In 1943, Julia Bell and James Martin first described the sex-linked heritable condition now termed Fragile X Syndrome (FXS). In their paper, “A Pedigree of Mental Deficit Showing Sex-Linkage”, they described a single kindred in which eleven males spanning two generations exhibited mental deficiency. After detailed investigation, the researchers concluded that the condition was heritable, sex-linked, and involved abnormal brain development. Since their initial description, much has been learned about Fragile X Syndrome, and yet the odyssey to lessen its impact on affected individuals and their families as well as future generations remains challenging.
Fragile X Syndrome is considered the most common cause of inherited intellectual disability. Although disease estimates are probably not precise for a number of reasons, the incidence among males is considered 1/4000 and among females 1/8000. In the 1990’s, the molecular basis for the disease was identified and found to lie within the FMR1 (Fragile X Mental Retardation 1) gene on the long arm of the X chromosome. Since that time, a whole new class of molecular disease has been characterized based on the presence of unstable and abnormal expansions of DNA triplets (trinucleotides). The normal FMR1 gene has CGG (cytosine-guanine-guanine) trinucleotide repeats in the range of 7-54 in the 5’ untranslated region. The gene codes for FMRP (Fragile X mental retardation protein) which is responsible for the regulation of a number of cellular processes, not the least important of which is the development of brain synapses and the relaying of nerve impulses. In FXS, the CGG repeat expands to over 200. It is this abnormally expanded and hypermethylated CGG segment that turns off (silences) the FMR1 gene and halts the production of FMRP. The loss or shortage (deficiency) of FMRP disrupts nervous system functions and leads to the signs and symptoms of FXS. Identifying trinucleotide repeats as the basis for disease has brought about a greater understanding not only of FXS but also a complex set of neurological diseases, such as Huntington’s Disease, the spinocerebellar ataxias, and myotonic dystrophy.
Since the FMR1 gene is located on the X chromosome and expansions of the CGG repeat can include greater than the normal but less than the over 200 with the full mutation, a number of different phenotypes are described based on the affected sex and the number of CGG repeats. In males, the mutation (> 200 trinucleotide repeats) often results in the full spectrum of FXS signs/symptoms, including intellectual disability, speech/language and developmental delay, facial characteristics ( long face, large ears, broad forehead, joint laxity, macroorchidism) which become more apparent with age, and behavioral disorders (social anxiety, ADHD, autism). In females with the full mutation, the symptoms are often less frequent and severe most probably due to females having two X chromosomes (as opposed to males having a single X chromosome) and skewing of X inactivation among females.
The males and females with lesser repeats of the CGG segment (55-200) but greater than normal are said to have an FMR1 gene premutation primarily because expansion to the full mutation can occur in succeeding generations (genetic anticipation). Individuals with the premutation typically are intellectually normal. However, they may have lower than normal amounts of FMRP and consequently exhibit milder versions of the physical features and emotional problems seen with the full mutation. On the other hand, two related disorders due to the premutation of the FMR1 gene are FXTAS (Fragile X-associated Tremor/Ataxia syndrome), a Parkinsonian-like syndrome occurring mostly in older males, and POI (Premature Ovarian Insufficiency) in females.
It is apparent that the spectrum of symptoms in individuals with the full mutation and with the premutation is extremely broad. In addition, the behavioral and developmental symptoms have significant overlay with autism and may be compounded by other neurologic disorders such as seizures. These features make the clinical diagnosis of FXS difficult and often time-consuming. Fortunately, Fragile X Syndrome can be diagnosed with the blood FMR1 DNA test using Southern Blot analysis or Polymerase Chain Reaction (PCR). Clearly, it is imperative that any child who presents with global developmental delay, autism, and/or intellectual disability be tested for FXS with the FMR1 gene test.
Despite advances in the molecular understanding of FXS and its pathophysiology, treatment remains for the most part symptomatic and includes special education, behavioral therapy, and medication specific for ADHD, seizures, and neuropsychiatric problems. Molecules aimed at targets in pathways that are dysregulated in the absence of FMRP continue to be developed and tested in order to offer effective drug therapies, but thus far overwhelming satisfaction has not been achieved. In the future, it is intriguing to envision the role of genome editing and CRISPR technology in the cure of this single gene disorder.