Increased Fragile X Awareness Can Allay Delayed Diagnosis, Small Study Suggests

The majority of Iranian patients with fragile X syndrome (FXS) may have a delayed diagnosis, a small study suggests. These results highlight the need to increase awareness among health professionals and the general population.

The small report, “Complications in Diagnosis of Susceptible Cases of Fragile X Syndrome,” was published in the Iranian Journal of Public Health.

Intellectual disability, characterized by impaired intellectual function and adaptive behavior before age 18, is estimated to affect 1-3% of the worldwide population. Fragile X syndrome is the most commonly known single-gene cause of inherited intellectual disability and autism spectrum disorders.

Fragile X syndrome is linked to an expansion of three nucleotides — CGG — in the FMR1 gene. Nucleotides are the building blocks of DNA. While a normal gene has about 30 CGG repeats, in fragile X patients, there can be more than 200.

The more repeats, the higher the risk of developing the disease. Also, some people carrying so-called pre-mutations, consisting of 55 to 200 CGG repeats in the FMR1 gene, develop fragile X-associated tremor/ataxia syndrome (FXTAS) or fragile X-associated primary ovarian insufficiency (FXPOI).

Researchers evaluated the prevalence and features of fragile X in children with intellectual disability and a possible diagnosis of fragile X at a genetic center in Mashhad, Iran, over a four-year period.

The study included 20 children (two girls and 18 boys) with a mean age of 10 years, and no history of diagnosed fragile X or other psychiatric disorders in the family.

Genetic tests were performed to assess the number of CGG repeats in the FMR1 gene or fragile X-associated abnormalities in chromosomes — rod-like structures within our cells that contain most of our DNA.

The team found that four children carried the full mutation in the FMR1 gene, and three children showed chromosomal abnormalities consistent with fragile X. Among these seven patients, four also had non-genetic features of the disease, suggestive of fragile X syndrome.

Among the 13 children who had a normal number of CGG repeats, two also showed features of fragile X. These patients may have a less common type of fragile X-causative mutations independent of CGG repeats, which have been previously reported.

In total, six children (30%) with a mean age of 11 had features of fragile X. Five of them had a history of intellectual disease other than fragile X in the family, but no association between these factors was found.

According to the researchers, the high rate of unexplained intellectual disability found in this study (70%) might be due to the cost of appropriate genetic tests, which might not be affordable for families in that region.

Also, while a fragile X diagnosis is reported to be established around two years of age (one year after the first symptoms), these children were referred to genetic testing at a mean age of 11, reflecting a delayed search for diagnosis.

“Re-educating medical professionals or using computer programs for recognition of genetic syndromes seems useful in reducing delayed diagnosis,” researchers wrote.