Hair Follicles a Potential Biomarker for Fragile X

Samplings that measure FMRP protein levels can be taken at home

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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A pilot study in the U.S. shows that repeated sampling of hair follicles in people with fragile X syndrome, collected both at home and clinics, can be used to measure the levels of FMRP protein — whose production is impaired in fragile X patients.

In addition, measuring FMRP levels using hair follicle, blood, or buccal swab collection samples did not show any notable difference when performed at home versus at a clinic.

Apart from the protein, the levels of FMR1 messenger RNA (mRNA) — the template used for FMRP protein production and which is based on the genetic code of the FMR1 gene — also can be measured in hair follicle samples.

“Findings demonstrated that repeated sampling of hair follicles in individuals with [fragile X], in both, home, and office settings, is feasible, repeatable, and can be used for measurement of FMR1 mRNA and FMRP,” the researchers wrote.

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The study, “The feasibility and utility of hair follicle sampling to measure FMRP and FMR1 mRNA in children with or without fragile X syndrome: a pilot study,” was published in the Journal of Neurodevelopmental Disorders.

Fragile X is caused by mutations in the FMR1 gene, which is located in chromosome X, one of the sex chromosomes. The FMR1 gene is transcribed into a mRNA molecule that is used as a template for the production of the FMRP protein.

This protein regulates the production of other proteins involved in nerve cell communication. As such, mutations in FMR1 gene affect FMRP protein production, leading to the cognitive, developmental, and behavioral symptoms characteristic of fragile X.

Since men have only one X chromosome (which they receive from their mother), those who inherit the mutated gene have more severe disease. For women, having two X chromosomes (one from each parent) means the healthy gene copy can compensate for the mutated one.

An innovative therapeutic approach being explored for fragile X is to reactivate the FMR1 gene and restore the production of FMRP protein, a type of disease-modifying approach. However, tools to assess FMR1 reactivation are needed to enable the testing of such potential therapies.

“For this, it is key to determine the feasibility of repeated collection of tissues or fluids to measure FMR1 mRNA and FMRP,” the researchers wrote.

The team, composed of researchers at the University of Massachusetts Medical School and Fulcrum Therapeutics, investigated if the repeated collection of hair follicles in fragile X patients is a feasible tool to quantify the FMRP and FMR1 mRNA levels. They compared the results to healthy participants and other sample biomarkers, namely blood samples and buccal swabs.

Home vs. clinic

They also analyzed whether the mRNA and protein levels for the three methods differed when obtained at home versus at a clinic.

In addition, the team wanted to know which methods used to assess FMR1 mRNA and FMRP levels were better at reflecting one’s cognitive function and behavior. For that, researchers used different tests to analyze patients’ characteristics, including oral expression and social communication.

The study was single-center and included 15 participants, ages 3 to 22 years. Ten were fragile X patients (mean age of 7 years) and five were healthy people (mean age of 8.2 years). The patient group was comprised of six boys and four girls, and the control group two boys and three girls.

Hair follicles were collected from all participants, at home and at clinic locations.

Results showed that repeated sampling of scalp follicles by plucking was a viable collection method in fragile X patients. In detail, a mean of 4.7 follicles per patient was obtained at the clinic visit, and 6.1 at home. These numbers were similar to the healthy participants (5.2 at the clinic and 4.8 at home).

FMRP protein levels were found to be considerably higher in healthy participants than in fragile X patients. Within this group, the boys had the lowest levels compared to girls. A similar result was observed for FMR1 mRNA levels.

“Hair follicle mean FMR1 mRNA levels were lower in [fragile X] participants compared to healthy participants,” the researchers wrote.

Measuring these levels across hair follicles, blood samples, and buccal swabs did not show any considerable variation, neither did the collection location (at home versus the clinic).

Furthermore, FMRP and FMR1 mRNA levels in blood samples were strongly associated with cognitive and behavioral measures for the fragile X patients. This correlation in blood samples was of greater magnitude than for hair follicles or buccal swabs.

Blood is better

“This data suggests that measurements in blood better reflect the clinical [features] than measurements in buccal swabs or hair follicles,” the researchers wrote.

Overall, the team concluded that “the current study provides support for the use of repeated hair follicle sampling in future clinical therapeutic studies as an effective biomarker of FMRP and FMR1 mRNA levels and highlights the need to improve the feasibility of repeated collection of blood in these individuals.”

The researchers also noted that the data shows the potential of these biomarkers “in the context of future therapeutic clinical trials that seek to reactivate FMR1 mRNA/FMRP.”

According to them, the next step is to replicate these findings in a larger sample size.