Physicians need to consider the possibility of fragile X mutations in patients of all ages and not just reserve testing for children with neurodevelopmental delays, according to two fragile X experts at the University of California-Davis.
In an editorial in the Nov. 26 issue of the Journal of the American Medical Association, Randi J. Hagerman, MD, a professor of pediatrics who serves as medical director of the MIND Institute at UC Davis, and Paul Hagerman, MD, PhD, her husband and professor of biochemistry and molecular biology, make the case for more widespread testing for fragile X throughout the lifespan.
In an interview with Neurology Today, Dr. Randi J. Hagerman said that “physicians from all different subspecialties need to be aware of the very broad range of involvement that can come from the fragile X mutation.”
While most physicians are familiar with fragile X syndrome, the most common heritable form of mental retardation, she said, they may be less aware that the mutations can cause autism, attention deficit disorder, and learning disabilities, anxiety disorders at all ages, early menopause, and tremor, ataxia, and dementia in older persons.
What looks like a more routine attention problem or learning difficulty might in fact be related to fragile X, and so, too, might symptoms assumed to be Parkinson disease or Alzheimer disease, according to Dr. Hagerman. The genetic abnormality can be passed from one generation to the next, with families unaware that there is a common explanation for seemingly unrelated conditions affecting various relatives. Often it's only when a child is diagnosed with fragile X syndrome that other family members get a correct diagnosis.
“Individuals can go undiagnosed for so long in the general population,” Dr. Hagerman said. “The goal is to have early identification and early intervention and treatment to help decrease the problems associated with this gene.”
Fragile X syndrome is caused by a mutation of the FMR1 gene on the X chromosome. Normally, there are fewer than 40 repeats of the CGG sequence in the FMR1 gene, but with fragile X syndrome there are 200 or more repeats.
“The gene is generally silenced, resulting in the absence of a protein (FMRP) important for synaptic function,” the Hagermans wrote. Thirty percent of boys with fragile X syndrome meet the diagnostic criteria for autism. Girls also can exhibit autistic-like characteristics; shyness, math disability, and social anxiety are also common.
FRAGILE X PREMUTATIONS
But people can also be affected by a premutation of the FMR1 gene — involving 55–200 CGG repeats — which leads to increased expression of RNA and toxicity. Children with premutations can have developmental and learning problems, though the symptoms might be more subtle. The premutation can cause premature ovarian failure in women, and a neurodegenerative condition known as FXTAS, or fragile X-associated tremor-ataxia syndrome in older people of either sex, though it's more common in men.
Because FXTAS was only identified as a disorder in 2001, physicians may not have it and other fragile X-related problems on their radar screen, Dr. Hagerman said. OB/GYNs, for instance, might not suspect fragile X when they see a patient who is having trouble conceiving. It is estimated that anywhere from 1 in 130 to 1 in 250 women and 1 in 250 to 1 in 800 men have a premutation of the FMR1 gene.
“It is time to seriously consider routine testing for fragile X in some patient groups, particularly in children with intellectual and developmental disabilities, developmental delays or autistic behaviors, adult women with features of early menopause, or older adults with gait ataxia, intention tremor, or both It is also important to test those individuals with cognitive deficits or dementia, peripheral neuropathy,. parkinsonism, atypical multiple sclerosis, and anxiety disorders, particularly if there is a family history of intellectual and developmental disability, autistic behavior or both,” Drs. Randi and Paul Hagerman wrote in JAMA.
EARLY IDENTIFICATION USEFUL
Dr. Hagerman said timely diagnosis can lead to better treatment and interventions, and provide valuable information for family planning purposes. When a child is diagnosed with fragile X syndrome, doctors usually recommend testing for other family members. Females who carry the fragile X premutation are at risk for having children with full-blown fragile X syndrome.
Flora Tassone, PhD, a member of the Hagermans' research team, developed a blood spot screening test that can detect both premutations and full mutations, and newborn screening is being tested at four medical centers around the country. She reported the advance last January in the Journal of Molecular Diagnostics. The NIH-funded research will help identify the benefits and drawbacks of newborn screening, Dr. Hagerman said.
Rush University Medical Center in Chicago offers newborn screening in conjunction with UC-Davis, as part of an NIH grant for fragile X centers. Elizabeth Berry-Kravis, MD, PhD, a professor of pediatrics, biochemistry, and neurology at Rush, said that about 60 percent of new parents consent to the screening.
“People are saying yes because they are interested in knowing every possible thing about their child,” and want to get help if necessary as soon as possible, Dr. Berry-Kravis said. She said parents decline the screening test for a variety of reasons, including the feeling that their child is fine and that there are no genetic diseases in their family.
Darryl C. De Vivo, MD, the Sidney Carter Professor of Neurology and Pediatrics and director of the Pediatric Neuromuscular Disease Center at Columbia University Medical Center, said that while he generally favors universal screening, the cost-benefit ratio needs to be considered before it is implemented. Also, he said, the downsides of genetic testing need to be weighed, including the implications of false negative and false positive results and the possibility that health insurers could deny coverage for a “pre-existing condition.”
“The advantages of early diagnosis are intervention in the pre-symptomatic phase, avoiding a second affected birth before the first case is diagnosed and avoiding the expense involved in pursuing other diagnoses,” he said.
Dr. Hagerman said screening can be done for about $5 per baby, and it likely will get cheaper as techniques improve. She and other researchers are especially interested in early identification of fragile X cases because of the possibility that targeted treatments could be developed to halt or reverse the damage brought about by the gene mutation. One promising line of research involves the use of metabotropic glutamate 5 receptor (mGluR5) antagonists that down-regulate the mGluR5 pathway that is overactive in fragile X syndrome.
“These trials, if successful, make the case of newborn screening far more compelling and raise the prospect of future intervention during the developmental period to prevent long-term disability,” the Hagermans concluded.
ARTICLE IN BRIEF
Two experts urge physicians to screen for fragile X across all age groups, especially when there is evidence of autism, attention deficit disorder, learning disabilities, anxiety disorders, early menopause, tremor, ataxia, and dementia in older persons.