Parker Roos was a toddler when his mother, Holly, suspected he might have developmental challenges. “He had met all the milestones for his large motor skills, but he wasn't meeting the milestones for fine motor control and he wasn't talking,” says Holly, who lives in Canton, IL, with Parker, now 22, and Parker's 19-year-old sibling, A. “A dozen developmental pediatricians told me I was a neurotic first-time mom.”
When Roos was pregnant with A, her mother—who's a nurse—attended a genetics conference in Chicago and came across a booth that had information about fragile X syndrome. “She called and started reading it to me, and it sounded just like Parker.”
A genetic disorder caused by variations in a gene known as FMR1, fragile X syndrome is the most common inherited cause of intellectual disability, affecting about one in 2,500 to 4,000 males and one in 7,000 to 8,000 females. The link between mutations in FMR1 and fragile X was identified in the early 1990s by a team of scientists, who named the mutation FRAXA.
When Roos went in for a well-baby checkup with her newborn daughter, A, who is now nonbinary, she persuaded the pediatrician to take a blood sample from Parker at the same time. He called back three weeks later and confirmed the fragile X diagnosis.
That was the beginning of Roos' journey into the genetics of fragile X syndrome. After some false starts and inaccurate information, she stumbled across a parent-founded research and advocacy organization called the FRAXA Research Foundation, which helped her locate a neurodevelopmental pediatrician and a genetic counselor with expertise in fragile X.
On the counselor's advice, A was tested, and they turned out to have the full mutation, although their symptoms are less visible. (The FMR1 gene is found on the X chromosome; since females are born with two X chromosomes, if there is a full mutation on one X chromosome, the other copy of the gene is usually working and can compensate.)
Like some other neurologic disorders, such as Huntington's disease, fragile X is caused by expanded DNA “repeats.” As the gene is passed on, the number of repeats can increase and begin to affect gene function. A full mutation of the fragile X gene, considered to be 200 or more repeats, produces the most severe symptoms, particularly in males. A “premutation” of the gene, involving 55 to 200 repeats, is much more common and has its own genetic consequences, including primary ovarian insufficiency (in which a female's ovaries fail as early as the teenage years) and an increased risk of fibromyalgia, thyroid and seizure disorders, and fragile X–associated tremor/ataxia syndrome, which has symptoms that are often confused with those of Parkinson's disease or Alzheimer's disease.
The genetics of neurologic disorders is a complicated and evolving field, says Lola Cook, a genetic counselor in the department of medical and molecular genetics at the Indiana University School of Medicine in Indianapolis. “Up until recently, genetic testing has been underused in neurology, especially for adult diseases. Now we are beginning to learn more about major gene variants as well as multiple minor changes that make genetic contributions to a wide range of neurologic disorders.”
Two categories of genes influence whether a person develops a disease. The first includes genes that cause a disease, known as causative. Variants in specific genes are causative for neurologic conditions such as fragile X, Huntington's disease, and spinal muscular atrophy (SMA). The second category includes risk genes. They don't cause the disease but increase a risk of developing it under the right conditions.
Researchers are still working to understand exactly how these variants interact with each other and with the environment to cause disease. Many of the more common neurologic conditions such as multiple sclerosis (MS), Parkinson's disease, and Alzheimer's disease are associated with less severe variants in multiple risk genes, but in some cases they are produced by variants in single causative genes.
“In amyotrophic lateral sclerosis (ALS), we currently know of about 30 genes that are relevant as causative,” says Anna Szekely, MD, an attending physician in the neurogenetics program at the Yale School of Medicine. There are also a number of risk genes with variants associated with ALS that, by themselves, don't necessarily cause the disease but can contribute to disease risk. This is the case with many other neurologic disorders as well. Research published in Science in 2019 identified 233 significant genetic variants linked to the risk of MS, and a study in Neurobiology of Disease in 2019 cited more than 90 variants that increase the risk of Parkinson's disease.
There are also two kinds of primary genetic testing—diagnostic and presymptomatic—which serve different purposes. Diagnostic testing is performed to identify the cause of a disorder when a person has symptoms of that disorder; the results may have implications for the rest of the family. Presymptomatic testing can determine whether a person who has no known symptoms but might be at risk based on family history and other factors carries an associated genetic mutation.
To Test or Not to Test
If people have puzzling neurologic signs or symptoms, or if one or more neurologic conditions seem to run in their families, should they pursue genetic testing?
The answer depends on the disorder and the usefulness of the information to people and their doctors, according to experts. For conditions like fragile X, SMA, and Huntington's disease, which are caused by changes in one specific gene, testing potentially provides information that patients and their families can use.
“Confirming a genetic diagnosis for certain conditions is crucial, especially for a disease like SMA,” says Lenika De Simone, a genetic counselor at the Ann & Robert H. Lurie Children's Hospital of Chicago. “Treatments targeting the gene that causes this disease have dramatically changed the prognosis for many of these patients. And even when there is not yet a treatment available, genetic testing can help family members understand their risk of carrying the gene and passing it on to their children.”
Sometimes genetic detective work can identify the underlying cause of a puzzling disorder and point to a novel treatment. “I had a patient with a progressive ataxic disorder, which is associated with balance and coordination problems, who was losing her ability to walk,” says Brent Fogel, MD, PhD, FAAN, director of the UCLA Clinical Neurogenomics Research Center. Genetic testing revealed that the patient had a condition called riboflavin transport deficiency, associated with mutations in the gene SLC52A2. “Knowing this allowed us to treat her with supplemental riboflavin and essentially cure her. But that kind of outcome is rare.
“I often get referrals for people who have a family history of Alzheimer's or Parkinson's who want to know if they need to worry because a family member had the disease,” says Dr. Fogel. “In most cases, genetic testing in these situations is not appropriate. These diseases do have a genetic basis, but our tools are designed to pinpoint a single causative gene, and often this genetic risk is due to an accumulation of changes in many genes, so there wouldn't be any useful information we could provide from our typical testing.”
For some patients, testing can provide answers. For example, some forms of Alzheimer's and Parkinson's result from causative genetic variants. A mutation in the PRKN gene contributes to young-onset Parkinson's (diagnosed before age 50), and other single-gene mutations are associated with early-onset forms of Alzheimer's (diagnosed before age 65). For people whose parents or grandparents developed early-onset Alzheimer's or Parkinson's disease, testing might identify a causative gene.
Ongoing research is revealing more about other genetic risk factors associated with later-onset forms of these conditions as well. Scientists have linked between 5 and 10 percent of Parkinson's cases to mutations in one of two genes: LRRK2 and GBA. Although no treatments exist for these mutations, clinical trials are underway to study potential therapies that target them.
Some genetic variants related to Parkinson's disease have other medical implications. “Most GBA mutations are also associated with Gaucher disease, a rare inherited metabolic disease,” Cook says. People with Gaucher disease are missing an enzyme that breaks down fatty substances known as lipids, which build up in organs like the liver and spleen, causing symptoms such as anemia, bruising, and bone problems. There are several different forms of Gaucher; the most severe, Gaucher type 2, occurs in infants and children and is usually fatal within the first two years of life.
Polygenic genetic risk scores (those that examine multiple minor genetic risk variants) are being studied for neurologic diseases such as Parkinson's and Alzheimer's, says Dr. Fogel, but they are not ready for widespread clinical use yet.
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