Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Institute of Mental Health (NIMH)

Overview of Rare Diseases Research Activities

The mission of the National Institute of Mental Health (NIMH) is to reduce the burden of mental illness and behavioral disorders through research on mind, brain, and behavior. As reported in the World Health Organization’s Global Burden of Disease study, mental disorders comprise four of the top five sources of premature death and disability in 15–44 year olds in the Western world. Serious mental illnesses such as schizophrenia, depression, bipolar disorder, anxiety disorders, and autism are the primary foci of research that NIMH supports and conducts. Additional research areas of significance to NIMH that can be classified as rare diseases include childhood-onset schizophrenia, pediatric bipolar disorder, Gaucher disease, William’s syndrome, Klinefelter’s syndrome, suicide, and pediatric and geriatric HIV/AIDS.

Recent Scientific Advances in Rare Diseases Research

Childhood-onset Schizophrenia

Childhood schizophrenia, defined as onset of psychosis by age 12, is a severe and unremitting form of the disorder. Patients with this rare, severe illness have profound impairment in development and resemble adult patients with poor-outcome schizophrenia. Several advances have been made in the study of childhood-onset schizophrenia (COS) this year at NIMH and further help elucidate the genetic vulnerabilities for the disorder.

Recent brain imaging studies have shown that COS is associated with striking progressive loss of cerebral volume during adolescence, but it was not known if these changes were specific to COS. MRI studies were used to compare COS patients with pediatric patients with transient psychosis and behavioral problems; both patient groups had similar early developmental patterns, cognitive functioning, medications, and hospitalizations. The results showed that the gray matter loss only occurred in the COS patients, which suggests that this loss is related to the illness and not related to medication. Ongoing MRI studies of siblings of COS patients will address whether this abnormal development may be a trait marker for the disease.

Although the above study showed distinct differences between COS and other childhood-onset psychotic disorders, there may be some genetic similarities between COS and bipolar disorder. The genetic component of COS was investigated in a study that looked at the relationship between two overlapping genes, G72 and G30, which have both been shown to be involved in the susceptibility to schizophrenia and bipolar disorder in adult patients. The study, which used patients diagnosed with COS or psychosis not otherwise specified, found significant associations between genetic markers at the G72/G30 locus and childhood-onset psychotic illness. It also found an association between the G72/G30 locus and the age of onset of psychotic symptoms, which was found to be close to adolescence. These findings confirm and strengthen previous reports that G72/G30 is a susceptibility locus both for schizophrenia and bipolar disorder.

Family, twin, and adoption studies have demonstrated that the development of schizophrenia is heavily influenced by genetic components. Studies have also shown that the synthesis and function of the neurotransmitter GABA may be affected in schizophrenia. Postmortem brain studies have shown deficits in the cortical GABA system of schizophrenic individuals compared to controls, including a decrease in the production of the major GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67). Genetic analysis of a group of children and adolescents with COS was used to explore a possible association between COS and alterations in the genes coding for GAD67, an enzyme involved in the synthesis of GABA. The results showed that there was a positive association between COS and specific variations in the genes encoding GAD67; these alterations in the gene encoding GAD67 could potentially prove to be a fairly common risk factor for schizophrenia.

Pediatric Bipolar Disorder

NIMH researchers are currently developing neuropsychological tests that would help investigate pediatric bipolar disorder. Existing neuropsychological tests for children with bipolar disorder are scarce and can only be used to investigate cognitive function, leaving the affective domain largely unexplored. Children with bipolar disorder exhibit affective symptoms that reflect an abnormal experience of pleasure. During depressive episodes these children exhibit an inability to seek or experience pleasure, whereas during manic episodes, pleasure-seeking behavior is heightened. In the first experimental study to examine associations between pediatric bipolar disorder and reward-related behaviors, reward behaviors in bipolar and control children were examined using a Wheel of Fortune task in which subjects could win or lose money based upon their decisions. The results showed that while bipolar children do not make risky choices more often than control children, they have significantly less confidence in favorable outcomes and a more emotional response to feedback. The ultimate goal of this work is to eventually use this task in conjunction with fMRI imaging to study reward pathways in pediatric bipolar disorder.

Gaucher Disease

Gaucher disease (GD) is a rare, inherited metabolic disorder in which deficiency of the enzyme glucocerebrosidase results in the accumulation of harmful quantities of certain lipids throughout the body, particularly within the bone marrow, spleen, and liver. The symptoms associated with GD vary greatly. There are three general classifications of GD, each defined by the extent of neurological complications. Type 1 GD is the most common form and involves essentially the peripheral organs and has no primary neuropathy. The onset of neuropathy begins in Type 2 GD and becomes chronic at Type 3. In order to understand this progressive neuropathy, NIMH researchers sought to identify specific patterns of neuronal injury associated with GD. Unique pathologic patterns were found in two specific regions of the brain, the hippocampus and calcarine cortex. The pathologic patterns were found in all three types of GD and the extent of these structural changes varied with the stage of the disease. This work suggests that GD, Parkinson’s disease, and diffuse Lewy body dementia (a condition with symptoms similar to those seen in Alzheimer’s or Parkinson’s disease that involves a specific pattern of neuronal loss, i.e., globe-shaped structures or lesions present in the nerve cells of the brainstem and cortical brain areas that cause symptoms similar to those seen in Alzheimer’s or Parkinson’s disease) have common cytotoxic pathogenic mechanisms affecting the cells of the nervous system.

Williams Syndrome

The genetic basis of Williams syndrome (WS) is remarkably well understood; it is caused by a hemizygous deletion of approximately 21 genes on chromosome 7. Disturbed visuospatial construction is a hallmark of the disorder and individuals with WS have a number of cognitive deficits, including mental retardation and learning disabilities. A hallmark of the disorder is a marked difficulty in visualizing an object as a set of parts and constructing a replica (e.g., assembling a puzzle or constructing a piece of furniture from separate parts). This deficit is referred to as disturbed visuospatial construction. People with WS also tend to be overly gregarious and anxious and often have mental retardation and learning disabilities. Scientists at NIMH used neuroimaging to trace the thinking deficit to underactivation of a circuit in the back of the brain that processes locations of objects in the visual field as compared to controls. Further analysis revealed that the nonfunctional and adjacent area of the brain that feeds information to the underactive areas was structurally altered in people with WS. This research confirms a long-standing hypothesis explaining disturbed visuospatial construction in WS and demonstrates the effects of a localized brain abnormality on visual information processing in humans. Finally, because the genetic basis of WS is so well understood, this study demonstrates ways in which known genetic abnormalities can lead to alterations in brain organization and function and, ultimately, to cognitive deficits. These structurally altered areas may also be important in other pathophysiological mechanisms in WS (structural neuroimaging showed a gray matter volume reduction in three brain regions of participants with WS) in addition to the cognitive deficit in visuospatial construction. This work demonstrates the effects of a localized abnormality on visual information processing in humans and defines a systems-level phenotype for mapping genetic determinants of visuoconstructive function.

Klinefelter’s Syndrome

XXY chromosome arrangement, instead of the usual male arrangement (XY), appears to be one of the most common genetic abnormalities known. The presence of an extra X chromosome is often related to atypical physical, cognitive, and behavioral features. NIMH researchers used fMRI to investigate changes in brain morphometry associated with Klinefelter’s syndrome. The results showed that compared to XY controls, XXY males exhibit pronounced brain volume reduction, which was localized in specific areas of the brain—the amygdala, hippocampus, insula, temporal gyri, cingulate, and occipital gyri. In addition to the reduction in volume in these specific areas, the results also found overall enlargement of ventricles and overall volume reduction of both white and gray matter in XXY males. Based on these results, future experiments will be designed to understand the behavioral correlates of the structurally altered regions.

Rare Disease-specific Request for Applications

HIV/AIDS and Aging

Following a meeting supported by ORD in April 2001 (“Mental Health Research Issues in HIV Infection and Aging”), RFA MH03-004 (“HIV/AIDS and Aging: Basic and Clinical Research”) was released. The following five grants were funded from this RFA, including projects in three basic research areas, clinical neuroAIDS, and clinical intervention:

  1. Haughey, Norman J; HIV-Associated CNS Dysfunction with Aging; R01 MH069177-01, R01 AG23471-01;
  2. Johnson, Rodney W; Aging, Brain Cytokines and HIV-Associated Dementia; R01 MH069148-01;
  3. Shiramizu, Bruce T; Activated Immune Parameters Associated with HIV and Aging; R21 MH069173-01;
  4. Gelman, Benjamin B; HIV and the Proteasome in the Aging Human Brain; R01 MH069200-01;
  5. Camp, Cameron J; HIV/AIDS and Aging: A Cognitive Clinical Intervention; R21 MH069199-01.

These studies will provide the foundation for further work focused on basic and clinical science aspects of HIV and aging, including increased emphasis on preventive interventions and their application internationally. It is hoped that this information will provide a foundation for expanding our efforts on the study of HIV and aging, with additional concentration on preventive interventions and their application in the international arena.

Significant Ongoing Rare Diseases Research Initiatives


Important ongoing work on suicide is being conducted through two NIMH projects that have received ORD supplementary support. One study on high-risk delinquents and young adults continues to assess suicidal behavior, noting a potential for the under-reporting of suicidal behavior in African-American subjects. The other study has made use of supplemental funding from the ORD to develop a methodology for assessing population-based approaches to the prevention of suicide. In FY 2002, ORD awarded two supplements to NIMH grantees, who then produced products from those awards in FY 2004. Dr. Linda Teplin of Northwestern University (MH5943) received monies to support assessment of suicidal behavior in high-risk delinquents and young adults. Her progress report (forthcoming to ORD) will include a summary of violent deaths in this cohort and raises the question of whether suicides in African-American males in her study cohort are underestimated. Dr. Hendricks Brown of the University of South Florida also received a supplement to develop a methodology for population-based approaches to the prevention of suicide. His progress report (also forthcoming to ORD) will describe how data can be combined across prevention trials through a meta-analytic approach to have sufficient power to detect preventive intervention effects for suicide deaths as well as steps necessary to address measurement error in death records.

In other work on suicide, an ongoing NIMH-funded randomized controlled trial is investigating the efficacy of a Youth-nominated Support Team Intervention (YST) that targets treatment adherence and family/social support among 13- to 17-year-old suicidal adolescents during the high-risk period following psychiatric hospitalization. The addition of the YST intervention to usual care is expected to result in reductions in psychiatric symptom severity and suicide attempts/ideation as well as improvements in treatment adherence, social support, and adaptive functioning. Results of this study will address an important gap in our understanding of strategies for improving treatment adherence and reducing suicide risk among these adolescents.

Several additional Career Awards focused on psychosocial and pharmacologic interventions for suicidal adolescents will help address a critical need for more research capacity in this area. These initiatives included awards to established investigators to support their efforts at mentoring new investigators and facilitating their development as independent investigators and an early career award to an investigator who is studying the feasibility and preliminary efficacy of cognitive-behavior therapy and pharmacotherapy for decreasing adolescents' depressive symptoms and suicidal behaviors.

Pediatric HIV/AIDS

Following a meeting supported by ORD in 2001, a study investigating the prevalence of psychiatric symptomatology—particularly focusing on attention deficit disorders in youth perinatally infected with or exposed to HIV-1—was designed. NIMH partnered with NICHD and NIAID to fund this study, conducted in cooperation with the Pediatric AIDS Clinical Trial Group (PACTG), and a PACTG protocol is in the final phases of approval. The PACTG is the largest clinical research program in the United States focused on the care and treatment of HIV-infected children and is funded by NIAID and NICHD. NIMH will fund this substudy to identify, quantify, and characterize the psychiatric consequences of living with HIV from birth. The goal is to develop an understanding of the mediating and moderating factors that lead to abnormalities and to ultimately develop interventions to prevent or lessen the psychiatric consequences of living with HIV in children and adolescents. The study will include both HIV-1-infected and uninfected but exposed children, and the impact of type and duration of antiretroviral treatment will be evaluated. This information will become of great importance in developing countries as antiretroviral therapy becomes more available and children and adults live longer.

Rare Disease-specific Conferences, Symposia, and Meetings


In October 2003, NIMH with cofunding from the ORD, CDC, SAMHSA, and the Annenberg Foundation held a workshop titled “The Science of Public Messages for Suicide Prevention.” No evaluations of public awareness campaigns for suicide prevention have been published, leaving minimal guidance for future efforts to create effective public messages that increase awareness that suicide is preventable. To address “how to” develop and evaluate public awareness campaigns, workshop participants (including suicide prevention advocates and experts in public health evaluation, suicide contagion, decision-making, and marketing) were asked to use logic models to define intended messages and audiences, assumed mechanisms of change, and outcomes. A summary of the meeting has been posted on the NIMH Web site ( and a longer summary has been accepted for publication in the journal Suicide and Life Threatening Behavior.

On September 9–10, 2004, NIMH with ORD support, the Annenberg Foundation, and Emerging Scholars Interdisciplinary Network co-sponsored a workshop titled “Pragmatic Considerations of Culture in Preventing Suicide” at the Annenberg Center in Philadelphia. U.S. suicide rate patterns associated with age, gender, and ethnicity provide profound evidence that culture is associated with suicide risk and protective factors. The purpose of the meeting was to examine how culture pertaining to ethnicity can be considered in the development and implementation of suicide prevention interventions. Three fielded studies were considered as examples in reducing suicide risk and included studies focused on African-American, Hispanic/Latino, and American Indian communities. For this workshop, culture was defined as self- and community-identity, community norms, and behavioral practices that can affect how an individual engages in behavior linked to life or death outcomes. Recognizing that this field is in an early stage of development, approaches to theory, measurement, and intervention development for each of the three studies were discussed with regard to their strengths and opportunities for further development. Experts knowledgeable about suicide risk for other understudied minority groups (e.g., Pacific Islanders) were asked to attend and provide feedback on the content and process of the workshop and recommend approaches for future meetings. A summary of the meeting has been drafted for the Web and has been submitted for clearance. Recommendations from this meeting are being used for planning a conference on suicide prevention among indigenous peoples in the Americas.


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Last Reviewed: July 22, 2005