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Fragile X syndrome: awareness coming of age.

Although it is autism that continues to grab the lion's share of the headlines, fragile X syndrome remains the most common cause of inherited cognitive deficit. It has an estimated incidence of 1 in 4,000 males and 1 in 6,000-8,000 females. Prevalence estimates have more than doubled since the 1980s, when they were at 1 in 1,500 males and 1 in 3,000 females, largely because of a switch from clinic-based estimates to more accurate population-based estimates.

Still, it is believed that the prevalence of fragile X may be even greater than currently thought, as many children with a milder phenotype often go undiagnosed. It is not uncommon to have a child who was previously identified as having a learning disability be diagnosed with fragile X at 7 or even 10 years of age.

The way in which fragile X is defined also has changed over the years, with the emphasis moving away from clinical signs and symptoms alone to an approach similar to that used for Down syndrome. Just as Down syndrome is diagnosed in any child with three copies of chromosome 21, fragile X is now being defined based on the specific genetic abnormality.

Fragile X syndrome is associated with a large expansion of a variable region--the CGG trinucleotide repeat within the 5' untranslated region--of the fragile X mental retardation--1 (FMR1) gene located on the X chromosome. Based on the number of repeats and their methylation status, alleles are classified as normal (5-44 repeats); intermediate or gray zone (45-54 repeats); premutation (55-200 repeats); or full mutation (more than 200 CGG repeats). The specific cutoff points change slightly depending on the population data. However, full mutation-size expansions are regularly associated with hypermethylation of the gene, which leads to its gene silencing and absence of the fragile X mental retardation protein (FMRP). An individual with fragile X syndrome is defined as a male or female who has the FMR1 full mutation, regardless of his or her clinical manifestations.

Although FMRP is absent or significantly reduced in males with the characteristic severe cognitive and behavioral manifestations of the syndrome, FMRP deficiency by itself doesn't explain the phenotypical variability of the disorder. A growing body of research has led to the "mGluR theory of fragile X mental retardation," which suggests that unchecked signaling by group 1 metabotropic glutamate receptors (mGluRs) contributes to the many central nervous system symptoms of fragile X (Trends Neurosci. 2004; 27;370-7).

A recent pivotal study showed that mGluR5--the major group 1 mGluR in the forebrain--contributes significantly to the pathogenesis of fragile X (Neuron 2007;56:955-62). These investigators demonstrated that by reducing mGluR5 protein expression by 50% in a mouse model of the disease, it was possible to bring all but one fragile X phenotype (macro-orchidism) significantly closer to normal. This suggests the exciting possibility that mGluR5 antagonists could be used in treating fragile X syndrome.

Fragile X is characterized physically by joint laxity and dysmorphia (mainly an elongated face, large or protruding ears, and predominant forehead and chin). These features may not be that obvious when the child is very young, and may become more noticeable at age 3 years or even later. The misperception still exists that the presence of these features can be used exclusively as the basis of a fragile X diagnosis, when in fact one needs a constellation of physical and neurologic symptoms, and--ultimately--the genetic demonstration of full mutation.

Hand-flapping and avoidance of eye contact are very characteristic and lead to the so-called "fragile X handshake," in which the body gets in close physical proximity, while the head and gaze are turned away. Once patients with fragile X become accustomed to a situation, which can occur in minutes or hours, this improves. But initially, the behavior is hard wired and has been misinterpreted as autism. Patients with fragile X also have extreme shyness, so the first contacts with these patients tend to be difficult.

In general, the severity of the fragile X phenotype is greater in males. Three neurologic symptoms are very common in boys: They have some intellectual delay or impairment, ranging from being at the low end of the normal IQ range to severe retardation; they have language delays, particularly in expressive rather than receptive language; and they have delays in nonverbal skills, including visual-spatial skills, visual memory, and mathematical computation or comprehension. Poor motor coordination and low muscle tone in children with fragile X can lead to problems in intonation and articulation, resulting in fast, high-pitched speech. Because they have limited output to begin with and what they do verbalize is hard to understand, this inability to express themselves can be frustrating for them, and can lead to bursts of aggression in younger or more impaired children.

Although females typically experience symptoms to a lesser degree than do males because of their second X (normal) chromosome, severe symptoms can occur in them as well. Approximately 20%-25% of girls will have decreased cognition, including moderate to severe retardation. What is more common in girls is anxiety, which can have a tremendous impact in adolescence. It's rare to see any girl with fragile X and autism.

Fragile X is the most common known cause of autism or autismlike behaviors. Approximately 4%-6% of children with autism have fragile X, with 20%-25% of boys with fragile X having autism alone and another 20% meeting the diagnostic criteria for autism spectrum disorders. It is important to determine if a child with fragile X has autism, because it will determine the type of intervention you are going to plan. For both groups, early interventions should be intensive and will usually focus on cognition, but after that, the treatment plans will diverge.

Fragile X is typically diagnosed by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion, polymerase chain reaction, and Southern blot analysis. Because both males and females can have a fragile X mutation, genetic testing is sometimes offered to other family members and siblings when a diagnosis has been made. I emphasize to parents that there are pros and cons to all genetic testing, but that there appear to be more benefits in the case of fragile X. Testing remains controversial in boys with premutation (carrier status) and no neurologic or physical problems, and in girls with full mutation who have such a mild phenotype that it isn't visible unless you test.

One of the issues that have changed the thinking about genetic testing is the recent discovery of fragile X-associated tremor ataxia syndrome (FXTAS) in individuals with premutation. FXTAS predominantly affects males, but is present in 5%-10% of females. It is characterized by progressive balance, gait, and cognitive problems, as well as tremor that occurs during activity but not at rest. Initial symptoms may be misdiagnosed as Parkinson's disease. Therefore, although there is no treatment for FXTAS, patients with premutation who undergo genetic testing may benefit by avoiding Parkinson's disease treatment, which is not trivial or without serious side effects. Identification of FXTAS also has raised awareness of the possible association of premutation with cognitive and behavioral problems, as there are many cases with intellectual disability and/or autism.

Much has changed over the years regarding our understanding of fragile X syndrome. The National Fragile X Foundation ( is a helpful resource for patients with fragile X, and for their families and the professionals who manage their care.

The American Academy of Pediatrics ( also is expected to publish its updated guidelines for the management of fragile X syndrome, written by members of the Fragile X Clinics Consortium, sometime later this year.

An international leader in the fields of research, treatment, and education for disorders and injuries of brain and spinal cord, Kennedy Krieger Institute provides a wide range of services to over 13,000 children each year with developmental concerns mild to severe, For more information, visit


DR. KAUFMANN is director of the Fragile X Syndrome Research Program and Clinic at the Kennedy Krieger Institute, Baltimore, as well as the Center for Genetic Disorders of Cognition and Behavior.
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Title Annotation:Special Needs: Realizing Potential
Author:Kaufmann, Walter
Publication:Pediatric News
Date:May 1, 2008
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