Fragile X Syndrome

She came a long way to find safety and peace for her family. She still has a long way to go in supporting her child with a rare genetic disease.

She was a young mother who immigrated to the US with her family two years ago.  I met her at a Family Medicine clinic where I was doing my clinical rotation.  She was always sweet and polite. Noticing I was new at the clinic, she asked where I was from and where I had been.  She also shared with me stories about her journey from her war-ridden country to the new home in this small town in the US.  She did not speak a single English word when she arrived.  Just in two years, she was able to converse nicely in English.  She is often exhausted because she was studying at the community college and has a son with mental disability who required a lot of care at home.  I met her son too and understood what challenges she faces everyday and I admired her courage and optimism.

One day during her routine visit, she appeared anxious.  She told me that she and her husband were considering having more children.  But they were worried.  Her son was previously diagnosed with fragile X syndrome and autism.  Will our next child have the same condition? She asked me.

What is fragile X syndrome?

Fragile X syndrome is the most common heritable intellectual disability 1.  It is caused by mutations in the FMR1 gene (Fragile X Mental Retardation-1) on X chromosome 2. The disease got its name because under microscope, the affected region on X chromosome appeared narrow and “fragile”.

How is fragile X syndrome inherited?

The affected gene FMR1 is on X chromosome.  Females have two X-chromosomes and typically carry one copy of mutation; thus females have 50% of chance to pass the mutation to children.  Males have one X-chromosome and will always pass it to children. 

The children who inherit the mutation could have very different clinical features.  Daughters who inherited the mutation usually have less severe symptoms than the affected sons.

How does FMR1 mutation cause disease?

FMR1 gene produces the FMR protein (FMRP), which is critical for brain development.  Mutations in FMR1 gene result in less or no production of FMRP and subsequent impaired brain function. 

The underlying molecular mechanisms are complex. 

Although DNA sequence in our genome is composed of all four nucleotides (A, C, T and G) that are more or less randomly dispersed, some regions in our genome are highly repetitive.  FMR1 gene contains a stretch of CGG trinucleotide repeats.  These repeats are subject to methylation, a common modification on DNA that negatively regulates gene transcription from DNA into RNA molecules.  RNA functions as a blueprint for making functional FMRP. 

Healthy individuals carry 5-44 CGG repeats in their FMR1 gene.  However, a repetitive DNA sequence can be unstable and expands to over 200 repeats when the gene is passed from parents to children.  The severe expansion in DNA repeats leads to excessive methylation, and consequent reduction or complete loss of functional FMRP.  This mechanism explains vast majority cases of fragile X syndrome.

Two types of mutation

Two terms are used to describe different extents of expansion:

When a person has >200 CGG repeats, it is defined as “full mutation” 2.  No FMR1 protein is being made and patients show developmental impairment at an early age.

When a person has 50-200 CGG repeats, it is defined as “premutation” 3.  FMR protein level is reduced but still present and patients have no symptoms or mild symptoms later in life.  However, premutation sequence is unstable and expansion occurs when a mother passes the gene to her children.  Of note, expansion rarely happens when a father passes the gene to his children.

Clinical features of fragile X syndrome

Individuals carrying the full mutation show a broad range of clinical features 4.  Patients typically have delay in physical and intellectual development in early childhood.  They often have behavioral patterns that overlap with ADHD, autism and anxiety.  Among children who carry full mutation, girls usually have milder symptoms than boys.

Individuals carrying premutation often have no symptoms.  Some of them develop premature ovary insufficiency or fragile X associated tremor/ataxia syndrome at an older age 5,6.

Diagnosis of fragile X syndrome

Currently there is no cure for fragile X syndrome.  However, early diagnosis is important as it will allow for early intervention including counseling and therapy. When should a child be tested?  A child who has shown delay in physical and intellectual development or autism with unknown causes should undergo screening test.

Laboratory tests are done on the DNA of patients 7.  Several DNA analysis techniques are available for accurate detection of qualitive and quantitative alteration in FMR1 gene.

Preconception counseling

Going back to our patient, we referred her to a fertility specialist for preconception counseling and testing.  Last time I saw her, I learned that she was found to carry premutation and her son has full mutation in FMR1. She and her husband understood that there is 50% of chance that the mutation will be passed to their next child.  The premutation will most likely expand to full mutation when it is passed to her children.

She told me she was glad that she and her family now had a clear explanation for their son’s condition.  She will see the specialist again to discuss options.  With her usual sweetness and a smile, she told me that her son had been doing well in a special need program at the school. 

Shortly after that, I finished my rotation and left the clinic to continue my training somewhere else.  As a research dedicated to genetic research on common and rare diseases, I think of her and her family often. Each time I read about new development in the field, I see new hope for her family and others who are affected 8.

References

1.         Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A 2014;164A(7):1648–58.

2.         Verkerk AJ, Pieretti M, Sutcliffe JS, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991;65(5):905–14.

3.         Nolin SL, Brown WT, Glicksman A, et al. Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 2003;72(2):454–64.

4.         Visootsak J, Warren ST, Anido A, Graham JM. Fragile X syndrome: an update and review for the primary pediatrician. Clin Pediatr (Phila) 2005;44(5):371–81.

5.         Marozzi A, Vegetti W, Manfredini E, et al. Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod 2000;15(1):197–202.

6.         Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004;74(5):1051–6.

7.         Brown WT, Houck GE, Jeziorowska A, et al. Rapid fragile X carrier screening and prenatal diagnosis using a nonradioactive PCR test. JAMA 1993;270(13):1569–75.

8.         National Fragile X Foundation.

About the Author Isabel Wang, MD/PhD

I received my MD from PUMC in Beijing China and my Ph.D. in Biochemistry from Stony Brook University on Long Island. Over the years, I have worked in the fields of genetic research and clinical medicine in different parts of the US, including PA, MO, CT, FL, NY and MI. My research has been published in multiple scientific journals. Currently I live in Ann Arbor, MI with my husband and our children and Mango the orange tabby. I love hiking, running, baking, cooking and biking.

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