HONOLULU— Psychiatry generally has characterized disorders phenotypically rather than etiologically. However, if a genetic mutation increases the probability of a syndrome occurring, should a patient be classified purely phenotypically? What if a genetic mutation exists but the syndrome is extremely complex and no direct relationship can be proven? It is precisely these types of questions that the research paradigm known as “behavioral neurogenetics” is seeking to answer about a number of neuropsychiatric disorders, especially as continued improvements in molecular and brain imaging methods enable far greater characterization and quantification of genetic and neurobiologic factors implicated in neuropsychiatric and mental disorders.

Currently, “the best we can do is define our disorders by constellations or clusters of symptoms that tend to co-occur,” said Allan L. Reiss, MD, Howard C. Robbins Professor of Psychiatry and Behavioral Sciences and Professor of Pediatrics at Stanford University, Palo Alto, California. Clinicians are assisted in this effort by the DSM-IV and the International Classification of Diseases. A patient’s history will reveal specific symptoms and signs and cognitive and behavioral features and, in clustering these together, “we then try to make some sense of the neurobiology, the genes, and perhaps the environment that may be contributing to that disorder. But I actually am going to make the case, softly, gently, that utilization of these diagnostic schemes may be impeding our research effort,” he said in his address to the 14th Annual Meeting of the American Neuropsychiatric Association.

THE GENESIS OF BEHAVIORAL NEUROGENETICS

Dr. Reiss coined the term behavioral neurogenetics to represent a paradigm that uses “presumably more homogeneous neurogenetic conditions as models for understanding neuropsychiatric disorders.” As an important complementary strategy, behavioral neurogenetics is, “first and foremost, an opportunity to improve our understanding of how genetic factors influence brain development,” Dr. Reiss said.

During the past two decades, Dr. Reiss has investigated several types of disorders; for each, “we attempt very carefully to define behavioral, emotional, perceptual, and cognitive parameters that are associated with a particular neurogenetic risk factor. We try to map brain structure and function that are associated, and then have quantitative methods for measuring the genetic traits that are also contributing to the phenotype, and try to pull it together.” He added, “Knowledge of these specific conditions will tell us something about neuropsychiatric disorders that we currently define phenomenologically but which may resemble parts or even significant components of the cognitive, behavioral, and emotional features that we see in these conditions.” During his presentation, Dr. Reiss focused on two disorders to illustrate his methodology: Fragile X syndrome and Williams syndrome.

BAHAVIORAL NEUROGENETICS AT WORK—FRAGILE X SYNDROME

In general, diagnosis of Fragile X syndrome cannot be made based on appearance alone, although adolescent and adult males may have facial features suggestive of this disorder: a long face and prominent ears, jaw, and forehead, Dr. Reiss said. Enlarged testes are also a common finding among adult males with Fragile X syndrome. “Any time you have a male or female child or adult who has autism or mental retardation of unknown etiology, you should test them for Fragile X, not only from the scientific, medical, clinical, and ethical points of view but [because] people have been successfully litigated against for not testing [for] Fragile X,” he added. “As a heritable disorder, it can be present in many branches of the family without them knowing.”

Fragile X syndrome, named for a test no longer performed that identified a marker on the distal end of the long arm of the X chromosome, q27.3, occurs in approximately one in 3,000 individuals across all ethnic and socioeconomic strata. “It is the single most common inherited cause of neurodevelopmental neuropsychiatric dysfunction that we know of, and we can diagnose it very specifically with a DNA test,” said Dr. Reiss. The premutation form of Fragile X syndrome is present in about 10 times that number, or one in 300 to 400.

Individuals with this X-linked, semidominant disorder have strengths in verbal tasks but tend to be particularly weak in the area of visual-spatial functioning, particularly math, as well as having problems with perseveration, echolalia, and responses to sensory stimuli. Dr. Reiss said that one of the things he found interesting about Fragile X syndrome was its proposed association with autism, particularly hyperarousal, which manifests in social situations as gaze aversion, stereotypic movements such as hand flapping, and qualitative abnormalities of communication such as repetitive speech and echolalia. In fact, those “with Fragile X will turn away from face-to-face eye contact more often than individuals who have idiopathic autism,” he noted, adding that many adolescent females will grow up to have schizotypal personality features.

ANATOMY AND PHYSIOLOGY

“Unlike many other mental retardation syndromes or disorders associated with cognitive deficits, cerebral brain size is normal or increased” in patients with Fragile X syndrome, Dr. Reiss said. Regions increased in size include the hippocampus and the striatuma, particularly the caudate; those decreased include the superior temporal gyrus and cerebellar vermis. Studies have shown correlations between these regions and measures of Fragile X mental retardation 1 protein (FMRP) and measures of cognition and behavior. One parametric functional MRI (fMRI) task found that in normal adolescent girls, prefrontal activation in the visual-spatial working memory spread to parietal regions as the task became more difficult. Those with Fragile X syndrome activate the same regions of the brain initially but do not show enhanced recruitment of additional neural resources to address this increased cognitive task, and their performance suffers. When the correlation between FMRP and percent activation in the medial midfrontal gyrus region is examined, the more normal the amount of protein found, the higher the activation, and the better the performance, Dr. Reiss explained.

In addition, the structural abnormalities seen in frontal-striatal pathways “may be contributing, at least in part, to some of the functional abnormalities that we’re detecting in fMRI,” he observed, adding that FMRP most likely plays a dual role: long-term development, as in the process of brain wiring and connectivity, and as a short-term, real-time response to changing environmental stimuli, such as increased motoric activity. A reduction in FMRP leads to deficits in synaptic maturation, plasticity, and axon pathfinding.

“As a possible paradigm of research, Fragile X really gives us great hope,” Dr. Reiss remarked. “Prior to the mid-1970s, we really didn’t even know there was a specific disorder associated with this gene, and now not only do we have the protein, the gene, we understand what the protein does, we have brain imaging studies, there is a mouse knockout model, and researchers are attempting various knock-ins and therapeutic strategies as well.”

WILLIAMS SYNDROME

Dr. Reiss also discussed Williams syndrome, which “presents one of the most mysterious, curious, enigmatic profiles of behavior and cognition one will ever encounter.” Once known as elfin facies syndrome, this rare disorder was first described in 1961 by a cardiologist who reported “the presence of supravalvular aortic stenosis in a group of children who happened to have unusual faces,” he said. Williams syndrome occurs in about one in 20,000 individuals, with males and females equally affected. It is specifically related to a deletion on 7q11.22 to 7q11.23 on one chromosome and detected by fluorescent in situ hybridization.

Williams syndrome is commonly associated with developmental delays and mental retardation; mean IQ is between 50 and 60. “Now if you just stop there, you’d say ‘Ah, here’s another mental retardation syndrome associated with a deletion.’ It’s anything but,” Dr. Reiss said. “These are individuals who have very complex social, interactional, emotional, and cognitive profiles.” In contrast to those with Fragile X syndrome, they present at the opposite end of the social spectrum, “violating your personal space, trying to get your attention, face to face, looking at you for longer periods of time.”

A typical drawing of an elephant by someone with Williams syndrome will include all its elements but “the global construct is completely missing,” noted Dr. Reiss. In contrast, someone with Down syndrome matched in age and cognition will draw an elephant with global and local elements present, albeit not in great detail, “but probably developmentally appropriate.” A recent fMRI study of gaze and face orientation found that compared with controls, patients with Williams syndrome had a significant impairment in their ability to utilize primary and secondary visual cortex to activate regions of the brain for this task.

“Typically, what you should see are areas involved in face and gaze processing being active: fusiform gyrus, superior temporal sulcus, amygdala, and so on,” Dr. Reiss remarked. However, in patients with Williams syndrome, there is an anterior shifting to regions such as the prefrontal cortex, anterior cingulate, thalamus, striatum, temporal lobe regions, hippocampus, and middle temporal gyrus, suggesting a deficit in visual-cortical processing. Similarly, superior temporal gyrus findings, both in terms of increased size and activation in a number of fMRI tasks, can be correlated with the language strengths seen in these patients. He said brains of patients with Williams syndrome can be identified on MRI by their abnormal shape, ie, significant curtailment of the posterior occipital cortex and preserved size of the cerebellum. Through brain mapping, “We hope we will begin to put together a picture of how genes really do relate to brain development and function and how that ultimately translates to neuropsychiatric phenotype,” added Dr. Reiss.

A DIAGNOSTIC REVOLUTION

“Ultimately, the payoff [of behavioral neurogenetics] will be very high, because in fact it is only through this type of work that we will be able to develop more specific treatments for the disorders that we study,” Dr. Reiss said, adding that he believed “this is going to be a great challenge for the current system of defining disorders, because we are going to have to completely change how we think about diagnoses; we are going to have to revamp the DSM.”

For example, Alzheimer’s disease and Rett syndrome are currently included in DSM-IV. “So what’s going to happen?” Dr. Reiss wondered. “Are we going to exclude them from the DSM-V because we have specific etiologies? No, I hope not. But I think there’s going to be a diagnostic revolution: We are going to give up a reliance on phenomenology and adopt a different approach and a different way of understanding genetic and environmental risk.”

—Debra Hughes

Suggested Reading
Levitin DJ, Menon V, Schmitt JE, et al. Neural correlates of auditory perception in Williams syndrome: an fMRI study. Neuroimage. 2003;18: 74-82.

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