Testing and Diagnosis

FXTAS only occurs in individuals who have a Fragile X (FMR1) premutation. Therefore, it is essential that anyone being considered for this diagnosis is tested for and confirmed as a premutation carrier. This involves DNA testing of the individual's FMR1 (Fragile X) gene. Once the genetic status is confirmed there are diagnostic criteria specific for FXTAS. In other words, being a premutation carrier and having one or two symptoms of FXTAS doesn't mean a person meets the diagnostic criteria for the condition. For example, some individuals may just have a hand tremor and no other symptoms and would not meet the criteria (though they may develop other symptoms at a later time). Below is a description of the testing for FXTAS and a listing of the diagnostic criteria.

Testing

Prior to 1991, a laboratory test (chromosome analysis or karyotyping) could identify people with fragile X syndrome only by looking under a microscope to see if there was a thinning or “fragile” site on the X chromosome. This was not a highly accurate test, especially for male and female carriers, because those with premutations did not have the typical “Fragile X” chromosome as seen under the microscope. Although chromosome analysis (karyotyping) detects many other causes of intellectual disability (such as Down syndrome), it is not an accurate test for fragile X.

Since 1991, an accurate DNA test has been available to determine whether a person has fragile X syndrome or an FMR1 premutation (and is thus a carrier). The test directly examines the FMR1 (Fragile X) gene. FMR1 testing is performed on a blood sample (and can be done on other tissues as well, such as amniotic fluid).

There are two technologies that laboratories use to analyze the FMR1 gene. One, called Southern blot, measures the approximate size of the CGG repeat and will determine the methylation status of the FMR1 gene. (See “Cause” and www.fragileX.org.)

The other technology, PCR (polymerase chain reaction), is more precise for measuring CGG repeat counts that are less than 200, and particularly for determining the exact CGG repeat number in premutations and smaller alleles (gene sizes). PCR should be used in conjunction with Southern blot to test for Fragile X. Occasionally PCR is used alone for carrier screening in individuals in the general population without a family history or clinical indication of Fragile X. However, the most comprehensive testing includes both PCR and Southern blot. The turnaround time for  results is often two to four weeks and costs $300-$500.

CPT and ICD-9 codes for lab testing

When ordering the FMR1 DNA test, if the CPT codes are needed, check with the lab where the test will be performed. However, here is a list of the CPT codes most commonly associated with FMR1 DNA testing:

83891 (1), 83892 (2), 83894 (1), 83896 (1), 83897 (1), 83898 (1), 83912(1)

The numbers in parenthesis must be included- they indicated the number of times that code’s procedure is performed.

Pertinent ICD-9 codes:

Fragile X syndrome :759.83

Testing of male for genetic disease carrier status: V26.34

Testing for genetic disease carrier status of female: V26.31

A new genetic test, called chromosome microarray, or CGH, is now available for individuals with unknown syndromes. This is not accurate for FMR1 and should not be ordered to diagnose fragile X syndrome or to determine FMR1 status.

Diagnosing FXTAS

When evaluating whether an individual has FXTAS, he or she must first be a confirmed premutation carrier. The symptoms of FXTAS are divided into “minor” and “major” clinical and MRI findings. The diagnosis is then categorized into “definite,” “probable” or “possible” FXTAS. The criteria were developed primarily as a reflection of the presenting symptoms in men. As we learn more about FXTAS in females, the diagnostic criteria may become different for females, since they usually have milder symptoms.

Also, there are symptoms of FXTAS that are considered “co-morbid,” which means they often occur in individuals with FXTAS but aren’t used to confirm the diagnosis (just as a sore throat is a symptom of strep throat, but cultures, fever, etc. are also used to make the diagnosis).

Major FXTAS Symptoms

Intention tremor: A tremor of the hand when using utensils, writing instruments, reaching for or pouring something. The tremor is not as apparent at rest.

1. Gait ataxias: Balance problems which may include falling, needed support when walking or going up/down stairs, trouble stepping on/off curbs, generalized instability, or display of a “wide-based” gait.
2. MRI findings specific for FXTAS. These are called “white matter lesions involving middle cerebellar peduncles”, or “MCP” signs
3. MRI findings called “FXTAS inclusions” (which are often diagnosed by FXTAS experts).

Minor FXTAS Symptoms

1. Parkinsonism (resting tremors).
2. Short -term memory problems. This can be difficult to determine since it is natural for short-term memory to deteriorate as we age. However, in FXTAS it can change more rapidly than normal or may be more dramatic, such as forgetting what one ate, said or did shortly after the event.
3. Problems with “executive function” and decision-making. Executive function includes the ability to initiate and complete an activity, to adapt and change behavior as needed, and to anticipate and plan for new tasks and situations. Executive functions allow us to anticipate outcomes, solve problems, and generalize from one situation to the next.
4. MRI findings that are more general than those listed above, referred to as “lesions of cerebral white matter.”
5. MRI findings indicating “moderate to severe generalized brain atrophy.”

Other FXTAS Symptoms (not considered “official” diagnostic criteria)

1. Neuropathy or numbness/tingling of the extremities.
2. Mood instability, irritability, explosive outbursts, personality changes.
3. Cognitive decline—loss of skills including math, reading, etc.
4. Impotence, loss of bladder or bowel functions (called “autonomic functioning” problems).
5. High blood pressure, thyroid disorders, fibromyalgia (more common in females and very common in the general population).

Definite vs. Probable vs. Possible FXTAS

Definite FXTAS:

• Individuals with one “major” clinical symptom (#1 or 2 under “major” symptoms) and one “major” radiological symptom (#3 or 4 under “major” symptoms).
• Any individual with the presence of FXTAS inclusions on an MRI.

Probable FXTAS:

• Individuals with two major clinical symptoms (both #1 and 2 under “major” symptoms).
• Individuals with one “minor” clinical symptom (#1, 2 or 3 under “minor symptoms) and one major radiological symptom (# 3 or 4 under “major” symptoms).

Possible FXTAS

• Individuals with one major clinical symptom (#1 or 2 under “major” symptoms) and one minor radiological symptom (#4 or 5 under “minor” symptoms).

Any individual who may be a Fragile X carrier (with or without a family history of Fragile X) or who has symptoms in any of these three categories should be seen by a neurologist, movement disorders specialist or psychiatrist familiar with FXTAS or the other Fragile X conditions.

Contributed by: Liane Abrams, MS, CGC