Explore the causes, symptoms, and support options available for Fragile X Syndrome, a genetic disorder, on Meri Sehat.

Fragile X Syndrome

Online Consultation

Ismail Munir

Overview

Fragile X syndrome is a genetic disorder that causes developmental issues, including learning difficulties, behavioral issues, physical changes, and cognitive impairment. It results from mutations in a gene on the X chromosome. 
&nbsp;

Fragile X syndrome (FXS) is also known as Martin-Bell syndrome or marker X syndrome. It&rsquo;s called fragile X syndrome because a portion of the X chromosome appears &quot;broken&quot; or &quot;fragile&quot; under a microscope. It is the most common chromosomal defect linked with learning impairment after Down syndrome. 
&nbsp;

The root cause of FXS is a mutation in a gene on the X chromosome. This alteration prevents the body from producing a protein required for appropriate brain growth. Hence, the most common presentation of the condition is learning disabilities, behavior issues, and intellectual disabilities. Symptoms are usually more severe in males, especially aggression, as compared to females. Physical characteristics observed in people with Fragile X syndrome can include long and narrow faces , large ears, unusually flexible fingers and a prominent jaw and forehead. 
&nbsp;

Although there is no cure for the condition, a detailed treatment plan with coordination between the child&rsquo;s parents, doctors, teachers, and caregivers can help the individual lead a quality life. 
&nbsp;

Researchers believe that globally, 1 in 8,000-11,000 females and 1 in 4,000-7,000 boys have FXS. 20% of girls and 60% of males with FXS are diagnosed with autism<a href="#accordion">[10]</a>. About 80% of the children who have FXS, also have <a href="https://merisehat.pk/disease/attention-deficit-hyperactivity-disorder-adhd">attention deficit hyperactivity disorder (ADHD)</a><a href="#accordion">[5]</a>. 
&nbsp;

Currently there are no known types of fragile X syndrome. However, there are 2 Fragile X-Associated Disorders: fragile x-associated tremor/ataxia syndrome (FXTAS) and fragile x-associated primary ovarian insufficiency (FXPOI). FXTAS is characterized by shaky hands, balance problems, memory loss, unstable mood, and numbness in the feet and hands, while FXPOI causes infertility, unpredictable or missing menstrual periods, reduced fertility, and premature menopause<a href="#accordion">[1]</a>. 
&nbsp;

Signs and Symptoms

Common symptoms of fragile X syndrome can be categorized into the following: 
&nbsp;

<h5>Intelligence Problems</h5>

<ul>
	<li>Learning disabilities, like having difficulty thinking, reasoning, and learning</li>
	<li>Low intelligence quotient (IQ) that further declines with increasing age</li>
	<li>Delayed developmental milestones, like not walking or talking at the same time as kids their age </li>
	<li>Delayed development of nonverbal communication, like using body language, gestures, and facial expressions.</li>
	<li>Problems with mathematics</li>
	<li>Processing disorder, causing issues like stuttering 
	&nbsp;</li>
</ul>

<h5>Mental Health Issues</h5>

<ul>
	<li><a href="https://merisehat.pk/disease/anxiety">Anxiety</a></li>
	<li><a href="https://merisehat.pk/disease/depression">Depression</a></li>
	<li><a href="https://merisehat.pk/disease/ocd-obsessive-compulsive-disorder">Obsessive-compulsive behavior</a></li>
	<li><a href="https://merisehat.pk/disease/absence-seizures">Seizures</a> 
	&nbsp;</li>
</ul>

<h5>Physical Features</h5>

<ul>
	<li>Large forehead</li>
	<li>Long narrow face</li>
	<li>Large jaw</li>
	<li>Soft skin</li>
	<li>Large ears </li>
	<li>Crossed or lazy eyes</li>
	<li>Flexible or double-jointed fingers</li>
	<li>Flat feet</li>
	<li>Enlarged testicles in males after puberty</li>
	<li>High-arched palate in the roof of the mouth</li>
	<li>Low muscle tone</li>
</ul>

Note: The physical features become more noticeable with age. 
&nbsp;

<h5>Behavioral Issues</h5>

<ul>
	<li>Social anxiety </li>
	<li>Flapping or biting of hands</li>
	<li>Attention-deficit/hyperactivity disorder (ADHD)</li>
	<li>Poor eye contact</li>
	<li>Sensory disorders, like being sensitive to touch, sounds, foods textures, bright light, and crowds</li>
	<li>Difficulty with picking up social cues</li>
	<li>Aggressive behavior in boys 
	&nbsp;</li>
</ul>

Causes

The cause of fragile X syndrome is the mutation of the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene present on the X chromosome. 
&nbsp;

The X chromosome is one of two types of sex chromosomes; the Y chromosome is the other. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. The FMR1 gene instructs the production of a protein called fragile X mental retardation 1 protein (FMRP), which assists in the formation of synapses as well as in the regulation of the synthesis of other proteins. Synapses play a crucial role in transmitting nerve impulses. This protein is necessary for a child&#39;s brain to develop appropriately. The issue is children with FXS either produce too little or none of this protein, given how much their gene is mutated. 
&nbsp;

The genes and chromosomes have a code, DNA, which has 4 bases &ndash; A, C, T, and G. The order of these chemical letters determines the information that each gene carries. The majority of instances of fragile X syndrome are caused by FMR1 gene&#39;s expansion of a DNA known as the &ldquo;CGG triplet repeat.&rdquo; This mutation is known as a dynamic mutation<a href="#accordion">[6]</a>. 
&nbsp;

There are 4 classifications of the fragile X mutation according to the number of times the CGG repeats in the DNA &ndash; normal, intermediate, premutation, and full mutation. 
&nbsp;

<ul>
	<li>Normal: 5-44 Repeats</li>
</ul>

Most males and females have 5-44 repeats in their FMR1 genes. They do not have FXS. Also, they don&rsquo;t carry the risk of passing FXS to their child(ren). 
&nbsp;

<ul>
	<li>Intermediate: 45-54 Repeats</li>
</ul>

People in this category do not have FXS. But, being borderline, they can pass it to the next generation.

When passed from the mother, the CGG repeats increase to a number with permutations.

When passed from the father, the CGG repeats do NOT increase to a number with permutations. 
&nbsp;

<ul>
	<li>Premutation: 55-200 Repeats</li>
</ul>

The repeats on the FMR1 genes can increase to a full mutation in one generation. The extent of expansion is dependent on the parent who passes the gene as well as the number of repeats on that gene. The more CGG repeats a woman has, the more likely her child will have an FMR1 gene with a full mutation.

Premutation from the father can be passed on to his daughters, but not his sons. Also, a man with premutation will not pass a full mutation to any child. 
&nbsp;

<ul>
	<li>Full Mutation: &gt;200 repeats</li>
</ul>

The individual has FXS. Women with FXS have a 50% chance of passing it on to their child during each pregnancy. 
&nbsp;

Please Note : Since a female has two copies of the FMR1 gene, one on each of her two X chromosomes, the number CGG repeats on each copy of the FMR1 gene differs for e.g. One copy of the FMR1 gene might have 20 repeats while the other might have 50 CGG repeats.&nbsp; The classification of a female&nbsp; (normal, intermediate, premutation, or full mutation, as mentioned earlier) is based on theFMR1 gene copy with the greatest number of CGG repeats.

Contrastingly in males since there is only one copy of the FMR1 gene on the X chromosome, so the classification of a male&nbsp; (normal, intermediate, premutation, or full mutation, as mentioned earlier) is based on the number of CGG repeats in that one copy. 
&nbsp;

<h5>Is It Hereditary?</h5>

Genes are found on chromosomes and every cell in the human body has 23 pairs of chromosomes. Each individual receives half of their chromosomes from their mother and the other half from their father. The 23rd pair is called the sex chromosomes &ndash; females have 2 XX chromosomes and males have 1 X and 1 Y. The FMR1 gene is present on the X chromosome.

Since fragile X syndrome follows an X-linked dominant pattern, there is a 50% chance that a child will inherit the FMR1 gene alteration from their mother. Only daughters can receive it from their father<a href="#accordion">[5]</a>. 
&nbsp;

Some people who have&nbsp;the fragile X gene are asymptomatic. They&#39;re known as carriers. However, gene alteration can still be passed on to children by carriers.

At times, people could have the mutated FMR1 gene but still have no symptoms of FXS. This could be because some people can make FMRP protein despite having the mutation because:

<ul>
	<li>They are females and, thus, less likely to get FXS</li>
	<li>The size of the mutation is small</li>
	<li>They have mosaicism, which means that some cells have the FMR1 mutation while others do not<a href="#accordion">[3][4][5]</a>. 
	 
	&nbsp;</li>
</ul>

Diagnosis

If there is a history of FXS in the family, the doctor may order prenatal tests. DNA from blood, amniotic fluid, or other tissues is needed to diagnose fragile X syndrome: 
&nbsp;

<ul>
	<li>Amniocentesis &ndash; A sample of the amniotic fluid is tested for the FMR1 gene</li>
	<li>Chorionic Villus Sampling (CVS) &ndash; A sample of cells from the placenta is tested for the FMR1 gene 
	&nbsp;</li>
</ul>

Sometimes, a parent or doctor may notice developmental delays or other visible indicators of the condition, such as a larger head circumference or slight changes in facial features, during the early years. Typically, boys exhibit symptoms around 35-37 months while girls show signs around 41.6 months<a href="#accordion">[4]</a>. 
&nbsp;

The FMR1 DNA test is a DNA blood test that searches for variations in the FMR1 gene linked to FXS. Other than that, a thorough developmental review by a speech and language therapist, a physical therapist, and an occupational therapist is advised. Repeat testing may be required as the patient develops. 
&nbsp;

Treatment

The symptoms of fragile X syndrome are not life-threatening and life expectancy is the same as any person without the condition. A lot of individuals can live independently. 8 out of 20 females and 1 out of 20 males with fragile X syndrome do not require help with daily activities<a href="#accordion">[5]</a>. 
&nbsp;

Although fragile X syndrome cannot be cured, its symptoms can be managed. The doctor may suggest some drugs, but a holistic treatment may also include special education, speech, and language therapy, occupational therapy, and behavior therapy 
&nbsp;

The medications, usually categorized by symptoms, include: 
&nbsp;

<ul>
	<li>
	<h5>Seizures Or Instability Of Mood</h5>
	</li>
</ul>

<ol>
	<li>Lithium carbonate</li>
	<li>Gabapentin 
	&nbsp;</li>
</ol>

<ul>
	<li>
	<h5>ADHD</h5>
	</li>
</ul>

<ol>
	<li>Methylphenidate and dextroamphetamine</li>
	<li>Venlafaxine and nefazodone 
	&nbsp;</li>
</ol>

<ul>
	<li>
	<h5>Aggression Or Obsessive-Compulsive Disorder</h5>
	</li>
</ul>

<ol>
	<li>Fluoxetine</li>
	<li>Sertraline and citalopram 
	&nbsp;</li>
</ol>

<ul>
	<li>
	<h5>Sleep Issues</h5>
	</li>
</ul>

<ol>
	<li>Trazodone</li>
	<li>Melatonin 
	&nbsp;</li>
</ol>

NOTE: Discuss any potential side effects and issues of&nbsp;each medicine with the practitioner. To come up with the best course of action, doctors may need to experiment with various dosages or drug combinations. 
&nbsp;

How Can Teachers Help At School

Based on the individual needs and abilities of a child with FXS, place them in an inclusive or special education classroom. IEPs should be designed by a team including parents, psychologists, teachers, and other specialists to help the child thrive academically<a href="#accordion">[7]</a>. Generally, teachers can foster learning by:

<ul>
	<li>Combining spoken instructions with visual clues</li>
	<li>Keeping extra break times so they can cope with anxiety and worry</li>
	<li>Allowing them to use noise-canceling headphones, turn down the lights, create quiet spaces, and minimize distractions in the classroom</li>
	<li>Teaching all kids how to regulate their emotions to prevent emotional outbursts<a href="#accordion">[1]</a>. 
	&nbsp;</li>
</ul>
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<ul>
	<li>People with FXS can have hearing problems, vision problems, heart problems, sleep problems, and obesity<a href="#accordion">[5]</a>.</li>
	<li>Females sometimes have trouble conceiving and may reach menopause earlier than normal<a href="#accordion">[5].</a></li>
	<li>The medications for the symptoms may have severe symptoms, which may take time to settle down.</li>
	<li>People with FXS may have other conditions such as autism, ADHD, and seizures.</li>
	<li>Males have a greater risk of developing FXTAS, which causes tremors and difficulty walking.</li>
	<li>Males are also at risk of dementia. 
	&nbsp;</li>
</ul>

A carrier can pass the FMR1 gene to their kid(s). 
&nbsp;

There are no known preventive measures as it is a genetically inherited condition. 
&nbsp;

Key Points

<ul>
	<li>Fragile X syndrome is a genetic disorder that causes developmental issues, including learning difficulties, behavioral issues, physical changes, and cognitive impairment. It results from mutations in a gene on the X chromosome. </li>
	<li>It is also known as fragile X syndrome because a portion of the X chromosome appears &quot;broken&quot; or &quot;fragile&quot; under a microscope.</li>
	<li>There is no cure for the condition. However, the symptoms can be treated efficiently with a detailed treatment plan that often requires coordination between the child&rsquo;s parents, doctors, teachers, and other caregivers.</li>
	<li>The FMR1 gene&#39;s expansion of a DNA known as the &ldquo;CGG triplet repeat&rdquo; results in the majority of instances of fragile X syndrome. This mutation is known as a dynamic mutation.</li>
	<li>The symptoms of fragile X syndrome are not life-threatening and the life expectancy is the same as any person without the condition. A lot of individuals can live independently.</li>
	<li>A child may be evaluated for FXS if they exhibit developmental delays or other visible indicators of the condition, such as a larger head circumference or slight changes in facial features, during their early years.</li>
	<li>The FMR1 DNA test, a DNA blood test, can be used to diagnose FXS. The test searches for variations in the FMR1 gene linked to FXS. 
	&nbsp;</li>
</ul>
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