GCB Masthead
Down Syndrome Down Syndrome is the most common genetic cause of mental retardation, with a prevalence of 1:800-1:1,000 live births. It is caused by non-dysjunction of chromosome 21 prior to or during conception. The diagnosis of Down syndrome is made by chromosome analysis, which can be initiated prenatally due to identified risk factors such as maternal age (>35 years), or postnatally due to the characteristic appearance of the infant. In recent years, the number of Down syndrome pregnancies has increased, most likely due to a concurrent increase in maternal age. Nonetheless, the number of terminated pregnancies has also increased, leading to a slight reduction in the prevalence of Down syndrome births. The phenotype of Down syndrome includes a variety of physical and neurobehavioral abnormalities. In addition to cardiac, gastrointestinal, and skeletal malformations, sensory, endocrine, and dermatological problems constitute the main life-long concerns in Down syndrome. From the neurologic viewpoint, cognitive deficit that includes some selective impairments (e.g., language delay), seizures, and behavioral abnormalities (e.g., attentional difficulties, oppositional disorder, autistic features) are the main manifestations. In adults, major neurobehavioral abnormalities include Alzheimer's disease (75% in patients >60 years) and psychiatric disorders such as depression (~6%). The recent sequencing of chromosome 21 has raised expectations with regard to delineating the pathogenesis of the major manifestations in Down syndrome, as well as in terms of explaining the neurobehavioral variability of the disorder. At present, over 300 genes are predicted on chromosome 21. Several of these genes are part of sets involved in the same biological system; approximately 10 genes are likely to play a role in the pathogenesis of abnormal brain development and neurodegeneration.

Down Syndrome Research The goal of the Down Syndrome Clinic team is to optimize the health and quality of life for children and adults with Down syndrome. As part of this goal, the clinic team continues to develop and conduct clinical research studies into the neurobiologic basis of cognitive impairment and co-morbid psychiatric disorders in Down syndrome; to study potential therapies for safety and efficacy; and to investigate genetic and environmental factors relevant to AV Canal defect. The Down Syndrome Clinic team continues to see children with complex neurobehavioral disorders (autistic-spectrum, self injury and aggressive/disruptive behaviors) as well as adults with mental health problems (depression, obsessive compulsive traits, motor slowing, and functional decline). Several clinical research protocols are currently being used to study these issues in greater detail. The staff anticipates further development in this area of research as they seek to identify the neurobiologic basis for these disorders. Involved in the projects are investigators at KKI and the Johns Hopkins University School of Medicine’s Departments of Pediatrics, Physiology, and Psychiatry.

Research Projects

ASD in Down Syndrome: A Model of Repetitive and Stereotypic Behavior In Idiopathic ASD

We are using modern scientific (molecular) methods and psychological testing to study how genes function, in able to dilneate the distinctive and specific features of Down syndrome and co-morbid Autism Spectrum Disorder (DS+ASD). The primary focus is on the characterization of the cognitive and behavioral profile of ASD and its differentiation from Stereotypic Movement Disorder (SMD) in DS boys. We hypothesize that ASD in DS is characterized by a distinctive profile, with predominance of severe and diverse stereotypic behavior. Secondly that the neurobehavioral profile of DS+ASD is distinguishable from that of other behavioral syndromes in DS such as stereotypic movement disorder. Lastly, we plan to collect and store serum and lymphoid samples to test the hypothesis that ASD in DS has a distinctive genetic/molecular profile that relates to its unique behavioral features.

Funded by Autism Speaks

A 20-week double blind placebo controlled clinical trial to evaluate the safety and efficacy of rivastigmine in children and adolescents (ages 10-18) with Down syndrome

While it is known that adults with Down syndrome (DS) exhibit a notable cholinergic deficiency, it is unclear how early in life presynaptic cholinergic deterioration begins. Acetylcholinesterase inhibitors (AchEIs) have been shown to improve attention, memory, and language function in adults with DS. This study, conducted in collaboration with investigators at Duke University, will examine the use of an AchEI called Rivastigmine in children and adolescents with DS to a) investigate short-term safety and efficacy of the drug and b) determine whether improvement in memory, language and other cognitive functions is observed following treatment. Results from this study will contribute to the body of evidence suggesting a role for AchEIs in the management of cognitive and language dysfunction in children & adolescents with DS.

Funded by a Private Family Foundation

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.

Neuropsychiatric Disorders in Down Syndrome

We are interested in learning about neuropsychiatric disorders in young adults with Down syndrome, particularly depression, obsessive-compulsive tendencies, movement disorder, or general functional decline. Depression, obsessive-compulsive features and movement disorders are not specific to Down syndrome, but their causes and progression in Down syndrome are poorly understood. We would like to understand the biological and psychological factors contributing to the development of such symptoms. Ultimately, we hope to be able to offer better treatment options.

Down Syndrome Phenotype Project

Down syndrome is caused by trisomy for human chromosome 21 (HSA21) and is characterized by a spectrum of phenotypes including increased risk for congenital heart defects, cognitive deficits, sleep apnea, and musculoskeletal affects. A key feature of DS is the significant variability in occurrence and severity of the various phenotypes that characterize the syndrome. Co-morbidities of occurrence and severity among individuals with DS can provide information about commonalities of etiology. We will employ a Cognitive Test Battery to characterize cognitive function; acquire and analyze 3dMD facial surface images and pigmentation as measures of neural crest involvement in DS; perform medical record review for major features of DS including obstructive sleep apnea syndrome (OSAS), congenital heart disease and gut disease; and collect relevant family, environment, and behavioral history data from parent questionnaires. Biological materials from probands and parents, suitable for genetic analysis of modifiers of DS phenotypes, will be added to our existing Biobank (DNA, cells, serum, etc.) and Phenotype Database of individuals with DS and their parents. This is a multicenter study, structured such that all data shared between sites will have been de-identified.

Funded by National Heart, Lung and Blood Institute; Down Syndrome Research and Treatment Foundation

Faculty Involved

George Capone, M.D.
Robert M. Gray, Ph.D.
Michael V. Johnston, M.D.
Walter E. Kaufmann, M.D.


Edgin JO, Mason GM, Allman MJ, Capone GT, Deleon I, Maslen C, Reeves RH, Sherman SL, Nadel LJ (2010) Development and validation of the Arizona Cognitive Test Battery for Down syndrome. Neurodev Disord 1;2:149-164.

Capone GT (2010) The emergence of pharmacotherapies for cognitive function in Down syndrome. Am J Med Genet A. 152A:3026-7.

Trois MS, Capone GT, Lutz JA, Melendres MC, Schwartz AR, Collop NA, Marcus CL (2009) Obstructive sleep apnea in adults with Down Syndrome. J Clin Sleep Med 5:317-23.

Skotko BG, Kishnani PS, Capone GT; Down Syndrome Study Group (2009) Prenatal diagnosis of Down syndrome: how best to deliver the news. Am J Med Genet A 149A:2361-7.

Skotko BG, Capone GT, Kishnani PS; Postnatal diagnosis of Down syndrome; synthesis of the evidence on how best to deliver the news. Pediatrics 124:e751-8. Review

Kishnani PS, Sommer BR, Handen BL, Seltzer B, Capone GT, Spiridigliozzi GA, Heller JH, Richardson S, McRae T (2009). The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome. Am J Med Genet A. 149A(8):1641-54.

Carter JC, Capone GT, Kaufmann WE (2008). Neuroanatomic correlates of autism and stereotypy in children with Down syndrome. Neuroreport. 9:653-6.

Carter JC, Capone GT, Gray RM, Cox CS, Kaufmann WE (2007). Autistic-spectrum disorders in Down syndrome: further delineation and distinction from other behavioral abnormalities. American Journal of Medical Genetics Part B Neuropsychiatric Genetics, 144:87-94.

Capone GT, Grados MA, Kaufmann WE, Bernad-Ripoll S, Jewell A (2005). Down syndrome and Comorbid autism-spectrum disorder: characterization using the aberrant behavior checklist. American Journal of Medical Genetics Part A 134:373-80.

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.

Capone GT, Kim P, Jovanovich S, Payne L, Freund L, Welch K, Miller E, Trush M (2002). Evidence for increased mitochondrial superoxide production in Down syndrome. Life Sciences, 70: 2885-95.

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.

Moran TH, Capone GT, Knipp S, Kavisson MT, Reeves RH, Gearhart JD (2002). The effects of piracetam on cognitive performance in a mouse model of Down’s syndrome. Physiology & Behavior, 77: 403-09.

Capone G (2001). Down Syndrome: Advances in molecular biology and the neurosciences. Journal of Developmental and Behavioral Pediatrics, 22: 40-59.

Pinter JD, Brown WE, Eliez S, Schmitt JE, Capone GT and Reiss AL (2001). Amygdala and hippocampal volumes in children with Down syndrome: A high–resolution MRI study. Neurology, 56: 972-74.

Pinter JD, Eliez S, Schmitt JE, Capone GT, Reiss AL (2001). Neuroanatomy of Down’s syndrome: a high-resolution MRI study. American Journal of Psychiatry, 158: 1659-65.

Coe DA, Matson JL, Russel DW, Slifer KJ, Capone GT, Baglio C, Stallings S (1999). Behavior problems of children with Down syndrome and life events. Journal of Autism and Developmental Disorders, 29: 149-56.

Down Syndrome Resources

See Family Resources: Down Syndrome