Psych · Intellectual disability — neurodevelopmental
Fragile X syndrome
Also known as FXS · Fragile X · FMR1-related disorder · Martin-Bell syndrome · Fragile X-associated tremor/ataxia syndrome · FXTAS · Fragile X-associated primary ovarian insufficiency · FXPOI · FMR1 premutation
Exam-exhaustive fellowship reference on fragile X syndrome and the FMR1 spectrum — CGG allele classes, FMRP loss and premutation RNA toxicity, X-linked inheritance and Sherman paradox, behavioural phenotype (ID, ASD features, anxiety, ADHD), female variability, FXTAS/FXPOI, ACMG molecular diagnosis, cascade counselling, and comorbidity-focused management without a proven disease-modifying core drug. FRANZCP-primary, globally tagged.
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Target exams
Red flags
- Unexplained intellectual disability or ASD/ADHD phenotype with maternal-line family history of ID, premature menopause, or late-onset tremor/ataxia — arrange molecular FMR1 testing, not karyotype alone
- New intention tremor, cerebellar ataxia or progressive executive decline in a middle-aged premutation carrier — consider FXTAS and neurological work-up
- Premutation woman with secondary amenorrhoea, infertility or elevated FSH before age 40 — evaluate FXPOI and offer reproductive counselling
- Severe sensory hyperarousal with aggression or self-injury — exclude pain, otitis, constipation and seizure before escalating psychotropics
- Promising experimental mGluR-targeted drugs as standard care — no approved disease-modifying core cure; treat comorbidities and support the family
- Index FXS diagnosis without cascade genetic counselling of at-risk relatives
Meet the patient
A 7-year-old boy is referred for assessment of intellectual disability and "autistic traits." He avoids eye contact, flaps his hands when excited, struggles to sit still at school, and has long ears that his mother has always wondered about. His mother mentions, almost in passing, that she went through early menopause at 34, and that her brother — "the quiet one" — lives in supported accommodation and never learned to read.[1][11]
Three threads are live, and each is a viva question: what is the diagnosis and how do you confirm it? what is the family carrying? and is there a treatment for the core condition? The maternal-line history is the clue that turns a behavioural referral into a molecular one.[1][2][11]
References12ShowHide
- [1]Hagerman RJ, Berry-Kravis E, Hazlett HC, et al. Fragile X syndrome Nat Rev Dis Primers, 2017.PMID 28960184
- [2]Hunter JE, Berry-Kravis E, Hipp H, Todd PK FMR1 Disorders GeneReviews, 1993.PMID 20301558
- [3]Garber KB, Visootsak J, Warren ST Fragile X syndrome Eur J Hum Genet, 2008.PMID 18398441
- [4]Hunter J, Rivero-Arias O, Angelov A, et al. Epidemiology of fragile X syndrome: a systematic review and meta-analysis Am J Med Genet A, 2014.PMID 24700618
- [5]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.PMID 1710175
- [6]Fu YH, Kuhl DP, Pizzuti A, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox Cell, 1991.PMID 1760838
- [7]Bear MF, Huber KM, Warren ST The mGluR theory of fragile X mental retardation Trends Neurosci, 2004.PMID 15219735
- [8]Cordeiro L, Ballinger E, Hagerman R, Hessl D Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization J Neurodev Disord, 2011.PMID 21475730
- [9]Yu TW, Berry-Kravis E Autism and fragile X syndrome Semin Neurol, 2014.PMID 25192504
- [10]Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population JAMA, 2004.PMID 14747503
- [11]Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, et al. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study Am J Med Genet, 1999.PMID 10208170
- [12]Spector E, Behlmann A, Kronquist K, et al. Laboratory testing for fragile X, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG) Genet Med, 2021.PMID 33795824