Understanding human development across the lifespan, including IDDs, was a primary reason NICHD was established in 1962. Since then, the institute has helped to establish a research community and research infrastructure for studying IDDs, including those that affect the nervous system, metabolism, and cell function and survival.
Through its many components, NICHD leads research efforts to understand IDDs, including (but not limited to): genetic and developmental causes of IDDs; the ways that IDDs affect learning, communication, cognition, and memory; characterization of the influence of IDDs on family and community dynamics; examination of the psychobiological and behavioral factors affecting social interactions and emotions in individuals with IDDs; and assessment of self-injurious behavior in individuals with IDDs.
NICHD research on IDDs seeks to identify the causes of these disorders, determine the number of individuals affected by IDDs and related conditions, and discover effective treatments. In addition, NICHD seeks to prevent IDDs and identify ways that women can have a healthy pregnancy.
Some of NICHD’s projects related to IDDs include (but are not limited to):
- Examination of the pathophysiological and genetic bases of IDDs
- Evaluation of how IDDs affect learning, cognition, and memory; evaluations include neuroanatomic, neurophysiologic, structural and functional imaging, and neuropsychologic studies
- Characterization of family and community relationships in IDDs and research on the processes of mutual influence between individuals with IDDs and other members of their families or communities
- Identification of the impact of motor and sensory limitations on communicative ability in individuals with IDDs, including verbal and nonverbal communication
- Evaluation of the psychobiological and behavioral factors and processes that influence social/emotional development and expression in IDDs
- Assessment of self-injurious behavior in individuals with IDDs, including studies of the pathophysiology and behavioral deficits associated with self-injurious behavior and other repetitive behaviors, and also identification of effective treatment strategies
NICHD organizational units support and conduct their own research on IDDs, and they also collaborate with other NIH Institutes and organizations on IDD research.
The IDDB sponsors research and research training aimed at preventing or ameliorating IDDs and related disabilities. The Branch supports biomedical, biobehavioral, behavioral, and translational research in etiology, pathophysiology, screening, prevention, treatment, and epidemiology related to IDDs. This research includes, but is not limited to:
- Behavioral, biobehavioral, and social science research related to IDDs, including studies of learning and cognition as well as family and community relationships
- Biochemical and metabolic research, including studies of metabolic and environmental causes of IDD
- Biomedical and genetic/genomic research, including studies of the central nervous system and cytogenetic and chromosomal abnormalities
- Newborn screening, population screening and diagnosis, and prenatal diagnosis, including developing and evaluating innovative therapies for screenable disorders
The IDDB also supports multiple topical research initiatives, networks, and programs. For more information, visit the Other Activities and Advances section.
Investigators in the DiPHR conduct research to understand the causes of IDDs. In the Upstate New York Developmental Screening Program, DIPHR researchers are working with the New York State Department of Health, and the University at Albany School of Public Health, to determine whether infertility treatments adversely affect the growth, motor, and social development of children from birth through age 3 years, or if these technologies are associated with differences in the timing or rates of infant and child development, including IDDs. This research includes use of standard developmental questionnaires as well as a specialized screening tool for autism spectrum disorders (ASDs).
The DBSVB supports basic and clinical research on normal and abnormal development that relates to the causes and prevention of congenital and genetic defects as well as research training in relevant academic and medical areas. Among the Branch’s high-priority areas is basic research on elucidating the biochemical, molecular biologic, genetic, and cellular mechanisms of early development and their importance in IDDs.
The PPB seeks to improve the health of mothers and children by focusing on maternal health, pregnancy, fetal well-being, labor and delivery, and the developing child. Among its research initiatives related to IDDs are studies that examine factors affecting a woman’s health during pregnancy, how a woman can improve her chances of having a healthy baby, and understanding how adverse health choices during pregnancy, such as alcohol use, contribute to IDDs.
Some recent findings from NICHD and NICHD-supported researchers include the following:
A Potential Biomarker for Dementia Status in Older Individuals with Down Syndrome
As individuals with Down syndrome age, they are increasingly at risk for a dementia similar to Alzheimer disease. The cognitive limitations that typify Down syndrome, however, make it challenging to diagnose the co-occurring cognitive decline and behavioral changes of dementia, especially in the early period of dementia that is often termed mild cognitive impairment. Scientists recently reported that the telomeres (end regions of chromosomes) for chromosome 21 are shorter in people with Down syndrome who also have dementia or mild cognitive impairment than in individuals who have only Down syndrome. The shorter length of the chromosome 21 telomere was found to be highly sensitive and highly specific in distinguishing between individuals with Down syndrome who did and who did not have dementia or mild cognitive impairment. With further research, shorter telomere length could become a biomarker for early stages of dementia in individuals with Down syndrome. Such a biomarker could support decisions on treatment and interventions early in the devastating progression of dementia in people with Down syndrome.
Source: Jenkins, E. C., Ye, L., Gu, H., Ni, S. A., Velinov, M., Pang, D., et al. (2010). Shorter telomeres may indicate dementia status in older individuals with Down syndrome. Neurobiology of Aging, 31, 765-771.
Angelman Syndrome Children Exhibit Alternations in Brain Pathways
Angelman syndrome is a neurogenetic disorder characterized by severe intellectual disability, absent speech, seizures, and outbursts of laughter. In a recent study, scientists showed that children with Angelman syndrome exhibited more severe alterations in white matter pathways than did those in typically developing children, and some of these alterations were associated with the severity of their Angelman symptoms in language, cognitive, and social functioning. The findings suggest a generalized alteration in white matter throughout the brain in those with Angelman syndrome, with alterations in temporal white matter pathways potentially having a stronger clinical impact.
Source: Peters, S. U., Kaufmann, W. E., Bacino, C. A., Anderson, A. W., Adapa, P., Chu, Z., et al. (2011). Alterations in white matter pathways in Angelman syndrome. Developmental Medicine & Child Neurology, 53, 361-367.
Maternal Transmission of a Rare Genetic Variant is Associated with ASDs
The more that scientists search for genetic factors in ASDs, the more they find multiple types of abnormal genetic material at various chromosome sites, often with only weak associations with ASDs. A promising method used by some researchers is to investigate rare genetic variants that are known to be associated with a strong effect. With NIH support, a group of scientists focused on the GABRB3 gene. This mutated gene is strongly associated with two conditions (Angelman and Prader-Willi syndromes) that are inherited from a mother and have features of autism. The scientists found a rare “missense” mutation in the maternal GABRB3 allele associated with autism and a co-occurring childhood epilepsy. The research provides the first evidence of maternal transmission of a gene variant within a chromosomal region that is known to be associated with autism. The research also suggests that, as with other complex diseases, rare genetic variants with stronger ASD risk effects will be found in common allele mutations with weaker effects.
Source: Delahanty, R. J., Kang, J. Q., Brune, C. W., Kistner, E. O., Courchesne E., Cox, N. J., et al. (2011). Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Molecular Psychiatry, 16, 86-96.
Intervention Helps Children with Autism Spectrum Disorders
The Early Start Denver Model (ESDM) is a comprehensive behavioral intervention for ASDs. This model uses a style of therapy that emphasizes breaking activities into small, measurable units that are then reinforced with reward. In this study, researchers performed a randomized, controlled trial of the intervention over 2 years and showed that it led to improvements in IQ, language abilities, and adaptive functioning (i.e., the skills necessary for everyday activities). During the study, 48 toddlers age 1½ to 2½ years who had been diagnosed with an ASD were randomly assigned to receive the ESDM or an intervention commonly available in the community. Children in the ESDM group received an average of 15 hours per week working one-on-one with a therapist trained in the technique. Parents were taught to continue the therapy at home for at least 5 hours per week. The other 24 toddlers worked with therapists in the area, receiving a range of conventional therapies, for an average of 9 hours per week and received an additional 9 hours of therapy in a specialized preschool or other group program. Overall, the average number of intervention hours was similar for the two groups. After 2 years, the children receiving the ESDM intervention showed a 17.6-point increase in IQ, versus a 7-point increase in the comparison group working with community therapists. The children in the ESDM group also showed continued growth in adaptive behaviors, such as brushing their teeth, getting dressed, and eating with utensils, while the other children fell further behind developing peers.
Source: Dawson, G., Rogers, S., Munson, J., Smith, M., Winter, J., Greenson, J., et al. (2010). Randomized, controlled trial of an intervention for toddlers with autism: The Early Start Denver Model. Pediatrics, 125, e17-23.
New Drug Target Identified for Fragile X Syndrome
NIH-supported researchers found that a class of drugs called phosphoinositide 3 (PI3)-kinase inhibitors can correct defects in the anatomy of neurons in a mouse model of Fragile X syndrome. In Fragile X syndrome, a gene mutation leads to the absence of the fragile X mental retardation protein (FMRP), which helps regulate protein production and signaling. Without FMRP to perform this function, individuals with Fragile X syndrome produce excess amounts of certain proteins at neuronal synapses. This leads to structural changes and an impairment of the ability of cells to respond to chemical signals, interfering with learning and memory. In the mouse model of Fragile X syndrome, inhibiting the action of the PI3-kinase enzyme decreased the synaptic proteins and could potentially reverse the resulting structural changes. The drug was able to restore normal levels of protein production at synapses, suggesting that PI3-kinase inhibitors could help improve learning and cognition in individuals with Fragile X syndrome.
Source: Gross, C., Nakamoto, M., Yao, X., Chan, C. B., Yim, S. Y., Ye, K., et al. (2010). Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. Journal of Neuroscience, 30, 10624-10638.
Long-Term Treatment with Losartan Reduced Mortality and Improved Heart Function in Animal Models of Duchenne Muscular Dystrophy (DMD)
DMD is a degenerative disorder that affects skeletal and cardiac muscle. There is no effective therapy for DMD. In boys, a typical progression of the disease involves muscle weakness by age 5, becoming wheelchair bound by the early to middle teens, and death from respiratory or heart failure by the early twenties. Losartan, a drug used to treat high blood pressure, has shown positive results on improving muscle function and strength in short-term studies of animal models with DMD. The next logical step was to conduct longer-term studies in animals. In addition, previous animal studies have not determined losartan’s impact on cardiac function. Identifying cardiovascular problems is especially important because heart failure is a common cause of death in young men with DMD.
Scientists examined the effects of long-term losartan treatment in mice with DMD. Researchers found that after long-term treatment with losartan, 88% of treated mice were alive, compared with only 44% of untreated mice. While cardiac muscle function was significantly preserved in the treated mice, there appeared to be no changes in the weight, morphology, or function of skeletal tissue. These findings suggest that losartan could be an important prophylactic treatment for heart disease associated with DMD but that the drug may not have a positive impact in the long run on DMD-associated skeletal muscle disease.
Source: Bish, L. T., Yarchoan, M., Sleeper, M. M., Gazzara, J. A., Morine, K. J., Acosta, P., et al. (2011). Chronic losartan administration reduces mortality and preserves cardiac but not skeletal muscle function in dystrophic mice. PLOS ONE, 6, e20856.
Accurately Assessing Pain in Nonverbal Adults with Intellectual Disabilities
Individuals with severe intellectual disabilities often have a very limited ability to communicate. This is a serious problem and even dangerous if caregivers or others cannot tell whether the individual is experiencing pain. Researchers tested a system based on well-defined discrete facial expressions to determine whether such a system could be used to assess pain in nonverbal adults with intellectual disability. The system uses 16 discrete facial movements, such as “lowering the brow,” “lip pucker,” “eyes closed,” and “jaw drop,” to monitor responses to sensory stimuli, including pain. The 44 individuals tested included 35 with profound intellectual disabilities, many of whom were completely nonverbal. Twenty-nine of the individuals exhibited self-injurious behavior. Five sensory stimuli were given: pinprick, warm, cool, deep pressure, and light touch.
The individuals tested had greater facial activity in response to stimuli than did a control group with no stimuli. Females showed significantly more facial activity than males, and individuals with chronic self-injurious behavior were more expressive than comparable individuals without that problem. The results demonstrated that individuals with significant intellectual disabilities reliably react to sensory stimulation regardless of verbal ability, and that observation of discrete facial movements can be used to assess pain in this highly vulnerable population. The observation of heightened expression in the self-injurious behavior group is contrary to a long-standing belief that this group has a blunted perception of pain. This result warrants additional attention regarding pain and sensory thresholds when developing therapies for self-injurious behavior in nonverbal adults with intellectual disabilities.
Source: Symons, F. J., Harper, V., Shinde, S. K., Clary, J., & Bodfish, J. W. (2010). Evaluating a sham-controlled sensory-testing protocol for nonverbal adults with neurodevelopmental disorders: Self-injury and gender effects. Journal of Pain, 11, 773-781.
NICHD’s IDDB supports a number of research initiatives, networks, and programs to study IDDs and related disorders. Some of these include:
- The Eunice Kennedy Shriver IDD Research Centers (IDDRCs) program, established 1 year after NICHD’s founding, supports researchers whose goals are to advance understanding of a variety of conditions and topics related to IDDs.
- Fragile X Syndrome Research Centers (FXSRCs) conduct research to improve the diagnosis and treatment of Fragile X syndrome and its related conditions.
- The NIH Rare Diseases Clinical Research Network, established in response to the Rare Disease Act of 2002 (Public Law 107-280), includes 19 distinct Rare Diseases Cooperative Research Consortia (RDCRC) that work together to improve the availability and increase the general awareness of information, treatment, and clinical studies on rare diseases for patients, families, and the medical/research community. NICHD supports several RDCRCs.
- The Paul D. Wellstone Muscular Dystrophy Specialized Research Centers (MDSRCs) were established in response to the Muscular Dystrophy Community Assistance, Research, and Education Amendments (MD-CARE Act) of 2001 (Public Law 107-84) with the goal of expanding and intensifying research on muscular dystrophies. The six centers are funded by NICHD, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Heart, Lung, and Blood Institute; and the National Institute of Neurological Disorders and Stroke.
- The NIH Autism Centers of Excellence (ACE) program is a trans-NIH initiative that supports large-scale multidisciplinary studies on autism spectrum disorders, with the goal of determining the disorders’ causes and the best treatments for them.