeats), premutation (61-199 repeats), or full mutation (200-2,000 repeats). Normal alleles are stably transmitted to the next generation, while premutated alleles tend to expand to the full mutation (typically when transmitted from a female). Full mutation-size expansions are regularly associated with hypermethylation, gene silencing, and the Fragile X phenotype. As an X-linked disorder, the severity of the Fragile X phenotype is greater in males. Premutation alleles appear to be linked to two FXD: Fragile X tremor ataxia syndrome (FXTAS) and Fragile X Primary Ovarian Insufficiency Syndrome (FXPOI,) and appear to be linked to other phenotypical manifestations as well. FXTAS is one of the most severe FXDs: it affects predominantly older (>50 years) males and includes gait ataxia, intention tremor, cognitive impairment, and other neurologic manifestations. FXPOI affects approximately 20% of females with Fragile X Premutation. FXPOI is characterized by cessation of menses before 40 years old. Women with Fragile X Premutation are at risk for FXPOI and other ovarian dysfunction, including decreased fertility. Although marked deficit of the FMR1 product, the Fragile X Mental Retardation Protein (FMRP), is seen in males with the characteristic severe cognitive and behavioral manifestations of Fragile X syndrome, FMRP deficiency per se does not explain the phenotypical variability of the disorder.
In addition to participating in research on Fragile X and FXD, the Center for Genetic Disorders of Cognition and Behavior directs Kennedy Krieger’s outpatient Fragile X Clinic
Fragile X Syndrome Research The Fragile X Syndrome Research Program is a multidisciplinary effort aiming at characterizing the neurobehavioral phenotypic spectrum of males affected by the disorder, as well as the molecular and neurobiological foundations of such phenotype. The program includes molecular, imaging, and neurobehavioral studies of young males with Fragile X and investigations using molecular and cell biological approaches on cell lines from patients and brains from the FMR1 knockout mouse and other relevant models. Involved in the program are investigators at KKI and the Johns Hopkins University School of Medicine’s Department of Neuroscience, and collaborators and consultants at the Johns Hopkins University School of Public Health’s Department of Epidemiology, Johns Hopkins University School of Medicine’s Department of Pharmacology, Columbia University College of Physicians and Surgeons, Emory University School of Medicine, and Erasmus University.
Current Research Projects
Gene Expression and Genetic Mental Retardation
We are using modern scientific (molecular) methods to study how genes function in boys with genetic developmental disabilities, namely Down syndrome and Fragile X syndrome. With these methods, we hope to uncover molecular defects that are common to these conditions, as well as to learn how genes involved in learning, reasoning and memory work in children who have difficulties in these areas. In particular, this study looks at the molecular abnormalities in boys with genetic developmental disabilities compared to typically developing boys, and relates these abnormalities to profiles of cognition and behavior.
Funded by the General Clinical Research Center (NIH) of the Johns Hopkins Medical Institutions.
To participate in this study please see our Appointments page.
Faculty Involved
Joe Bressler, Ph.D.
Dejan B. Budimirovic, M.D.
Robert M. Gray, Ph.D.
Walter E. Kaufmann, M.D.
Elaine Tierney, M.D.
Tao Wang, M.D., Ph.D.
Publications
Hernandez RN, Feinberg RL, Vaurio R, Passanante NM, Thompson RE, Kaufmann WE (2009) Autism spectrum disorder in Fragile X syndrome: a longitudinal evaluation. American Journal of Medical Genetics Part A: 149A(6):1125-37.
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.
Kaufmann WE, Capone GT, Clarke M, Budimirovic DB (2008) Autism in genetic intellectual disability: insights into idiopathic autism. In Zimmerman AW (Ed). Autism: Current Theories and Evidence. Totowa, NJ: The Humana Press Inc., pp. 81-108.
Park S, Park JM, Kim S, Kim J-A, Shepherd JD, Smith-Hicks CL, Chowdhury S, Kaufmann W, Kuhl D, Ryazanov AG, Huganir RL, Linden DJ, Worley PF (2008) Eukaryotic Elongation Factor 2 (eEF2) and Fragile X Mental Retardation Protein (FMRP) control the dynamic translation of Arc/Arg3.1 essential for mGluR-dependent synaptic depression. Neuron 59:70-83.
Coffee B, Ikeda M, Budimirovic DB, Hjelm LN, Kaufmann WE, Warren ST. (2008) Mosaic FMR1 deletion causes fragile X syndrome and can lead to molecular misdiagnosis: a case report and review of the literature. American Journal of Medical Genetics 146A(10):1358-67
Roberts JE, Weisenfeld LA, Hatton DD, Heath M, Kaufmann WE (2007). Social approach and autistic behavior in children with fragile X syndrome. Journal of Autism and Developmental Disorders, 37: 1748-60.
Budimirovic DB, Bukelis I, Cox C, Gray RM, Tierney E, Kaufmann WE (2006). Autism spectrum disorder in fragile X syndrome: differential contribution of adaptive socialization and social withdrawal. American Journal of Medical Genetics Part A: 140A(17):1814-26.
Kaufmann WE, Cortell R, Kau ASM, Bukelis I, Tierney E, Gray RM, Cox C, Capone GT, Stanard P (2004). Autism spectrum disorder in Fragile X syndrome: communication, social interaction, and specific behaviors. American Journal of Medical Genetics: 129A: 225-34.
Kau ASM, Tierney E, Bukelis I, Stump MH, Kates WR, Trescher WH, Kaufmann WE (2004). Social behavior profile in young males with Fragile X syndrome: characteristics and specificity. American Journal of Medical Genetics, 126A: 9-17.
Kaufmann WE, Cooper KL, Mostofsky SH, Capone GT, Kates WR, Newschaffer CJ, Bukelis I, Stump MH, Jann AE, Lanham DC (2003). Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study. Journal of Child Neurology, 18: 463-70.
Kates WR, Folley BS, Lanham DC, Capone GT, Kaufmann WE (2002). Cerebral growth in Fragile X syndrome: review and comparison with Down syndrome. Microscopy Research and Technique, 57: 159-67.
Kaufmann WE, Cohen S, Sun HT, Ho G (2002). Molecular phenotype of Fragile X syndrome: FMRP, FXRPs, and protein targets. Microscopy Research and Technique, 57: 135-44.
Kaufmann WE (2002). Neurobiology of Fragile X syndrome: from molecular genetics to neurobehavioral phenotype. Microscopy Research and Technique, 57: 131-34.
Sun HT, Cohen S, Kaufmann WE (2001). Annexin 1 is abnormally expressed in Fragile X syndrome: a two-dimensional electrophoresis study in lymphocytes. American Journal of Medical Genetics, 103: 81-90.
Kaufmann WE, Moser HW (2000). Dendritic anomalies in disorders associated with mental retardation. Cerebral Cortex, 10: 981-91.
Kaufmann WE, Abrams MT, Chen W, Reiss AL (1999). Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome. American Journal of Medical Genetics, 88: 286-95.
Abrams MT, Kaufmann WE, Rousseau F, Oostra BA, Wolozin B, Taylor CV, Lishaa N, Morel ML, Hoogeveen A, Reiss AL (1999) FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome. American Journal of Medical Genetics, 82: 25-30.
Kaufmann WE, Reiss AL (1999). Molecular and cellular genetics of Fragile X syndrome. American Journal of Medical Genetics, 88: 11-24.
Kates WR, Abrams MT, Kaufmann WE, Breiter SN, Reiss AL (1997) Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile x syndrome. Psychiatry Res 75:31-48.
In most cases, Fragile X syndrome is associated with an unstable expansion of a CGG trinucleotide repeat within the 5’ UTR region of the translational regulator FMR1. Based on the size of this expansion, alleles are classified as normal (5-40 repeats), intermediate or gray zone (41-60 repeats), premutation (61-199 repeats), or full mutation (200-2,000 repeats). Normal alleles are stably transmitted to the next generation, while premutated alleles tend to expand to the full mutation (typically when transmitted from a female). Full mutation-size expansions are regularly associated with hypermethylation, gene silencing, and the Fragile X phenotype. As an X-linked disorder, the severity of the Fragile X phenotype is greater in males. Premutation alleles appear to be linked to two FXD: Fragile X tremor ataxia syndrome (FXTAS) and Fragile X Primary Ovarian Insufficiency Syndrome (FXPOI,) and appear to be linked to other phenotypical manifestations as well. FXTAS is one of the most severe FXDs: it affects predominantly older (>50 years) males and includes gait ataxia, intention tremor, cognitive impairment, and other neurologic manifestations. FXPOI affects approximately 20% of females with Fragile X Premutation. FXPOI is characterized by cessation of menses before 40 years old. Women with Fragile X Premutation are at risk for FXPOI and other ovarian dysfunction, including decreased fertility. Although marked deficit of the FMR1 product, the Fragile X Mental Retardation Protein (FMRP), is seen in males with the characteristic severe cognitive and behavioral manifestations of Fragile X syndrome, FMRP deficiency per se does not explain the phenotypical variability of the disorder.
In addition to participating in research on Fragile X and FXD, the Center for Genetic Disorders of Cognition and Behavior directs Kennedy Krieger’s outpatient Fragile X Clinic
Fragile X Syndrome Research The Fragile X Syndrome Research Program is a multidisciplinary effort aiming at characterizing the neurobehavioral phenotypic spectrum of males affected by the disorder, as well as the molecular and neurobiological foundations of such phenotype. The program includes molecular, imaging, and neurobehavioral studies of young males with Fragile X and investigations using molecular and cell biological approaches on cell lines from patients and brains from the FMR1 knockout mouse and other relevant models. Involved in the program are investigators at KKI and the Johns Hopkins University School of Medicine’s Department of Neuroscience, and collaborators and consultants at the Johns Hopkins University School of Public Health’s Department of Epidemiology, Johns Hopkins University School of Medicine’s Department of Pharmacology, Columbia University College of Physicians and Surgeons, Emory University School of Medicine, and Erasmus University.
Current Research Projects
Gene Expression and Genetic Mental Retardation
We are using modern scientific (molecular) methods to study how genes function in boys with genetic developmental disabilities, namely Down syndrome and Fragile X syndrome. With these methods, we hope to uncover molecular defects that are common to these conditions, as well as to learn how genes involved in learning, reasoning and memory work in children who have difficulties in these areas. In particular, this study looks at the molecular abnormalities in boys with genetic developmental disabilities compared to typically developing boys, and relates these abnormalities to profiles of cognition and behavior.
Funded by the General Clinical Research Center (NIH) of the Johns Hopkins Medical Institutions.
To participate in this study please see our Appointments page.
Faculty Involved
Joe Bressler, Ph.D.
Dejan B. Budimirovic, M.D.
Robert M. Gray, Ph.D.
Walter E. Kaufmann, M.D.
Elaine Tierney, M.D.
Tao Wang, M.D., Ph.D.
Publications
Hernandez RN, Feinberg RL, Vaurio R, Passanante NM, Thompson RE, Kaufmann WE (2009) Autism spectrum disorder in Fragile X syndrome: a longitudinal evaluation. American Journal of Medical Genetics Part A: 149A(6):1125-37.
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.
Kaufmann WE, Capone GT, Clarke M, Budimirovic DB (2008) Autism in genetic intellectual disability: insights into idiopathic autism. In Zimmerman AW (Ed). Autism: Current Theories and Evidence. Totowa, NJ: The Humana Press Inc., pp. 81-108.
Park S, Park JM, Kim S, Kim J-A, Shepherd JD, Smith-Hicks CL, Chowdhury S, Kaufmann W, Kuhl D, Ryazanov AG, Huganir RL, Linden DJ, Worley PF (2008) Eukaryotic Elongation Factor 2 (eEF2) and Fragile X Mental Retardation Protein (FMRP) control the dynamic translation of Arc/Arg3.1 essential for mGluR-dependent synaptic depression. Neuron 59:70-83.
Coffee B, Ikeda M, Budimirovic DB, Hjelm LN, Kaufmann WE, Warren ST. (2008) Mosaic FMR1 deletion causes fragile X syndrome and can lead to molecular misdiagnosis: a case report and review of the literature. American Journal of Medical Genetics 146A(10):1358-67
Roberts JE, Weisenfeld LA, Hatton DD, Heath M, Kaufmann WE (2007). Social approach and autistic behavior in children with fragile X syndrome. Journal of Autism and Developmental Disorders, 37: 1748-60.
Budimirovic DB, Bukelis I, Cox C, Gray RM, Tierney E, Kaufmann WE (2006). Autism spectrum disorder in fragile X syndrome: differential contribution of adaptive socialization and social withdrawal. American Journal of Medical Genetics Part A: 140A(17):1814-26.
Kaufmann WE, Cortell R, Kau ASM, Bukelis I, Tierney E, Gray RM, Cox C, Capone GT, Stanard P (2004). Autism spectrum disorder in Fragile X syndrome: communication, social interaction, and specific behaviors. American Journal of Medical Genetics: 129A: 225-34.
Kau ASM, Tierney E, Bukelis I, Stump MH, Kates WR, Trescher WH, Kaufmann WE (2004). Social behavior profile in young males with Fragile X syndrome: characteristics and specificity. American Journal of Medical Genetics, 126A: 9-17.
Kaufmann WE, Cooper KL, Mostofsky SH, Capone GT, Kates WR, Newschaffer CJ, Bukelis I, Stump MH, Jann AE, Lanham DC (2003). Specificity of cerebellar vermian abnormalities in autism: a quantitative magnetic resonance imaging study. Journal of Child Neurology, 18: 463-70.
Kates WR, Folley BS, Lanham DC, Capone GT, Kaufmann WE (2002). Cerebral growth in Fragile X syndrome: review and comparison with Down syndrome. Microscopy Research and Technique, 57: 159-67.
Kaufmann WE, Cohen S, Sun HT, Ho G (2002). Molecular phenotype of Fragile X syndrome: FMRP, FXRPs, and protein targets. Microscopy Research and Technique, 57: 135-44.
Kaufmann WE (2002). Neurobiology of Fragile X syndrome: from molecular genetics to neurobehavioral phenotype. Microscopy Research and Technique, 57: 131-34.
Sun HT, Cohen S, Kaufmann WE (2001). Annexin 1 is abnormally expressed in Fragile X syndrome: a two-dimensional electrophoresis study in lymphocytes. American Journal of Medical Genetics, 103: 81-90.
Kaufmann WE, Moser HW (2000). Dendritic anomalies in disorders associated with mental retardation. Cerebral Cortex, 10: 981-91.
Kaufmann WE, Abrams MT, Chen W, Reiss AL (1999). Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome. American Journal of Medical Genetics, 88: 286-95.
Abrams MT, Kaufmann WE, Rousseau F, Oostra BA, Wolozin B, Taylor CV, Lishaa N, Morel ML, Hoogeveen A, Reiss AL (1999) FMR1 gene expression in olfactory neuroblasts from two males with fragile X syndrome. American Journal of Medical Genetics, 82: 25-30.
Kaufmann WE, Reiss AL (1999). Molecular and cellular genetics of Fragile X syndrome. American Journal of Medical Genetics, 88: 11-24.
Kates WR, Abrams MT, Kaufmann WE, Breiter SN, Reiss AL (1997) Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile x syndrome. Psychiatry Res 75:31-48.
Top
Center for Genetic Disorders of Cognition and Behavior
Contact Info - © 2004 - Kennedy Krieger Institute - Privacy Policy
Please send questions or comments about the Center or this website to gcbcenter@kennedykrieger.org