Martin, Bell, and the History of Fragile X syndrome

By Nelson Tang

What is the Martin-Bell syndrome or what is more commonly known as Fragile X syndrome? What are the symptoms and signs associated with this disorder? This article will answer such questions and other ones such as how common is Fragile X syndrome or why or how does it occur? It will also take a look at its discovery and what has changed since then about what we know now and the advancements in the field so far. Moreover, it will also discuss the treatments and diagnosis. Lastly, it will talk about who Julia Bell and James Martin were and what were their contributions and connections to Fragile X syndrome.

Fragile X syndrome is a genetic disorder and is a non-Mendelian trinucleotide repeat disorder. Moreover, it is the most widespread cause of intellectual disability that ranges from mild to severe. It is also the most common monogenic cause of autism spectrum disorder and accounts for about half of all X-linked intellectual disability as well being the most common cause of mental impairment after trisomy 21. [5]. The rate of occurrence difference when it comes to males versus females as it is more likely to manifest in one more than the other. In males, it is 1 in 4000 whereas it is 1 in 8000 for females. The name comes from the section of the lower half of the X chromosome appearing to be “fragile.” Specifically, it is the FMRI gene on the X chromosome where mutation occurs and is the most common mechanism of genetic abnormality. Deletion of the FMRI gene is another possibility. [4]. 

Fragile X syndrome affects individuals in different ways and differs from person to person. Mainly, it affects communication and cognitive skills, physical appearance, and sensitivity to things such as light and noise. Data shows that symptoms are midler in females compared to males. Most people with this disorder struggle when it comes to intelligence and learning. It ranges from mild to severe from learning disorders to intellectual or developmental disability. In other words, it affects an individual's ability to think,reason, and learn. When it comes to infants or young children, there are no specific physical characteristics as it appears more with age. Some common characteristics include a narrow face, large head, large ears, flexible joints, flat feet, and a prominent forehead. Most children with this condition struggle with behavioral challenges whether it be behavioral, social, or emotional.

Examples include anxiety when it comes to new or different situations, trouble to maintain attention or eye contact, aggression, or hyperactivity. When it comes to issues with speech and language, it seems that it is more common among boys with Fragile X syndrome. They may struggle with speaking clearly and stutter or leave words out of sentences. Furthermore, they may also fail in understanding social cues, tone, or body language of others. They may also begin talking later in the developmental stage or be nonverbal their entire lives. Lastly, individuals may have a hypersensitivity to certain things such as bright lights, loud noises, or even the way clothing feels on their skin. [3].

When it comes to the diagnosis of Fragile X syndrome, there are several different ways to go about it. A diagnosis can be done as early as infancy if the infant exhibits any signs of developmental delay, intellectual disability or autism. When it comes to the report of the diagnosis, the average age is 36 months or 3 years for boys and 42 months for girls. Another method is genetic testing. A diagnosis of full mutation is when an excess of 200 CGG repeats in the FMR1 gene on the X chromosome alongside abnormal methylation is shown. Although there are multiple genetic tests,there is one that is the most common and effective. This method is targeted mutation analysis and methylation analysis.  In some cases, testing can be done during pregnancy through prenatal testing by looking at the amniotic fluid and cells in the placenta. [4].

When it comes to treatment, it will depend on the symptoms and severity affecting the individual. Therefore, there is no single or specific treatment when it comes to Fragile X syndrome. There are many ways to minimize the condition and help in improving the quality of life. Treatments include specialized education, speech and language therapy, behavioral or physical therapy, and medication. It is best if treatment begins as early as possible as the brain is still developing and the earlier the better. It gives a greater chance at developing a full range of skill and control over them. [3].

Fragile X syndrome was discovered by two people who were Julia Bell and James Purdon Martin in 1943 where it was first documented. [1]. Julia Bell was a geneticist, while James Purdon Martin was a neurologist. In this discovery, they reported a family case study in which intellectual disability appeared to be inherited and linked to the X chromosome. Furthermore, Dr. Herbert Lubs made the observation of a characteristic fragile site on the lower end of the X chromosome in 1969. [4]. In a biography of Bell by Jesse King, she stated that “After interviewing affected individuals and detailing the family's history, Martin and Bell suggested that the condition was sex linked, heritable and caused specific sections of the brain to develop improperly.” [2]. 

In 1991, molecular diagnosis would go on to replace the cytogenetic marker, which is the FMRI gene. A theory would emerge in 2002 to explain the cognitive and intellectual delays associated with Fragile X syndrome known as the “mGluR Theory of FXS.” Other major advancements since the discovery include the development of a new drug called BPN14770. This drug has the potential in promoting the regeneration of impaired neurons in people with Fragile X syndrome. [1]. In other words, it can help in repair and increase cognitive functions. With more allocated funding and research, there is the possibility that intellectual and developmental disabilities could one day be reversed or cured.  

References:

[1]. Asare, Makeda, et al. “An Investigation on the History and Current Research of Fragile X Syndrome.” Digital Scholarship@UNLV, digitalscholarship.unlv.edu/durep_posters/2/#:~:text=Fragile%20X%20was%20first%20documented,showed%20symptoms%20of%20intellectual%20disabilities

[2]. Dumbrepatil, Arti. “Fragile X Syndrome: 80 Years since Its Discovery.” American Society for Biochemistry and Molecular Biology, 21 July 2023, www.asbmb.org/asbmb-today/science/072123/fragile-x-syndrome. 

[3]. “Fragile X Syndrome.” Eunice Kennedy Shriver National Institute of Child Health and Human Development, U.S. Department of Health and Human Services, www.nichd.nih.gov/health/topics/fragilex

[4]. “History and Prevalence of Fragile X Syndrome.” History & Prevalence, findresources.co.uk/the-syndromes/fragile-x/history-prevalence

[5]. Stone, William L. “Fragile X Syndrome.” StatPearls [Internet]., U.S. National Library of Medicine, 28 Oct. 2023, www.ncbi.nlm.nih.gov/books/NBK459243/