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Fragile X Syndrome Test Found Reliable

Valeo, Tom

doi: 10.1097/01.NT.0000427247.66648.9a

A newborn screening test for the genetic defect that causes fragile X syndrome has been shown to be inexpensive and reliable, but ethical challenges may limit widespread adoption, according to the authors of a paper published in the Dec. 21, 2012, online edition of Genome Medicine.

The new screening test was performed on 14,207 newborns at three hospitals in the US. Using blood spots obtained from routine heel pricks, the test was able to detect CGG repeats in the fragile X mental retardation 1 gene (FMR1). Normal babies contain 4-44 CGG repeats. The test reliably identifies babies with fragile X syndrome, who have 200 or more CGG repeats, as well as carriers of premutations containing 55-200 CGG repeats, which have been linked to a variety of problems in children and adults. Carriers of 45-54 CGG repeats are considered to be in the “gray zone,” which means the expansion may get larger as it is passed on to subsequent generations.

The study, which was funded in part by the NIH National Institute of Child Health & Development, found the prevalence of premutations to be slightly higher than previously estimated among certain racial and ethnic groups, and twice as high among males. A 2002 study of 10,572 males found a premutation rate of 1:813 males, while this study found 1:430 males — similar to a 2012 study of older adults in Wisconsin, that found premutations in 1:468 males.

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While identifying the presence of fragile X syndrome immediately after birth has distinct advantages, the knowledge that the parents and their blood relatives carry premutations can be a source of anxiety, according to lead author Flora Tassone, PhD, a professor in the department of biochemistry and molecular medicine at the MIND Institute of the University of California, Davis, in Sacramento.

“I don't think there is any argument about identifying people with the full mutation for fragile X,” she said. “The problem arises when you identify carriers of a premutation.”

After the age of 50, some individuals with a CGG expanded allele develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder that causes balance problems, hand tremor, and other parkinsonian-like symptoms, as well as memory problems, mood instability, and cognitive decline. Adult female carriers may develop fragile X-associated primary ovarian insufficiency, which produces symptoms of menopause, and signals an increased risk of giving birth to a baby with a fragile X syndrome.

CGG expansions in the FMR1 gene have also been linked to such diverse problems as learning and emotional difficulties, social anxiety, attention deficit-hyperactivity disorder, and sleep apnea.

So a baby born with CGG expansions, while free of the intellectual disabilities caused by fragile X syndrome, may still face problems years later.

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“There are a lot of ethical issues to be sorted out,” Dr. Tassone said. “When you screen for this expansion in the FMR1 gene, you are also identifying carriers of a mutation that might lead to a neurodegenerative disorder when they're 50.”

Don Bailey, PhD, one of the co-authors of the paper, has studied the ethical implications of newborn screening for fragile X, and agrees that the clear benefits of early detection are offset somewhat by the anxiety that the results can arouse.

“Late diagnosis means the children get into intervention programs late,” said Dr. Bailey, a Distinguished Fellow with RTI International, a non-profit research institute affiliated with three North Carolina universities.

Also, since fragile X syndrome is diagnosed, on average, at about 36 months of age, parents often have a second child who is at risk for the disorder.

“We've found about 30 percent of parents have at least two children with fragile X,” said Dr. Bailey, who directs the North Carolina Fragile X Newborn Screening Study at University of North Carolina Hospitals.

However, screening all newborns, already mandatory in almost every state for cystic fibrosis, sickle cell anemia, and other conditions, is not justified for fragile X under existing guidelines, he added.

“Newborn screening is considered ethical for problems that threaten irreparable damage or death, which could be avoided by an available treatment,” Dr. Bailey said. “Fragile X syndrome doesn't meet those criteria. We have evidence that early intervention helps children with disabilities caused by fragile X, and we have emerging data on fragile X-specific treatment, but that's a ways away.”

As a result, parents must provide informed consent for fragile X screening, and they should receive help if their child proves to have a premutation, but such services barely exist.

To provide informed consent, “parents must understand that they might learn they have a child who doesn't currently have a condition, but is a carrier for a condition that might emerge in 30 or 40 years,” Dr. Bailey said. “So there must be parent education, and also follow-up counseling. There needs to be an infrastructure to provide counseling and follow-up for families, and the infrastructure to support the families of the large number of carrier babies that would be identified just isn't there.”

Currently, when asked for informed consent about 30-40 percent of parents say no to screening, according to Dr. Bailey. “Some say they can't decide; some say they don't want to know carrier status so they can have a normal bonding period with child,” Dr. Bailey said. “When you have that many parents who say they don't want this, it suggests it shouldn't be a mandatory screening.”

So he has come to the conclusion that despite the advantages, “fragile X screening should be a choice, not a mandate. I started out being a passionate advocate for early identification and newborn screening, and I still am, but I've become more cautious about when and how we push this.”

Dr. Bailey recently was appointed to the Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children, which recommends criteria for newborn screening, and fragile X does not qualify under existing guidelines, but genome screening may soon make that irrelevant.

“If newborn screening labs move toward whole-genome and exome sequencing as the technique for detecting most disorders, then it will start picking up things like fragile X syndrome and fragile X carrier status,” Dr. Bailey said. “When that happens that will change newborn screening as we know it.”

Even though knowledge of carrier status may arouse anxiety in parents, identifying such children may have benefits if they start to show problems associated with their CGG expansion, according to co-author Randi J. Hagerman, MD, medical director of the MIND Institute and endowed chair in fragile X Research at the University of California Davis Health System.

Such children may have developmental problems such as speech and motor delays, or emotional problems such as shyness and social anxiety, that can be addressed with therapy, according to Dr. Hagerman. “Thinking early on about stress reduction techniques can be helpful in childhood,” she said.

Also, treatments to counteract the effects of a CGG expansion are also emerging.

“Medications such as minocycline might help,” Dr. Hagerman said. “If you are an upper end premutation carrier you're likely to have lower levels of fragile X protein (FMRP). When you get lower levels of FMRP there's dysregulation of many different systems. For example, the MMP9 (matrix metalloproteinase 9) levels go way up, and minocycline can bring those levels down to normal.”

In addition, widespread newborn screening would help to determine the prevalence of CGG expansions, and expand the understanding of specific problems in childhood and in aging individuals that are linked to the premutation.

“Disorders you find in a family tree, such as emotional issues, hypertension, neurological issues such as neuropathy, or autoimmune problems such as hypothyroidism or fibromyalgia, appear to be linked to this premutation, and it is important to receive early intervention,” Dr. Hagerman said. “I think these are important and common problems in the general population, and the premutation can predispose individuals to these difficulties.”

The prospect of widespread screening for fragile X syndrome and CGG expansions is exciting for geneticists, according to David L. Nelson, PhD, Cullen Foundation professor in the department of molecular and human genetics at Baylor College of Medicine, who was not involved with the study.

“I think the field has needed this sort of study to understand the prevalence of all the allele classes of FMR1,” he said.

However, without effective treatments for the problems caused by the mutations, such screening may arouse anxiety in people while leaving them with few options.

“Without a demonstrated effective treatment for each phenotype, it's hard to see real clinical applications for the individual patient ascertained at birth beyond the academic interest,” Dr. Nelson said. “But for other members of families, screening can have profound implications.”

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• Tassone F, Long KP, Hagerman RJ, et al. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med 2012;4(12):100; E-pub 2012 Dec. 21.
    • Seltzer MM, Baker MW, Mandel D, et al. Prevalence of CGG expansions of the FMR1 gene in a US population-based sample. Am J Med Genet B Neuropsychiatr Genet 2012;159:589–597.
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