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Fragile X syndrome and learning disability: guide for GP trainees

  • FXS is the most common inherited cause of learning difficulties.

  • It is also a single-gene (monogenic) cause of autism spectrum disorder (ASD).


  • How common?

    • Affects about 1 in every 4,000 boys and 1 in every 6,000 girls in the UK.

    • Around 125 babies are born with FXS in the UK each year.


    • What Does "X-linked" Mean?

      • FXS is inherited in an X-linked pattern:

        • Males (XY) have only one X chromosome → if it's affected, symptoms are usually more severe.

        • Females (XX) have two X chromosomes → the unaffected X can partially "balance out" the other


  • What causes it?

    • A change (repeat expansion) in a gene called FMR1 on the X chromosome.

    • This change causes the gene to stop working properly.


Category CGG Repeats What It Means
Normal <45 No risk; gene works normally
Intermediate 45–54 “Grey zone”; usually no symptoms or expansion
Premutation 55–200 Carrier status; gene still works, but can expand in next generation
Full Mutation >200 Fragile X Syndrome; gene is silenced → ↓ FMRP → symptoms develop


  • What does this mean for the brain?

    • The gene normally makes a protein called FMRP, which is important for brain development.

    • Without enough FMRP, children may have learning delays, behaviour challenges, and autistic features.


Inheritance Summary & Link to Male Presentation


Fragile X Syndrome (FXS) follows an X-linked inheritance pattern with anticipation, meaning the genetic mutation (CGG repeat expansion in the FMR1 gene) can worsen through generations.


  • Female premutation carriers (55–200 CGG repeats) often show no or mild symptoms, but can pass on a larger expansion to their children, especially sons.

  • Male premutation carriers typically pass the premutation unchanged to all daughters (who become carriers), but never to sons.

  • The larger the premutation, the higher the risk it will expand to a full mutation (>200 repeats), causing FXS in the next generation.

In males with a full mutation, the impact is more severe because they only have one X chromosome. Almost all affected males show moderate to severe intellectual disability, with IQs typically ranging from 35 to 70. Over time, IQ scores may decline further due to progressive neurological involvement.


System Key Features
Cognition Males: Moderate–severe ID (avg IQ ~40)
Females: Variable; mild or no ID
Speech Delayed onset (first words ~2 yrs)
Echolalia, perseverative speech
Behaviour ADHD (↑ in males), ASD (30–50%)
Anxiety, shyness, hyperarousal
Repetitive Behaviour Hand flapping, hand biting, poor eye contact, stereotypies
Sensory Sensory hypersensitivity (↑ tactile, noise sensitivity)
Seizures 13–18% of males
Focal onset, often ↓ with age
Physical Long face, large ears, ↑ macroorchidism (post-puberty)
Flat feet, soft skin
Musculoskeletal Joint hypermobility, scoliosis, hypotonia
Cardiac ↑ MVP (22–50%), ↑ aortic root dilatation
ENT/Ophtho Strabismus, recurrent otitis media, refractive errors
Other Sleep disturbances, GI issues (↑ reflux, constipation), inguinal hernias


Fragile X Syndrome: Diagnosis & Investigation Summary

🔍 When to Suspect FXS

  • Developmental delay, learning disability, or autism — especially in males

  • Characteristic facial features: long face, large ears; macroorchidism after puberty

  • Family history: intellectual disability, premature ovarian insufficiency (POI), or FXTAS


Who Should Be Tested (FMR1 Gene Testing)


Group When to Test
Children - Any unexplained developmental delay or learning disability
- Autism or autistic traits (FXS = 1–6% of ASD cases)
- Speech/language delay
Males - Moderate to severe learning disability
Females - Mild to severe learning disability (especially if family history positive)
- Early menopause, primary ovarian insufficiency (POI), infertility, ↑ FSH
Adults - Unexplained intellectual disability without prior testing
- Family history of intellectual disability, autism, or developmental delay
Older Adults - Late-onset tremor/ataxia (consider FXTAS)
- Family history of similar neurological symptoms


Diagnostic Testing

  • Current UK practice: Fragile X testing via Whole Genome Sequencing (WGS) pathways

  • Standalone R53 test withdrawn (March 2025)

  • Includes PCR-based CGG repeat sizing ± methylation analysis

  • Diagnosis delays common: average age 3 years (boys), 3.5 years (girls)


Referral Pathways

  • Refer via: paediatrics, clinical genetics, psychiatry, neurology, or learning disability services

  • GPs should refer any patient with unexplained learning disability


Post-Diagnosis Actions

  • Genetic counselling:

    • Explain inheritance and recurrence risk

    • Offer cascade testing to family (esp. maternal relatives)

    • Support reproductive decision-making (e.g. prenatal testing, IVF with PGD)

  • Pedigree analysis: Identify at-risk individuals


Core Management Principles – Fragile X Syndrome


Management Area Key Principles
Multidisciplinary Care Coordinate with paediatrics, genetics, SALT, OT, physio, psychiatry, psychology, education, and learning disability teams.
Family Support Offer genetic counselling, pedigree analysis, and cascade testing. Support carers. Signpost to Fragile X Society.
Post-Diagnosis Essential genetic counselling. Discuss inheritance risk. Offer reproductive advice (e.g. prenatal testing, PGD).
Annual GP Health Checks All individuals ≥14y with LD are eligible. Use in-person reviews. Include cardiovascular, neurological, ENT, MSK, dental, GI, and mental health assessments.
Early Intervention Begin SALT, OT, physio early to address hypotonia, speech delay, feeding issues, and fine/gross motor development.
Education & Behaviour Use structured learning, visual aids. Address sensory needs. Create behaviour support plans. EHCPs required.
Mental Health ADHD: Behaviour first-line → stimulants if severe.
Anxiety: Prefer therapy → SSRIs (e.g. sertraline) if needed.
Challenging behaviour: Follow NICE; use meds only with clear goals.
Seizures Seen in ~12%. Onset usually 4–10y. Treat per type (oxcarbazepine, levetiracetam, lamotrigine). May remit in adulthood.
Physical Monitoring Screen for MVP, aortic dilation, scoliosis, hernias, strabismus, recurrent otitis media, constipation, ↑ BMI. Refer to specialists as needed.
Reproductive Health Monitor females for POI (↑ risk in premutation carriers). Consider HRT. Offer fertility counselling and gynaecology referral.
Transition Planning Start early. Ensure continuity from child to adult services. Support for vocational training, independent living, and EHCP continuation until age 25.
Premutation Conditions FXTAS: tremor, ataxia, cognitive decline → refer neurology.
FXPOI: early menopause, infertility → refer gynaecology.
GP Role Identify undiagnosed cases. Coordinate care. Monitor physical/mental health. Avoid diagnostic overshadowing. Safeguard vulnerable patients.
AKT Relevance Know: genetic causes of LD, comorbidities, annual check eligibility, safeguarding, diagnostic overshadowing, and life course management.


Conclusion

Fragile X Syndrome (FXS) is a common inherited cause of learning disability, often under-recognised and diagnosed late. General practitioners play a central role in early identification, referral for genetic testing, and lifelong care coordination. People with FXS need regular reviews for developmental, physical, and mental health needs, with support for communication, education, and family wellbeing.

Providing person-centred, multidisciplinary, and proactive care improves outcomes and helps individuals with FXS reach their full potential.


References

[1](https://www.fragilex.org.uk/testing)

[2](https://biologicalsciences.leeds.ac.uk/biological-sciences/news/article/504/fragile-x-syndrome-what-you-need-to-know-about-this-rare-genetic-condition)

[3](https://www.pure.ed.ac.uk/ws/portalfiles/portal/415007543/Research_Intellect_Disabil_-_2024_-_Johnson_-_A_holistic_approach_to_fragile_X_syndrome_integrated_guidance_for.pdf)

[4](https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/fragile-x-syndrome/)

[5](https://www.research.ed.ac.uk/files/415007543/Research_Intellect_Disabil_-_2024_-_Johnson_-_A_holistic_approach_to_fragile_X_syndrome_integrated_guidance_for.pdf)

[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC8460441/)

[7](https://pmc.ncbi.nlm.nih.gov/articles/PMC6715460/pdf/bjgpsep-2019-69-686-460-oa.pdf)

[8](https://fragilex.org/resources/treatment/genetic-counseling/)

[9](https://www.fragilex.org.uk/syndrome)

[10](https://en.wikipedia.org/wiki/Fragile_X)

[11](https://www.cdc.gov/fragile-x-syndrome/related-concerns/index.html)

[12](https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2014.00355/full)

[13](https://www.fragilex.org.uk/fragile-x-and-autism)

[14](https://en.wikipedia.org/wiki/Fragile_X_syndrome)

[15](https://fdna.com/health/resource-center/fragile-x-facial-features/)

[16](https://fragilex.org/fx/signs-symptoms/)

[17](https://rarediseases.org/rare-diseases/fragile-x-syndrome/)

[18](https://www.genomicseducation.hee.nhs.uk/genotes/in-the-clinic/presentation-clinical-suspicion-of-fragile-x-syndrome-in-an-adult-with-a-personal-and-family-history-of-neurodevelopmental-disorder/)

[19](https://southeastgenomics.nhs.uk/tool/fragile-x/)

[20](https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2016.00353/full)

[21](https://fragilex.org/resources/treatment/seizures/)

[22](https://pmc.ncbi.nlm.nih.gov/articles/PMC8756611/)

[23](http://fragilex.org/fxs/topics/autism/)

[24](https://cerebra.org.uk/wp-content/uploads/2022/12/autism-genetic-syndromes-2022-low-res.pdf)

[25](http://ddprimarycare.surreyplace.ca/wp-content/uploads/2018/03/HWT_Fragile-X.pdf)

[26](https://heart.bmj.com/content/61/3/289)

[27](https://pmc.ncbi.nlm.nih.gov/articles/PMC1216660/)

[28](https://publications.aap.org/pediatrics/article/91/4/714/58198/Cardiovascular-Abnormalities-in-Children-With)

[29](https://fragilex.org/fxs/topics/medical/)

[30](https://orca.cardiff.ac.uk/id/eprint/166514/1/jar.13214.pdf)

[31](https://www.ncbi.nlm.nih.gov/books/NBK459243/)

[32](https://www.mangen.co.uk/wp-content/uploads/2020/03/Male-UKGTN-fraX-request-form.pdf)

[33](https://www.ucsfhealth.org/education/faq-carrier-testing-for-fragile-x-syndrome)

[34](https://academic.oup.com/molehr/article/26/10/727/5890487)

[35](https://fragilex.org/premutation/fx-conditions/fxtas/)

[36](https://www.eastgenomics.nhs.uk/about-us/news-and-events/simplification-testing-developmental-disorders/)

[37](https://www.nbt.nhs.uk/sites/default/files/Fragile%20X%20syndrome%20(FMR1).pdf)

[38](https://www.cdc.gov/fragile-x-syndrome/data/index.html)

[39](https://www.racgp.org.au/afp/2017/july/fragile-x-associated-disorders-don-t-miss-them)

[40](https://www.jscreen.org/blog/fragile-x-carrier-testing-what-to-expect-and-why-it-matters)

[41](https://www.nhs.uk/conditions/learning-disabilities/annual-health-checks/)

[42](https://contact.org.uk/help-for-families/information-advice-services/health-medical-information/annual-health-checks/)

[43](https://www.england.nhs.uk/wp-content/uploads/2019/10/improving-identification-of-people-with-a-learning-disability-guidance-for-general-practice.pdf)

[44](https://pmc.ncbi.nlm.nih.gov/articles/PMC4995426/)

[45](https://my.clevelandclinic.org/health/diseases/5476-fragile-x-syndrome)

[46](https://fragilex.org/wp-content/uploads/seizures-fxs-treatment-recommendations.pdf)

[47](http://familiesforfragilex.com/about-fragile-x/treatments.php)

[48](https://www.asdclinic.co.uk/conditions/fragile-x-syndrome/speech-and-language-therapy-for-fragile-x-syndrome.php)

[49](https://www.asdclinic.co.uk/conditions/fragile-x-syndrome/occupational-therapy-for-fragile-x-syndrome.php)

[50](https://fragilex.org/resources/treatment/sensory/)

[51](https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/therapytreatments)

[52](https://www.fragilex.org.uk/fxtas)

[53](https://en.wikipedia.org/wiki/Fragile_X-associated_tremor/ataxia_syndrome)

[54](https://www.acgs.uk.com/media/10768/frx_bpg_final_nov_2014.pdf)

[55](https://med.emory.edu/departments/human-genetics/_documents/fragile-x-male.pdf)

[56](https://my.klarity.health/fragile-x-associated-disorders-fxpoi-and-fxtas/)

[57](https://fragilex.org/premutation/fx-conditions/fxpoi/)

[58](https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2020.00266/full)

[59](https://fragilex.org.nz/fragile-x-associated-disorders/)

[60](https://www.rcgp.org.uk/getmedia/c56afa16-b7da-4581-9e15-3ade7e0679f2/Neurodevelopmental-disability-2021-Final.pdf)

[61](https://www.rcgp.org.uk/mrcgp-exams/gp-curriculum/learning-disability)

[62](https://www.shropscommunityhealth.nhs.uk/content/doclib/13302.pdf)

[63](https://view-health-screening-recommendations.service.gov.uk/fragile-x/)

[64](https://gpnotebook.com/en-GB/pages/paediatrics/fragile-x-syndrome)

[65](https://www.rcgp.org.uk/getmedia/524f7fcd-bce1-45ee-bfbf-329707df0662/topic-guides-2025.pdf)

[66](https://cambspborochildrenshealth.nhs.uk/services/cambridgeshire-community-paediatrics/developmental-delay/genetic-conditions/)

[67](https://www.choiceforum.org/docs/circ.pdf)

[68](https://www.ncbi.nlm.nih.gov/books/NBK1384/)

[69](https://pmc.ncbi.nlm.nih.gov/articles/PMC9356544/)

[70](https://www.gov.uk/government/publications/learning-disability-applying-all-our-health/learning-disabilities-applying-all-our-health)

[71](https://www.fraxa.org/fragile-x-syndrome/)

[72](https://medlineplus.gov/genetics/condition/fragile-x-syndrome/)

[73](https://www.england.nhs.uk/wp-content/uploads/2024/07/national-genomic-test-directory-rare-and-inherited-disease-eligibility-criteria-v7.pdf)

[74](https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.1024)

[75](https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2017.00254/full)

[76](https://www.jewishgenetics.org/articles/similarities-and-differences-in-fragile-x-syndrome-and-autism/)

[77](https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2021.736255/full)

[78](https://www.cdc.gov/fragile-x-syndrome/about/index.html)

[79](https://pmc.ncbi.nlm.nih.gov/articles/PMC6900367/)

[80](https://www.womenshealthmag.com/health/a66351059/genetic-carrier-testing-increase/)

[81](https://heart.bmj.com/content/heartjnl/61/3/289.full.pdf)

[82](https://www.ahajournals.org/doi/10.1161/JAHA.121.020919)

[83](https://www.rcgp.org.uk/getmedia/e3a10024-e7fb-4426-a7ac-f3696eff4746/Learning-disability-SCCG-2025.pdf)

[84](https://www.ahajournals.org/doi/pdf/10.1161/JAHA.121.020919)

[85](https://fragilex.org/wp-content/uploads/2024/12/physical-problems-fxs-treatment-recommendation.pdf)

[86](https://www.selondonics.org/wp-content/uploads/dlm_uploads/RCGP-AHC-toolkit.pdf)