Report on the Rare Diseases and Conditions Research Activities of the National Institutes of Health 1998
National Institute of Mental Health (NIMH)
The National Institute of Mental Health 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 central nervous system have been gained.
Current research on the genetics and biochemical subtyping of major psychiatric disorders indicates that multiple underlying pathophysiologic 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. At present, 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 presently constitute populations of under 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. A major focus of NIMH-sponsored research is identifying the genes that confer susceptibility, which will pave the way for improvements in diagnosis, treatment, and ultimately prevention. Evidence strongly suggests the involvement of multiple susceptibility genes. A two-stage genome search for susceptibility loci was performed recently on 99 families with inherited autism. Regions on six chromosomes were identified, with the region on 7q being the most statistically significant. Another study identified two children with interstitial chromosome 15 duplications. Linkage disequilibrium between autism and a marker in the g-aminobutyric acid (GABA) receptor subunit gene was found. While not yet confirmed, these results provide exciting leads to pursue in ongoing NIMH-supported projects.
An NIMH-supported investigator, studying the brain-behavior correlates of attention deficit in autism using functional magnetic resonance imaging (fMRI) and evoked potential recording techniques, has developed a series of hypotheses as to the origins of this disorder. Essentially, he hypothesizes that as a result of autism, the cerebellum shows signs of significant functional reorganization, resulting from a reduction in the number of Purkinje cells. In this reorganization, cerebellar function appears to become fractionated, disrupting some cognitive and attention related functions as overcompensation takes place to maintain or increase the participation of the cerebellum for some purely motor functions. Further studies related to these hypotheses are being conducted.
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. Although schizophrenia affects up to 1 percent of the general population, only about one in 10 cases of schizophrenia are familial. A major focus of NIMH-sponsored research is identifying the genes that confer susceptibility, paving the way for improvements in diagnosis, treatment and, ultimately, prevention. Evidence strongly suggests that multiple susceptibility genes are involved, and over the last year a number of promising leads have emerged to help locate some of these genes in the human genome. NIMH-supported investigators conducted a genome-wide scan in 54 multiplex pedigrees. They found significant evidence for a susceptibility locus on chromosome 13q32 and suggestive evidence for another on 8p21-22. In a follow-up sample of 51 multiplex pedigrees, these investigators verified suggestive evidence for the 13q linkage. While the target regions need to be reduced, the results represent an important lead for future studies. Opportunities are available to confirm or disconfirm these findings in larger data sets, given that NIMH 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 prior to age 12) schizophrenia is a rare form of the disease, occurring at about 1/300 the rate of adult onset cases. NIMH investigators have demonstrated clear abnormalities in brain development in early-onset schizophrenia through imaging studies of anatomic brain development in adolescents. Specifically, subjects with early-onset schizophrenia show a disease-specific pattern of increased ventricular volume, decreased hippocampal (but not amygdala) volume, and decreased cortical gray volume, particularly in the frontal and temporal lobes. These late changes may be related to the triggering of the disorder. Further molecular based studies on these patterns may guide future pharmaceutical developments.
The umbrella heading "eating disorders" encompasses a range of conditions from diagnosable disorders through sub-syndromal conditions to discrete, disordered eating behaviors. In their more severe forms, eating disorders are associated with high rates of morbidity and mortality. NIMH supports research on the diagnosable neuropsychiatric disorders anorexia nervosa, bulimia nervosa, and binge eating disorder. However, because of increased awareness and recognition of bulimia nervosa, it now appears that more than 250,000 people may suffer from this disorder, indicating that it no longer meets the DHHS definition of a rare disease; this disorder is, therefore, not included in this report.
Anorexia nervosa, a syndrome of extreme, and often life-threatening, weight loss associated with a distorted body image and a pathological fear of gaining weight, is estimated to have a life-time prevalence among women of about 0.5 percent, with most cases occurring in adolescent and young adult women; the prevalence among men is about one tenth that among women. A variety of treatment approaches are effective in the acute phase of weight restoration for anorexia nervosa; however, follow-up studies indicate that in spite of initial progress during the acute weight-gain phase of inpatient care, approximately 30-50 percent of individuals relapse to the extent that they require repeated hospitalizations and, even in cases not requiring rehospitalizations, the majority of patients continue to report serious emotional and functional impairment. Clearly, more effective treatments are needed.
NIMH-supported investigators have found elevated concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid of long-term recovered anorexia nervosa patients, suggesting that altered serotonin activity is characteristic of this disorder. In addition, they have found that selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are ineffective in treating anorexia nervosa in patients who are malnourished and under weight. However, when administered after weight restoration, fluoxetine can reduce the rate of relapse in anorexia nervosa, presumably by reducing obsessionality and negative mood. These findings raise the possibility that a disturbance of serotonin activity may create a vulnerability for this disorder. Further neuroimaging studies will be conducted to examine the role of serotonin receptors and serotonin activity in the pathogenesis of anorexia nervosa and to shed light on core behaviors associated with this disorder.
Infantile anorexia is a rare eating disorder that affects infants and toddlers, manifesting itself with food refusal and resulting in growth delay and mother-child conflict. An NIMH-supported investigator has been developed a psychotherapeutic intervention specifically focused on this disorder and further work is being done to test the efficacy of this intervention.
Gilles de la Tourette's syndrome (TS) is characterized by motor tics and vocal tic, the patterns and severity of which may change over time and may include echolalia (the repetition of words) and coprolalia (the uttering of obscenities). NIMH funds a multi-faceted research program that uses neuroimaging and genetic approaches to examine the neurobiology, genetics, pathogenesis, and treatment of TS, obsessive-compulsive disorder (OCD), and attention-deficit/hyperactivity disorder (ADHD). ADHD is very common among TS patients and can cause significant academic difficulties and functional impairment for these patients. In genetic research, two very promising chromosomal regions have been identified that may contain vulnerability genes for TS in families with siblings affected with the disorder. Neuroimaging has been used to identify brain circuits associated with the expression and severity of tic symptoms in TS. Morphological studies have found alterations in basal ganglia volumes and associated thalamic and cortical areas in TS patients. Other studies have assessed a series of novel pharmacotherapies which may lead to safer, more effective, and better tolerated treatments of TS. Currently, Guanafacine, believed to enhance prefrontal cortical functioning, is being studied to treat ADHD in children with tic disorders, and Ziprasidone, an atypical antipsychotic, for TS in children and adolescents. Nonpharmacologic interventions, such as cognitive behavior therapies, are also under study. These novel treatment interventions have the potential to alter the long term course and outcome of TS.
Although suicide is not a disease, it is a rare behavior that nearly 90 percent of the time occurs in the context of a mental and/or substance abuse disorder. Preliminary 1997 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 persons who attempt suicide. For example, estimates of attempted suicide indicate that twice as many women attempt suicide than men. However, five times as many men as women commit suicide. To best determine risk factors for completed suicide, compared to attempted suicide, researchers have focused on post-mortem 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 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 system 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 number 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 dopamine 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.
Carbohydrate Deficient Glycoprotein Syndrome
Carbohydrate-deficient Glycoprotein syndrome (CDGS) is a group of rare metabolic disorders that presents with severe neurologic manifestations and involves multiple systems. CDGS results from the defective assembly of N-linked oligosaccharides. This complex synthetic pathway has over 200 steps, making the correlation between clinical phenotype, underlying metabolic defect, and molecular mechanism unpredictable. NIMH investigators are defining the clinical features of CDGS, elucidating the underlying glycobiologic mechanisms, and characterizing the genes involved in illness. Several different enzymatic defects underlying CDGS have been identified.
Rare Diseases Research Initiatives
With increasing evidence that the etiology of autism is linked to aberrant brain development, NIMH and the National Institute of Neurological Disorders and Stroke (NINDS) provided $80,000 of supplemental funding in FY 1998 to the Harvard Brain Bank to increase the collection of brains from individuals diagnosed with autism. Successful recruitment and collection of post-mortem brains and other tissues will facilitate neurobiological investigations of this disease.
Pediatric neuroimaging provides unique opportunities to study autism by investigating brain development in both normal children and in those afflicted with brain diseases and behavioral disorders. A workshop held in 1997 emphasized the need to develop a normative database for brain development. In response, NIMH, NINDS, and NICHD issued a Request for Information (NINDS-98-RFI-01) in May 1998 about current neuroimaging data acquisition and image analysis protocols to aid in planning and developing a request for pediatric study centers. NIMH issued a RFP for a Data Coordinating Center in May 1998. This project seeks to establish a database with which to generate a comprehensive study of the structure, chemical composition, and metabolic state of the developing human brain, and to provide a reliable source of normative data for studies on childhood disorders and diseases that affect the brain.
Schizophrenia Subtypes: Familial-onset Schizophrenia
NIMH issued an RFA (MH-99-005) to support genetic analyses and collection of additional large data sets for familial schizophrenia.
Rare Diseases-Related Program Activities
NIMH, along with three other NIH institutes, Cure Autism Now, and the National Alliance for Autism Research, held a workshop, "Building Animal Models for Autism Through Translational Neuroscience Research," in Oct. 1998. Participants included 33 basic or clinical neuroscientists engaged in research on autism. The workshop made recommendations for the development of multidisciplinary, state-of-the-art animal research programs to help elucidate the neurobiological basis of autism.
In May 1998, NIMH and the Office of Rare Diseases jointly sponsored an international research conference on Munchausen syndrome (Factitious Disorder) by Proxy, a rare psychiatric disorder in which a caretaker seeks medical treatment for a child for fictitious or induced medical conditions. This disorder is a type of psychiatric disorder in the caretaker and a form of child abuse. The child faces a significant risk of both physical and psychiatric morbidity and, even, of mortality. Few research studies have been conducted on this disorder and much needs to be learned concerning epidemiology, characteristics and course, risk factors, and outcomes of this disorder. This workshop brought together pediatric and child psychiatric researchers who conduct research on Munchausen syndrome by Proxy or related issues. The researchers gave presentations and discussed current knowledge of this seemingly difficult to understand form of child maltreatment. A set of papers resulting from the conference will be published. Bipolar disorder occurs very infrequently in children; it is often comorbid with ADHD and the two disorders are difficult to distinguish diagnostically. In Nov. 1998, the Journal of Affective Disorders published a special issue, "Current Issues in Childhood Bipolarity," the result of a 1997 workshop organized by NIMH and co-sponsored by the NIH Office of Rare Diseases on prepubertal bipolar disorder. Research recommendations from the workshop focused on assessment issues (including the need for new diagnostic criteria, new measures of children's functioning and factors that affect it, and new instruments that discriminate ADHD from bipolar disorder), as well as the need for treatment, genetic, and biologic studies. In April 1998, NIMH held a workshop, "Targeted Approaches to Suicide Prevention," to review the current knowledge on risk factors and targeted preventions based on those risk factors. About 50 participants reviewed the evidence and pointed to gaps in the knowledge base. Several of these gaps will be addressed in workshops in 1999.
