Genetic Testing Assists With Difficult Diagnoses
By Jeffrey L. Clothier, M.D.
Psychiatry is the branch of medicine that deals with uniquely human conditions. These disorders and diseases include a group of disorders that arise from atypical neurodevelopment. We have known for decades that these neurodevelopmental disorders and more classic psychiatric disorders both feature strong heritability. Until the 21st century, however, our molecular understanding of these conditions was limited. The standard diagnostic algorithms in psychiatry have typically ignored biology. Part of this is due to the focus on broad groups of behaviors that have multiple biological pathways, such as depression and schizophrenia. Since the sequencing of the human genome more biologic details about brain development have been pieced together, sometimes in surprising ways.
The Neurodiversity Clinic at the Psychiatric Research Institute is a specialty clinic staffed by psychiatrists as well as genetic specialists. The goal of this clinic is to identify the molecular diagnosis underlying atypical neuropsychiatric functioning. It began about six years ago as a combined psychiatry/adult genetics clinic with myself, Kent McKelvey, M.D., and Brad Schaefer, M.D. Prior to that, this group often collaborated on several inpatients with atypical clinical features. With the price of genetic testing falling rapidly in the last 10 years, opportunities to more completely evaluate a patient have become the standard of care for neurodevelopmental disorders. We have identified a number of conditions in patients who had previously been diagnosed as having severe mental illness that resulted in changes in treatment plans for both psychiatric and medical conditions.
The clinic operates via a consultation model where the psychiatrists and the genetics specialist review the referral information and determine what if any testing needs to be done. Entrance into the clinic is by referral from a mental health provider only. The current focus is on patients with histories suggesting a neurodevelopmental disorder, atypical medication response or autoimmune disorder. Records must be received prior to the patient receiving an appointment. The team will evaluate the patient and provide any recommendations to the patients referring physician. There are currently two sites of care, one in Fayetteville in collaboration with Dr. Schaefer and one in Little Rock in the Walker Family Clinic in collaboration with Dr. McKelvey. We are fortunate to have access to both of these geneticists. Dr. Schaefer is well known for his work in neurodevelopmental disorders and co-authored the most recent guidelines on the genetic evaluation of autism. Dr. McKelvey was one of the co-authors on the only comprehensive guideline for the care of adults with Down’s syndrome that was published recently in
JAMA.
There are reasons for doing the deep dive in characterizing these patients. The first is the importance in “naming” the disorder. This can give closure to patients and the families who have struggled for decades to understand the challenges they face. Neurodevelopmental disorders often affect only one member of the family. Understanding the molecular diagnosis can provide important information about potential recurrence or risk for siblings who may wish to have children. It can also help parents understand the basis of the disorder is not some error in parenting. Knowing the basis of the disorder can also suggest specific changes to treatment plans for both behavioral and non-behavioral conditions for which the patient may be at risk. Conditions we have identified in this clinic have included mitochondrial disorders, inborn errors of metabolism, a newly described mutation in a gene responsible for frontotemporal dementia and myopathy, Rett’s, Down’s, deGeorge’s syndrome, Phelan McDermid syndrome and others. Another hope of the clinic is to be able to provide insights into the biology of the brain behavior relationship in more typical psychiatric disorders.
The clinic has been described as a Unicorn and Zebra clinic. During training, medical students are taught to think about horses when they hear hoof beats. Nature, however, has several other animals that also produce hoof beats. We are also taught that looking for never described conditions is “looking for unicorns.” While these aphorisms are good for general medicine, they ignore a large block of disorders. Rare disorders are disorders that occur in less than one in 200,000 people. There are thousands of these conditions. It is more common to have a rare disorder than diabetes. I think in the future, as we learn more about the molecular characteristics of these human diseases, we will occasionally run into previously undescribed disorders that have been labeled as psychiatric disorders. Rare Disease Day is Feb. 28, so be sure to go “show your stripes.”
Jeffrey L. Clothier, M.D., is medical director of the Psychiatric Research Institute and vice chair of the UAMS Department of Psychiatry.