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Report on Research on Rare Diseases in Children: FY 2000 to FY 2005

National Institute of Mental Health (NIMH)

Overview of NIMH Rare Diseases in Children Research Activities, FY 2000–FY 2005

The mission of NIMH is to reduce the burden of mental illness and behavioral disorders through research on mind, brain, and behavior. As documented in the landmark Global Burden of Disease study, conducted by Harvard University, the World Health Organization (WHO), and the World Bank, the challenges before NIMH are immense, with common and prevalent mental disorders accounting for 4 of the 10 leading causes of disability in the United States.

The massive public health burden notwithstanding, NIMH directs substantial attention to less common disorders and conditions that occur across the life span and meet the criteria for "rare diseases," that is, including a prevalence of fewer than 200,000 affected individuals in the United States. In the arena of childhood disorders, such conditions may be subtypes of common adult disorders; prepubertal bipolar disorder and child-onset schizophrenia are two examples. In other instances (autism, for example), rare disorders appear to be pathophysiologic and clinical entities unto themselves. As understanding of the genetic, neurobiological, and behavioral bases of mental disorders expands, insights into a number of rare diseases of the brain and central nervous systems are accumulating. Conversely, research into relatively rare, early-onset subtypes of disorder has value-added benefit for the light it often sheds on the more prevalent adult forms of the disorder. An example is seen in imaging studies of brain volume in child-onset schizophrenia, which has helped to pinpoint when critical changes in apparently healthy brain structure and function occur that, when seen in adult subjects, appear to be unexplained concomitants of the illness.

Recent Scientific Advances in Rare Diseases in Children Research


Autism is a biologically based developmental disorder characterized by qualitative impairments in social interaction and both verbal and nonverbal communication and behaviors, resulting in a markedly restricted repertoire of activities. The origins of autism are not known. In FY 2000, a NIMH-funded research team working in collaboration with four others published results from genome scans in autism. Regions on chromosomes 1, 2, 4, 5, 6, 7, 10, 13, 15, 16, 17, 18, 19, X, and 22 were identified as putative locations for disease vulnerability genes. Pooling and meta-analyses of these small data sets will be a useful next scientific step. Examination of linkage signals across studies to date shows that one region (7q) has been identified in all studies; however, none of the studies has reported evidence that is conclusive. In another set of subsequent analyses, NIMH-funded teams re-examined a genomic region on chromosome 15q and two specific genes, HOXA1 (chromosome 7p) and HOXB1 (chromosome 17q), which had been implicated in previous studies. Evidence was not found for involvement of this genomic region or for these two genes in vulnerability to autism, suggesting that their roles are at best minimal in the majority of individuals with autism.

In FY 2000, a NIMH-funded network of research units on pediatric psychopharmacology (RUPPs) completed enrollment of the first multi-site controlled trial of the antipsychotic medication risperidone in children with autism, with results scheduled to become available in 2001.

In FY 2000, NIMH and NICHD co-sponsored an RFA entitled, "Neurobiology and Genetics of Fragile X Syndrome," which solicited innovative research applications that address the epidemiology, genetics, and neurobiology of fragile X syndrome. (FY 2000 through FY 2005)

NIMH and NICHD organized a conference in April 2000 entitled, "Fragile X Mental Retardation Gene Protein (FMRP): What Does it Do?" on the genetic and neurobiological basis of fragile X syndrome. The conference allowed the development of efficient research strategies by which the genetic dissection of other mental disorders might occur.

Schizophrenia Subtypes: Childhood-onset Schizophrenia

Schizophrenia usually manifests in late adolescence and early adulthood. Childhood-onset schizophrenia (onset before age 12) is a rare form of the disease, occurring at about 1/300 the rate of adult-onset cases. Brain imaging of adult schizophrenia patients has usually found slightly decreased total brain volume, enlarged ventricular volume, and smaller medial temporal lobe structures such as the hippocampus. Earlier studies in child-onset schizophrenia also showed these decreases in brain volume, but these changes seemed progressive, which does not appear to be the case in adult-onset schizophrenia. New data from a larger cohort of patients, including adolescents, have reconciled these findings. The new findings show that reductions in brain volume seen in child-onset schizophrenia slow and stabilize during adolescence. This suggests a common causal mechanism for both the adult- and child-onset disorder. Adolescence offers a unique window of opportunity to study late brain changes in child-onset schizophrenia. These findings also have implications for better drug treatment of child-onset schizophrenia because drug dosing can be matched to brain changes that appear to correlate with symptoms. (Ongoing NIMH intramural research)

Childhood Bipolar Disorder

Early-onset bipolar disorder has only recently been recognized in adolescents. NIMH-supported research, based on a community sample that has been followed since adolescence, reported a prevalence of 1% during adolescence and found that less than 1% of adolescents with major depression switch to bipolar disorder by age 24. An ongoing study of prepubertal and early adolescent bipolar disorder (PEA-BP) is examining the course of early-onset bipolar disorder in children who also have a diagnosis of attention deficit hyperactivity disorder (ADHD). Ninety-three children (ages 8-13) with a current diagnosis of severe mania or hypomania with elated mood and/or grandiosity were compared to children with ADHD and no manic symptoms as well as normal controls. Compared to both groups, the PEA-BP children had significantly greater impairment on items that assessed maternal-child warmth, maternal-child and paternal-child tension, and peer relationships. At 6-month follow-up, 86% of the PEA-BP children still met full criteria and severity level for mania or hypomania, with elated mood and grandiosity highly stable. These findings suggest that PEA-BP may be a stable, valid, and previously under-recognized condition. (FY 1995 through FY 2001)

To advance research on the identification of prepubertal bipolar disorder, NIMH held a workshop in FY 2000 that focused on research methods to detect bipolar disorder in children. In the same year, NIMH funded the first multi-site controlled study of lithium and valproate as treatment of children with acute mania. The study is being conducted at 3 sites and will enroll about 150 children. (FY 2000 through FY 2004)

In FY 2000, NIMH awarded funds for a 3-site collaborative study of the course and outcome of 12- to 17-year-old adolescents with bipolar illness. It is the first large-scale comprehensive naturalistic evaluation of the long-term course of bipolar disorder in this age group. It will track the naturalistic course of episode recovery and relapse, predictors of course, psychosocial outcomes, and naturalistic treatment effects.

Youth Suicide

Suicide is a rare behavior that, in an estimated 90% of instances, occurs in the context of a mental and/or substance abuse disorder. In 2000, NIMH-funded research on youth suicide included family genetic studies, long-term follow-up of depressed youth, and a co-funded (multiple NIH institutes, Centers for Disease Control and Prevention [CDC], Substance Abuse and Mental Health Services Administration [SAMHSA]) conference grant focused, in its first year, on youth suicide. Annual conferences are planned for 2000 through 2004.

Other research studies are focused on youth who attempt suicide. A number of studies are following adolescent suicide attempters over time, but few researchers are willing to test treatments for adolescent attempters due to liability concerns; the need to develop research eligibility criteria for suicidal individuals of all ages is being addressed by NIMH and the larger research community. A workshop om this topic funded by ORD is scheduled for summer 2001.

Pediatric HIV Infection

In the United States, due to medication advances during prenatal care for HIV-infected mothers, the incidence of HIV infection among children has slowed considerably. However, it is estimated that there are still between 500 and 1,000 new cases of infection per year of children younger than age 13. Moreover, many of the much larger cohort of children born with HIV before the routine use of antiretroviral therapy (ART) during pregnancy have now survived into pre-adolescence. These children with pediatric AIDS, their families, and their treatment providers are dealing with a host of sequelae from HIV disease.

Neuropsychological deficits and developmental delays continue to be a significant cause of morbidity in HIV-infected children. In the 1990s, NIMH-sponsored research demonstrated that these deficits may be related to elevated concentrations of the neurotoxin quinolinate in the cerebrospinal fluid (CSF). Notably, there was also a correlation between the levels of CSF quinolinate and the degree of brain atrophy as assessed by magnetic resonance imaging (MRI). More recent efforts in NIMH's extramural program indicate that the biological and psychosocial effects of HIV disease include neuropsychological deficits, emergence of behavioral/social disorders and school-related problems (oppositional behavior, learning disabilities, ADHD), treatment adherence difficulties, and other co-morbid mental health issues. Clinicians are also observing abnormalities that may be attributable to the toxicities of long-term use of medications for HIV (i.e., antiretroviral therapies). There is a pressing need for more systematic understanding of these problems, their interaction, and how best to provide integrated treatment. A workshop on this topic, funded by ORD, will be held in September 2001. An RFA with funding for FY 2002 through FY 2003, followed by meetings in 2004 and 2005 that encourage collaboration with international researchers working on similar problems in developing countries, is planned.

Ongoing, New, and Planned Research Initiatives in Rare Diseases in Children

Rare Childhood Mental Disorder Research Initiatives–FY 2001 Through FY 2005

Autism and Related Conditions

NIMH plans a joint initiative with NIA and the National Institute of Neurological Disorders and Stroke (NINDS) to promote the identification of genes that cause or contribute to human neurological and neurobehavioral diseases. Autism and fragile X projects will be solicited to encourage applications for genetics research projects. Because of the interdisciplinary nature of such projects, collaborative studies are encouraged. Another initiative will fund high-throughput projects, including those focusing on autism, that target the whole genome to identify in patients with mental disorders the genetic basis of therapeutic response to one of several compounds (e.g., anxiolytic, antidepressant, antipsychotic, and antimanic drugs). Also planned are proteomics projects in mammalian species that will develop novel technologies or apply existing state-of-the-art approaches to the analysis of the complete repertoire of proteins in the nervous system.

In March 2001, NIMH funded a conference grant to hold a series of five annual interdisciplinary conferences on basic and clinical research relevant to fragile X syndrome, intended to bring together a broad range of scientists, including those working on fragile X syndrome and others in allied relevant fields.

NIMH will convene a workshop in FY 2002 to examine co-morbid symptomatology between fragile X and other mental disorders such as anxiety and mood disorders. The workshop will explore approaches to accelerate neurobiologic research to identify underlying circuits and pathways common to fragile X and other mental disorders. This may help point the way to understand common pathophysiological mechanisms and to identify new targets useful for therapeutic drug discovery.

Highlights of autism-related research activities begun in FY 2001 include a NIMH-funded study that will use MRI and magnetic resonance spectroscopy (MRS) to investigate the structural anatomy and biochemistry of the brain in developmental language disorder (DLD) and autistic groups of children. These structural anatomical and biochemical measures would then be examined in relation to quantifiable aspects of social communication using measures of formal thought disorder and discourse. The proposed study has the potential to contribute to our knowledge of the neuroanatomical and neurochemical abnormalities associated with the social communication deficits seen in autistic and developmental language disorders in children. In a separate project, an investigator proposes to assess the relation between brain morphology and autism through structural neuroimaging of siblings discordant for autism.

The results of these studies have the potential to allow investigators greater experimental control of those genetic and environmental factors that influence normal and abnormal brain development and may clarify biologically based subtypes of autism. Another study will use structural and functional MRI (fMRI) to assess how the abnormal structure and function of the neural systems in persons with autism may affect the processing of emotional information, particularly emotional information conveyed through faces and facial expressions.

Human focal cortical dysplasia (FCD) is a developmental brain malformation characterized histologically by disorganized cerebral cortical cytoarchitecture and lamination. FCD is associated with several mental disorders, including mental retardation and autism. A newly funded project will test the hypothesis that FCD is the result of abnormal neuronal migration occurring because of a failure to develop appropriate and necessary genes for migration. Anatomical and molecular experiments will assess the presence of immature or other abnormal genes in individual abnormal cells in cortical dysplasia.

In 2001, a RUPP network will launch a new protocol to test the efficacy and safety of treatments of inattention and hyperactivity in children with autism. An expansion of the network is planned for FY 2002 through FY 2003.

In December 2000, NIMH held a workshop entitled, "Genetics in the New Millennium: Modeling Autism." This meeting was an initial step to foster development of new models in the area of autism and the translation of research to the clinical treatment of this devastating disease. One of the main questions raised had to do with whether the assembled group could help define phenotypes that could be defined genetically in the mouse. Several possible approaches were outlined: 1) identify associated genetic markers, 2) map the disease vulnerability gene(s), 3) re-synthesize the disease in mice, or 4) survey inbred strains for important phenotypes and perform further quantitative trait loci mapping.

Childhood Schizophrenia

In 2001, NIMH plans to fund the first multi-site trial of the efficacy and safety of different antipsychotics for the treatment of childhood schizophrenia. This will be a four-site randomized controlled study with extended treatment and follow-up.

Childhood Bipolar Disorder

Responding to the need to understand how prepubertal bipolar disorder develops and what treatments are effective, the NIMH intramural program established (in FY 2001) a research unit to study the etiology and pathophysiology of childhood bipolar disorder. The Unit, which will complement ongoing extramural activities, will collaborate with the newly created Intramural Program in Mood and Anxiety Disorders to understand the major differences between childhood and adult forms of the disorder. The Unit will address questions regarding the phenomenology of the illness, probe the neural circuitry of emotion in patients with bipolar disorder compared to psychiatrically normal adolescents, develop and test innovative therapies for childhood bipolar disorder, and capitalize on the unique opportunities that early-onset probands provide to understanding the genetic basis of bipolar disorder.

In 2001, NIMH plans to fund a controlled study of antipsychotic medications for children with bipolar disorder who have psychosis and/or aggression.

In FY 2001, NIMH will award supplements to grants involved in the three-site collaborative study of course and outcome of child/adolescent bipolar disorder to extend the age range downward to include 7- to 11-year-old children. NIMH will also fund a study to evaluate 7- to 18-year-old children of bipolar parents and follow prospectively only those who do not have bipolar disorder at intake. At intake and annual follow-up, children will be assessed for differential incidence of psychopathology, behavior and emotion regulation, psychosocial functioning, pubertal status, and family psychiatric history. The study is expected to provide information on early manifestations of childhood-onset bipolar disorder and on the boundary between bipolar and disruptive disorders, seeking to identify prodromal symptoms and factors that may promote or prevent the onset of bipolar disorder in children.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS)

Following up on an FY 2000 research workshop to discuss new investigations on tic disorders associated with streptococcal infections (PANDAS), NIMH has received new applications for research in this area and plans to fund new studies in 2001 and 2002. Public awareness of the potential link between common childhood infections and neuropsychiatric disorders has outpaced the scientific knowledge base, with particular need for studies of basic cellular and immune mechanisms underlying PANDAS.

Youth Suicide

ORD is co-funding an NIMH-sponsored workshop on the safety and ethics of clinical trials in June 2001, where approaches to research for individuals at risk for suicidal behavior, including youth, will be considered.

Pediatric HIV Infection

NIMH has expanded its program focus on coping with pediatric AIDS, both in the United States and internationally, where the implications of this research may affect millions of infected children. NIMH will convene a workshop on September 10-11, 2001, to summarize what is known about the effects of AIDS and its treatment on the development of children. The meeting will include representatives from government (e.g., the Office of AIDS Research [OAR], NIMH), academia, clinicians/treatment providers, and basic scientists, all with interest and expertise in pediatric HIV/AIDS treatment and prevention. The outcome will be a road map for immediate, short-term, and long-term goals for research in this area.

Rare Diseases-Related Program Activities in Children–FY 2001 Through FY 2005


In collaboration with the other Institutes represented on the NIH Autism Coordinating Committee, NIMH has initiated a planning process for activities that would implement the provisions of the recently enacted Children's Health Act of 2000 (Public Law No. 106-310). A major component of these activities will be a collaborative effort to support broadly based Centers of Excellence in Autism. This effort will provide additional infrastructure, organization, and focus to autism research efforts by establishing nodes of activity with a critical mass of expertise and resources.

NIMH plans an FY 2001 workshop to bring together outstanding human statistical and molecular geneticists and neuroscientists to identify strategies to accelerate the discovery of vulnerability genes for mental disorders (including autism).

In FY 2002, NIMH plans to bring together diverse groups of genetics researchers and develop strategies by which all available data sets may be assembled. Such efforts will enhance the power to detect vulnerability genes and elucidate their functions.

In December 2000, the NIH Autism Coordinating Committee, supported by NIMH, NICHD, NINDS, and NIDCD, issued an RFA for innovative methods and feasibility studies in the area of treatments for autism. The definition of its focus and scope grew out of a workshop hosted by these Institutes.

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Last Reviewed: May 15, 2003
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