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Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health 1999

National Institute of Mental Health

Overview of Rare Diseases Research Activities

NIMH is dedicated to ensuring and improving the scientific foundation for the diagnosis, treatment, and prevention of mental illnesses. To continue to expand this scientific base, NIMH conducts and supports research in basic and clinical neurosciences, behavioral sciences, epidemiology, and mental health services and service systems. As understanding of the neurobiological and behavioral bases of mental disorders has grown, insights into a number of rare diseases of the CNS have been gained.

Current research on the genetics and biochemical subtyping of major psychiatric disorders indicates that multiple underlying pathophysiological processes may be involved in more prevalent mental illnesses, such as schizophrenia and depression. As biochemically identifiable subtypes of these illnesses emerge, discrete and relatively rare illness subtypes for which orphan drugs can be developed will be defined precisely. Currently, a process of exclusion (i.e., failure of patients to respond to standard therapies) defines such probable disorder subtypes. As an example, refractory-to-treatment patients currently constitute populations of fewer than 200,000 for bipolar disorder and certain forms of schizophrenia.

Recent Scientific Advances in Rare Diseases Research


Autism is a childhood disorder characterized by qualitative impairments in social interaction and both verbal and nonverbal communication, resulting in a markedly restrictive repertoire of activities. An NIMH-supported investigator is examining the pathogenesis of autism through research in molecular genetics, neuroimaging, and family-behavioral studies. The findings from this laboratory and others strongly suggest that genes causing autism are present in defined regions on chromosomes 7q31-32 and chromosome 15q11-13. In related studies, these investigators have used neuroimaging to demonstrate that the brains of autistic individuals are enlarged. The enlargement is restricted to specific structures and may be limited to the gray matter. Measurements of head circumference over time indicate that the enlargement may be present at birth, and that, for autistic individuals, the brain may grow faster than normal through early childhood. To further characterize these unusual changes, MRI studies are being conducted in which autistic patients will be scanned periodically over a 2-year period, starting at age 2. Identification of a gene or genes underlying autism will make it possible to develop rational treatments for this disorder by understanding the underlying pathophysiology (i.e., which genes are involved, what the products of those genes are, and how they result in changes in the brain), and the characterization of changes in brain structure over time will make it possible to identify underlying brain abnormalities in autism and eventually tie them to particular genes and behavioral abnormalities.

Controversy exists regarding the role of pediatric immunizations—particularly the MMR (measles, mumps, rubella) vaccine—in the pathogenesis of autism. Using measures of the neurotoxin quinolinate (quinolinic acid) in cerebral spinal fluid as a surrogate marker of the presence of immune activation within the CNS, NIMH intramural investigators found no elevations in quinolinate levels in children with autism, which indicates that pediatric immunizations may not play a role in the pathogenesis of autism.

Childhood Bipolar Disorder

Bipolar disorder (manic-depressive illness) is a common mental disorder in adults; however, a relatively rare form, childhood-onset bipolar disorder, has recently been recognized in children. 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. NIMH has expanded research aimed at better characterizing childhood-onset bipolar disorder, assessing its validity, and evaluating new treatments. An ongoing 5-year prospective study of the age-specific clinical manifestations and naturalistic course of bipolar disorders in children and adolescents aged 7 to 16 will be expanded to study familial genetic and nonshared environmental contributions to this disorder.

Schizophrenia Subtypes: Childhood-Onset Schizophrenia

Schizophrenia is a disease that usually starts 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 have 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, has now 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. Moreover, adolescence is 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.

Anorexia and Bulimia Nervosa

Recent studies have shown that anorexia and bulimia nervosa run in families, and studies in twins suggest a genetic basis for the high rate of these eating disorders in certain families; 50% to 80% of the factors contributing to the development of eating disorders are genetic. This means that anorexia and bulimia nervosa may be as heritable as schizophrenia or bipolar disorder; illnesses that have long been regarded as exhibiting some degree of genetic vulnerability. Genetic factors contributing to eating disorders may become activated during puberty. How genes cause eating disorders is not certain; however, recent studies show that increased brain serotonin activity may be present in anorexia and bulimia nervosa. This activity, in turn, may contribute to certain vulnerabilities, such as restricted eating, obsessive thoughts, perfectionism, and anxiety that may increase the risk of developing an eating disorder. In fact, some studies have suggested that a genetic alteration of a specific subtype of serotonin receptor may play a role in anorexia or obsessive behaviors. Other exciting new technologies, such as brain imaging with PET using serotonin-specific molecules, have found alterations of brain serotonin receptors in areas of the brain that contribute to feeding, mood, and impulse control in women who have recovered from anorexia and bulimia nervosa. Moreover, new data raise the question of whether people with anorexia nervosa may starve themselves in an effort to reduce brain serotonin activity and thus reduce anxious obsessional feelings. In summary, twin, family, and genetic studies support the possibility that some underlying trait, such as a vulnerability to an imbalance in the serotonin system, could place someone at risk for developing an eating disorder. Eating disorders are often chronic relapsing disorders that have some of the highest death rates of any psychiatric illness. New understanding of the causes of these illnesses will help in devising more effective treatments.

Body Dysmorphic Disorder

Body dysmorphic disorder (BDD) is a rare, but relatively understudied, clinical problem. The distress and dysfunction associated with this disorder, although variable, can lead to repeated hospitalization, suicide attempts, and completed suicide. Individuals with BDD often pursue and receive general medical, dental, or surgical procedures to rectify their imagined defects. An NIMH-supported investigator is initiating the first prospective study of this disorder. This new research will better characterize the clinical course, predictors and risk factors, surgical or dermatological service use, and psychosocial functioning of individuals with this disorder.

Head Trauma and Child Abuse

An NIMH intramural investigator has demonstrated that head trauma as a result of vehicular accident, falls, or child abuse causes an increase in concentrations of the neurotoxin quinolinate in the cerebrospinal fluid (CSF). Quinolinate, or quinolinic acid, is produced by activated macrophages in response to injury and is toxic to nerve cells. Although the marked increases in CSF quinolinate resulting from vehicular accident or falls were delayed for approximately 3 days after the primary trauma, victims of child abuse often arrived at the emergency room with levels already substantially elevated. This observation is consistent with either a delay in bringing the child to medical attention or evidence of chronic abuse. Future studies will examine whether CSF quinolinate measures can be used to differentiate acute versus subacute/chronic traumatic brain injury.

Spinal Cord Injury

An NIMH intramural investigator has demonstrated large elevations of the neurotoxin quinolinate following spinal cord injury. In an animal model of secondary damage after spinal cord injury, a drug that blocks the formation and accumulation of quinolinate in spinal cord reduced inflammation-dependent functional deficits and helped preserve white matter tracts.

Glutaric Aciduria Type I

Glutaric aciduria type I is an autosomal recessive aminoacidopathy characterized by accumulation and excretion of glutaric acid, which leads to death by the end of the first decade of life. An NIMH intramural investigator has hypothesized that the neurotoxin quinolinate is overproduced in children with glutaric aciduria type I and contributes to the neurodegeneration and their symptoms of mental retardation and dystonia. NIMH investigators have taken a first step in replicating the metabolic lesion in mice and have demonstrated that brain quinolinate levels are indeed elevated.

Pediatric HIV Infection

In the United States, there were 310 new cases of HIV infection among children under age 13 in 1997. Neuropsychological deficits and developmental delays are a significant cause of morbidity in HIV-infected children. An NIMH intramural investigator has demonstrated a quantitative correlation between elevated concentrations of the neurotoxin quinolinate in the CSF and the degree of neuropsychiatric impairments and developmental delays in HIV-infected children. Notably, there was also a correlation between the levels of CSF quinolinate and the degree of brain atrophy as assessed by MRI. Drugs to reduce the accumulations in quinolinate are a potential approach to therapy.

Juvenile Myoclonic Epilepsy: A Genetic Disorder With Unique Neuropsychiatric Symptoms

Juvenile myoclonic epilepsy (JME) is a subtype of idiopathic generalized epilepsy (AGE) characterized by brief absence attacks and bilateral myoclonic jerks, usually appearing early in the day. The myoclonic jerks are often seen on awakening. The disorder appears at or around age 10 or later, in contrast to other forms of AGE; childhood absence epilepsy may appear as early as ages 2 to 5. Family studies have shown that AGE is strongly genetic and may be inherited in the female line. In neuropsychological studies of patients with JME, intramural investigators at NIMH found that neuropsychological functions (i.e., sustained attention) are impaired in probands and their first-degree relatives. However, relatives of patients with JME also show a unique neuropsychological deficit that is not seen in the probands themselves, an impaired ability to shift attentional focus, which may be an alternative expression of the epilepsy gene(s). Investigators also found highly significant correlations between the sustained-attention performance of probands with JME and their relatives. These patterns of impairment are not seen in probands or relatives of probands with focal, temporal lobe epilepsy. The loci of the genetic abnormalities in JME are being actively investigated. JME is itself being subdivided into several separate disorders, depending on whether it stems from a Northern or a Southern European background and whether absence attacks are a major symptom of the disorder. These different subtypes thus appear to have different genotypic profiles and distinct phenotypic expressions. Neuropsychological tests may help to define the phenotypes further, and provide clues to the nature of the genotypes. Therefore, neuropsychological assessment of probands and relatives, in conjunction with genotyping, could lead to better identification of the genes involved in the symptoms of AGE and increase knowledge of the vulnerability to such disorders.

Heart/Heart-Lung Transplant Recipients

Heart-lung and lung transplant recipients face significant mental health issues that impact medication adherence, quality of life, and well-being. An NIMH-supported researcher examined depression, anxiety, and anger/hostility, as well as overall quality of life, in a cohort of 50 lung and heart-lung transplant recipients. Only the subjects’ mean anxiety symptoms were substantially elevated over normative levels. However, nearly half of the sample showed clinically significant distress in one or more of the three symptoms areas. Pretransplant psychiatric history, educational level, posttransplant caregiver support, and health concerns were the most important independent correlates of the recipients’ psychological outcome. Low sense of mastery and poorer physical functional status also showed some evidence of association with mental health.

Completed Suicide

Suicide is a rare behavior that occurs in the context of a mental and/or substance abuse disorder nearly 90% of the time. Preliminary 1998 statistics indicate that approximately 29,000 Americans took their own lives. However, for every completed suicide, there are an estimated 8 to 25 suicide attempts. Individuals who complete suicide have overlapping but quite distinct characteristics from individuals who attempt suicide. For example, estimates of attempted suicide indicate that twice as many women attempt suicide as men; however, five times as many men as women actually commit suicide. To best determine risk factors for completed suicide, compared to attempted suicide, researchers have focused on postmortem research methods to develop both psychological and biological risk profiles.

The psychological autopsy (PA) is a method used to determine risk factors for suicide. NIMH has funded PA research for youths and is currently funding a PA study focused on older adults. Youth suicide victims are more likely to have a mood, conduct, and/or substance abuse disorder and a history of a past suicide attempts. In contrast, older suicide victims are more likely to have a later-onset mood disorder or a physical illness but less likely to have a substance abuse disorder or to have made prior suicide attempts. NIMH-supported research from long-term studies of depression has found that recurrent hopelessness is a key risk factor for poor treatment adherence and consequent death by suicide.

NIMH-supported research on biological risk factors for suicide has focused on postmortem brain tissue from suicide victims. The brain’s serotonergic, noradrenergic, and dopaminergic neurotransmitter systems have yielded some clues. Studies of the serotonergic system have found decreases in presynaptic serotonin nerve terminal binding sites such as the serotonin transporter site and a related serotonin nontransporter site. More recent autoradiographic studies of postmortem brain tissue have suggested that these abnormalities are more pronounced in the ventral versus the dorsolateral prefrontal cortex. Similarly, postsynaptic serotonin receptors, such as the 5-HT1A and the 5-HT2A receptor, appear to be increased in the prefrontal cortex of suicide victims. Although the explanation for the increases is uncertain, compensatory upregulation in response to reduced serotonin activity is one possibility. Alterations in noradrenergic indices, although less consistent than those for the serotonergic system, are also reported in suicide victims. In the dopaminergic system, decreased D1 and D2 dopaminergic binding in the prefrontal cortex of adolescent suicide victims has been reported, but further studies need to determine whether there are changes in DA or homovanillic acid (HVA), its major metabolite, in either prefrontal cortex or brainstem. However, given the level of this metabolite in people with major depression who attempt suicide and reports linking reduced dopaminergic function to major depression, further research may help us understand the changes in the dopaminergic system in suicidal patients.

New and ongoing NIMH-supported studies are focusing on the role of specific neurotransmitter systems in the brain in suicide. NIMH-supported research demonstrates an association between suicide and reduced serotonin neurotransmission, indicated by a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HT1A receptors in ventral prefrontal cortex of suicides. The ventral prefrontal cortex is involved in behavioral inhibition. Consequently, it is hypothesized that impaired serotonin input may underlie the predisposition for suicidal behavior. Researchers suspect there may be differences between suicides with major depression, because postmortem studies have found that a history of major depression is associated with a diffuse decrease in SERT binding throughout the dorsal ventral extent of the prefrontal cortex. This more diffuse biological disturbance is consistent with the more complex psychopathology associated with major depression, which would involve more brain regions. To determine the reason for these receptor changes, the researchers examined SERT binding, mRNA expression (the precursor to receptor protein synthesis) and 5-HT1A autoreceptor changes in the dorsal raphe nucleus (DRN) in the brainstem of nine matched pairs of controls and depressed suicide victims. 5-HT1A and SERT binding in the brainstem and SERT mRNA were reduced by approximately 30% in the suicides. In suicides, 50% fewer dorsal raphe neurons expressed SERT mRNA. These findings suggest less control of the activity of the DRN neurons because they lack the necessary receptors. The investigators call this phenomenon "hypofunction" of the dorsal raphe and are seeking to better understand the molecular components of hypofunction and potential causes.

Rare Diseases Research Initiatives


NIMH has initiated a clinical trial, Placebo-Controlled Study of Risperidone for the Treatment of Children and Adolescents With Autism and Behavioral Symptoms, to assess the potential value of this drug as therapy for autism.

Schizophrenia Subtypes: Familial-Onset Schizophrenia

Schizophrenia, the most disabling and chronic of the severe mental disorders, is characterized by psychosis, severely disrupted mood, and profound and lasting behavioral impairment. The worldwide prevalence of schizophrenia is 0.5% to 1%. A fraction of cases are found in families with two or more affected members. Genes that predispose people to developing schizophrenia may be easier to find in such families. NIMH has identified large families with many affected individuals in Morocco and Tunisia. The family members with schizophrenia will be characterized and blood obtained from them and their parents for genetic analysis, with the hope that this will reveal which chromosomal loci harbor "schizophrenia genes." Findings can be confirmed in larger data sets, because NIMH also has funded a large collaborative project collecting schizophrenia pedigrees in China and Taiwan.

Schizophrenia Subtypes: Childhood-Onset Schizophrenia

Adolescence is a time of enormous activity in healthy brain development that provides a window for studying the changes in brain development that occur in schizophrenia. Childhood-onset (onset before age 12) schizophrenia is a rare form of the disease, occurring at about 1/300 the rate of adult onset cases. Genetic risk factors for childhood-onset schizophrenia appear to be increased relative to those for community control subjects and to those for adult-onset schizophrenia. Cytogenetic abnormalities, and familial psychopathology are higher for these early-onset cases. NIMH plans a multicenter linkage study because knowledge of genetic factors in this extreme population may be particularly informative for all forms of schizophrenia.

Completed Suicide

In March 2000, NIMH and NIDA released the PA Interventions for Suicidal Youth to support efforts to develop and test interventions that build on both risk and protective factors for youth suicidal behavior. This PA identifies the need to test the effectiveness of interventions for reducing suicidal behavior for several of approaches, ranging from broad-based community or school-based prevention efforts to more targeted approaches that reduce suicidal behavior in youth with identified mental disorders or substance use disorders (SUD).

In late 1999, NIMH commissioned two comprehensive reviews of assessment instruments for suicidal behaviors and cognitions, one for children and one for adults. These reviews will soon be available on the NIMH Web page. Recent NIMH initiatives have also encouraged the inclusion of more diverse samples of patients, including suicidal patients, in treatment protocols. To help protect these patients and to encourage more researchers to include suicidal patients in research, NIMH staff have worked with experts in bioethics and suicide treatment research to develop a paper that describes various approaches to considering the ethical issues in treating suicidal patients and ways to increase the safety and monitoring of suicidal patients in clinical trials. This paper will also soon be available on the NIMH Web page.

Rare Diseases-Related Program Activities

Anorexia Nervosa

In December 1998, NIMH brought together experts in treatment, prevention, and genetic and basic neuroscience research, as well as clinicians and patient representatives for a workshop on new research approaches to eating disorders. Research needs and opportunities were identified in the area of treatment and prevention of eating disorders, especially of anorexia nervosa. The meeting also emphasized the need for the integration of basic research on the neurochemistry and brain circuitry of feeding behavior and reward mechanisms and other research focused on understanding the causes of eating disorders. Recent neuroscience findings in the molecular regulation of food intake and obesity can offer new perspectives on understanding the neuropathological basis of eating disorders. A third area of focus was the genetics of eating disorders that can contribute to the identification of relevant risk factors.


NIMH, along with NINDS, NICHD, and NIDCD, organized a meeting on the genetic basis of autism in January 1999. Participants included investigators from all major groups in the United States and Europe that are currently studying the genetics of autism and representatives from the Autism Society of America Foundation, National Alliance for Autism Research, and Cure Autism Now. The focus of the meeting was to facilitate gene discovery by discussing the development of collaborative research efforts.

Completed Suicide

In March 1999, ORD assisted in the funding of a NIMH/American Foundation for Suicide Prevention workshop on intervention research with suicidal patients. In addition to reviewing the limited evidence for treatments for suicidal people, the workshop also examined the legal and ethical/safety challenges to developing and testing treatments for this high-risk population. Another limiting factor in advancing the science of treatments for suicidal persons was the variation in approaches to assessing suicidal behavior in treatment trials.

In December 1999, NIMH provided staff consultation to the WHO to develop a review of current knowledge of risk and protective factors for suicide among the English-speaking American nations. NIMH staff members are working with WHO staff to share updates on national and regional suicide prevention strategy efforts.

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Last Reviewed: January 27, 2005
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