Current FXTAS Diagnostic Criteria Show Low Accuracy, Study Finds

Given the genetic variability behind the disease, current clinical diagnostic criteria for fragile X-linked tremor/ataxia syndrome do not accurately detect late-onset ataxia (abnormal, uncoordinated movements), a study suggests.

The research, “Low Diagnostic Accuracy of Fragile X Tremor/Ataxia Syndrome Diagnostic Criteria in Late Onset Ataxia” was published as a letter in Movement Disorders. A letter is a short report of original research that is of interest to investigators in other fields.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease characterized by progressive tremor, ataxia, and cognitive deficits.

It affects people (mainly men) who carry the fragile X premutation, meaning those who have 55 to 199 CGG repeats in the fragile X gene FMR1. When people have over 200 CGG, they develop fragile X syndrome.

Diagnosis is based on magnetic resonance imaging (MRI) evidence of cerebral white matter lesions and presence of one of two major clinical symptoms — intentional tremor and gait ataxia. But, researchers noted, “reliability usually is low.”

Investigators from the National Institute of Neurology and Neurosurgery in Mexico set out to determine FXTAS clinical diagnostic criteria accuracy in diagnosing late-onset ataxia.

A total of 106 Mexican Mestizo patients (54 women, 52 men) with late-onset ataxia (manifested after age 30) were examined by a movement disorder expert and a geneticist.

Previous molecular and clinical testing ruled out Parkinson’s disease and common causes of hereditary ataxia, such as spinocerebellar ataxia 2, 3, 7, 10, and 17, and Friedreich’s ataxia.

Thirty percent of participants exhibited parkinsonism, 21% had intentional tremor and 14% presented with mild cognitive impairment.

Subjects were grouped based on current clinical and MRI criteria: those in need of FXTAS molecular screening (possible, probable and definitive diagnosis of FXTAS) and those who would not need further testing (do not meet criteria for definitive, probable, or possible case).

In a laboratory setting, scientists can make many copies of a specific DNA region (called target DNA) by using a technique known as polymerase chain reaction (PCR). In PCR, the target DNA is mixed up with specific enzymes, small DNA plus other organic molecules and submitted to a series of cycled temperature changes that will allow many copies of the target region to be produced. After that, the amplified portion of DNA can be quantified (i.e. DNA sequence length can be determined) or used for other purposes.

Researchers analyzed 160 variant forms (alleles) of the FMR1 gene using PCR. Results revealed that around 10% of participants (11 of 106 patients; six women and five men) had a FMR1 expansion that ranged from 48 to over 200 CGG.

DNA methylation happens when a methyl group (chemical group containing one carbon and three hydrogen atoms) is added to a DNA molecule, which modifies gene function and affects gene expression.

Methylation levels were higher in female patients. Results suggest FXTAS manifests differently because of variable length of CGG repeats and methylation levels, specifically in women.

Current diagnostic criteria had a 36% chance of accurately detecting disease (sensitivity) and a 43% chance of properly detecting all negative cases of disease (specificity).

Among those who had a positive criteria-based diagnosis, the probability of disease was 7%, while in subjects considered not to have FXTAS the probability of being disease-free was 85%.

Of the 11 molecularly confirmed FXTAS cases, one had definite, four had probable, two had possible and four had an unlikely criteria-based diagnosis.

The final clinical diagnosis was: 1% of all individuals had a definite diagnosis of FXTAS, 23% were probable FXTAS (one major radiological sign plus one minor clinical symptom or two major clinical symptoms), 34% had possible disease (one major clinical plus one minor radiological sign) and 42% did not meet any of the diagnostic criteria. In all, the use of criteria as a diagnostic test showed a sensitivity of 36%, as specificity of 43% and a diagnostic accuracy of 42%.

FXTAS appears to comprise an array of variable genetic, and subsequently physical, expression that is influenced by sex. Therefore, it should be defined as such, instead of a clinical entity that fits within limited criteria.

“[I]n our sample, the current clinical criteria would likely lead to underdiagnoses in late-onset ataxia patients, and we suggest conducting further studies to properly define the spectrum of FXTAS to improve the suspicion index in general practice, which would lead to timely diagnosis, and developing interventions such as proper genetic counseling,” researchers concluded.