Fragile X vs. Down Syndrome

Fragile X syndrome (FXS) and Down syndrome (DS) are two of the most prevalent genetic causes of intellectual disability.¹ Intellectual disability results in impaired cognitive development and daily functioning. Both FXS and DS also share deficits in expressive language ability (skill in verbal and nonverbal communication, such as gesture and facial expression, to convey a message) and increased rates of Autism Spectrum Disorder (ASD), seizure disorders, and other mental health disorders.²

Intellectual disability due to FXS and DS involves similar pathways. Both conditions share disturbances in how the nervous system develops and communicates signals within the brain. Transmission of information with the brain is challenged, resulting in intellectual disability.¹ Despite these similarities, there are significant differences between the two conditions.³

What Is Fragile X Syndrome?

Fragile X syndrome is an inherited genetic disorder caused by the full mutation of the FMR1 gene (Fragile X Messenger Ribonucleoprotein 1) located on the X chromosome, where a DNA segment known as “CGG triplet repeat” is expanded more than 200 times. This DNA segment is normally repeated five to 40 times in unaffected people.⁴ The name Fragile X syndrome stems from the fact that the X chromosome appears broken or fragile under a microscope. The prevalence of Fragile X syndrome has been documented across all major racial and ethnic populations.⁷

FMR1 produces FMRP (Fragile X RNA-binding protein), a protein needed for brain development.⁵ FMRP production is significantly reduced or absent in FXS, causing intellectual disability, learning and behavioral issues, and various physical characteristics.⁶Individuals with an FMR1 premutation (between 55 to 200 repeats) can produce some FMRP and are at an increased risk of developing other Fragile X-associated disorders, such as Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) or Fragile X-associated Primary Ovarian Insufficiency (FXPOI).⁴

Fragile X syndrome affects males and females, although females tend to have milder symptoms. Females experience milder symptoms due to the presence of a second, unaffected X chromosome helps compensate for the effects of the affected chromosome.⁶

Signs and Symptoms of Fragile X Syndrome

Fragile X syndrome is often characterized by moderate to severe intellectual disability in males and more mild to moderate intellectual disability in females. Physical features may include a large head, long face, prominent forehead and chin, protruding ears, flexible joints, flat feet, high arched palate, and large testes in post pubertal males.⁷ Other symptoms can include motor and language delays and behavioral issues such as Attention Deficit Hyperactivity Disorder (ADHD), ASD, poor eye contact, anxiety, increased risk for aggression, and sleep disorders.⁶ Some individuals may also have co-occurring conditions such as frequent ear infections, dental problems, strabismus (crossed eyes), heart problems such as mitral valve prolapse, and seizures.⁷

Diagnosis of Fragile X Syndrome

Fragile X syndrome can be diagnosed through genetic testing. Genetic testing can also help identify premutation in the FMR1 gene that can lead to other Fragile X-associated disorders.⁵ A diagnosis of Fragile X syndrome is crucial as it can help explain a person’s intellectual disabilities and behavioral issues. It also allows family members and friends to learn more about Fragile X syndrome and manage expectations and care so that the person can reach their full potential. Since FXS is a hereditary disease, the results from genetic tests can affect other family members and raise many concerns.⁵ Because of the complexity of FXS and Fragile-X associated disorders, affected families may wish to consult with a genetic counselor or geneticist, their healthcare provider, or a Fragile X clinic to understand the implications of testing results.

What Is Down Syndrome?

Down syndrome is the most common, chromosome-related genetic condition in the U.S., affecting about 6,000 babies born yearly.⁸ It occurs when abnormal cell division leads to an extra chromosome.⁹ Chromosomes are small bundles of genes in the body that determine how a baby’s body forms and functions during and after pregnancy. Generally, a baby is born with 46 chromosomes, 23 from the father and 23 from the mother. Babies with DS have an extra copy of one of these chromosomes, chromosome 21. This extra copy affects how the baby’s brain and body develop, causing various mental and physical challenges. Having an extra chromosome copy is medically known as “trisomy.”⁸ DS, also called Trisomy 21, occurs randomly and cannot be prevented.¹⁰ Unlike FXS, DS is not inherited.³

Signs and Symptoms of Down Syndrome

Individuals with Down syndrome can have a wide range of observable characteristics and different health issues.⁸Some people may need considerable attention and care, while others lead healthy lives.¹⁰

People with DS usually have an Intelligence Quotient (IQ) ranging from mildly-to-moderately low and are slower to speak than children without an intellectual disability. Physical features include flattened facial features, especially the bridge of the nose, almond-shaped eyes that slant up, a short neck, small ears, tiny white spots on the eye’s iris, a tongue that tends to stick out of the mouth, small pinky fingers that sometimes curl toward the thumb, and poor muscle tone or loose joints. Most people with DS also tend to be shorter in height and have small hands and feet and a single line across the palm (palmar crease).⁸

Behavioral characteristics include obsessive-compulsive behavior, attention problems, and stubbornness or tantrums. Some individuals with DS are also at an increased risk of developing certain medical conditions, including gastroesophageal reflux, celiac disease, thyroid problems, seizures, and heart defects. Some also have an increased risk of vision and hearing impairment. A small percentage of children with DS also develop cancer of blood-forming cells (leukemia).¹¹

Diagnosis of Down Syndrome

Two main tests are available to detect DS during pregnancy: screening and diagnostic tests. Prenatal screenings can inform a mother and her physician if her child is at risk for developing DS. These tests do not provide a definitive diagnosis but are relatively safer for the mother and the unborn baby. Diagnostic tests, on the other hand, can identify whether or not a baby will have DS. However, this form of testing can be riskier for the mother and the unborn child. It is important to note that screening and diagnostic tests cannot predict the full impact of DS on a child.8

A karyotype test (chromosome analysis) can help confirm DS diagnosis if a doctor suspects it after a baby is born. It is typically performed on a blood sample, and the chromosomes are grouped by size, number, and appearance to look for any differences.¹⁰

Differences Between Fragile X Syndrome and Down Syndrome

Despite the presence of intellectual disability and increased risk of communication impairment in both conditions, there are important differences in the observable characteristics or traits between individuals with FXS and those with DS.³

FXS tends to have a higher prevalence or severity of behavioral symptoms and impaired social language skills. While both individuals with DS and those with FXS can suffer from language impairments, impairments in structural language skills or the ability to express one’s self in appropriately formed sentences, are more severe in individuals with DS. Difficulties with social communications seem comparable across both syndromes.³

Individuals with FXS, particularly males, generally display a variety of behavioral problems that emerge early in childhood. These include hyperarousal, hyperactivity, increased sensitivity to sensory stimuli, impulsivity, inattention, aggression and self-injury, and ASD-like behaviors. Autistic behaviors present in more than 90% of males with FXS.³

In contrast, individuals with DS are claimed to display fewer behavioral symptoms compared to individuals with other developmental disabilities, including FXS. Nevertheless, some aspects of behavior are impaired in DS compared to the general population. For example, individuals with DS have difficulty controlling impulses and managing frustration in late childhood and adolescence. This frustration may be due to the barriers they face while trying to express themselves or understand others. As these individuals get older, these externalizing behaviors, such as acting out, tend to decline, and internalizing symptoms, such as social withdrawal, depression, and anxiety, are more likely to occur.³

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References

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Susco SG, Ghosh S, Mazzucato P, Angelini G, Beccard A, Barrera V, Berryer MH, Messana A, Lam D, Hazelbaker DZ, Barrett LE. Molecular convergence between Down syndrome and fragile X syndrome identified using human pluripotent stem cell models. Cell Rep. 2022 Sep 6;40(10):111312. https://doi.org/10.1016/j.celrep.2022.111312
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