Fragile X Syndrome

Fragile X syndrome (FXS) is the commonest inherited cause of intellectual disability and the commonest single gene cause of autism spectrum disorder. Prevalence is about 1 in 4,000 males and 1 in 6,000 to 8,000 females. It is X-linked, caused by an expansion of a CGG trinucleotide repeat in the 5' untranslated region of FMR1 (Xq27.3).

Normal alleles carry 5 to 44 repeats, intermediate (grey zone) 45 to 54, premutation 55 to 200, and full mutation above 200. Full mutation alleles are hypermethylated, silencing FMR1 and abolishing production of FMRP. FMRP is an RNA-binding protein that regulates translation of synaptic proteins and restrains metabotropic glutamate receptor 5 signalling.

Premutation alleles expand to full mutation only on maternal transmission, and the risk rises with repeat size (about 4% for 55 to 59 repeats, above 95% for over 100 repeats). Paternal premutations pass to all daughters unchanged or slightly contracted. AGG interruptions within the repeat stabilise it and lower expansion risk.

Premutation carriers have their own disorders.

• Fragile X-associated tremor/ataxia syndrome (FXTAS): late onset intention tremor, cerebellar ataxia, parkinsonism and cognitive decline. Penetrance is about 40% in male and 8 to 16% in female carriers over 50.
• Fragile X-associated primary ovarian insufficiency (FXPOI): about 20% of female carriers, with menopause before 40.
• Neuropsychiatric problems: anxiety, depression, ADHD.

• Infancy and early childhood: hypotonia, gastro oesophageal reflux, recurrent otitis media, global developmental delay with speech delay as the dominant early feature
• Physical phenotype (often subtle before puberty): long narrow face, prominent forehead and chin, large protruding ears, joint hyperlaxity, soft velvety skin, flat feet, high arched palate, mitral valve prolapse (uncommon), pectus excavatum, strabismus, and macro orchidism (post-pubertal, 90%; testicular volume above 25 mL)
• Behaviour: hyperarousal, gaze aversion, hand flapping and hand biting, tactile defensiveness, ADHD features (80% of males), anxiety (especially social), aggression and tantrums, autism spectrum features (about 30 to 50%)
• Cognition: moderate intellectual disability in most males (IQ 35 to 70, declining relative to peers with age); females with a full mutation are variably affected (about 25% have IQ under 70), with learning disability, shyness and anxiety
• Seizures in 10 to 20% (usually focal, benign, resolving in adolescence)

• Indications: unexplained developmental delay, intellectual disability or autism, a family history of FXS, FXTAS or POI, and screening of at risk relatives.
  1. FMR1 CGG repeat sizing by PCR with Southern blot or methylation specific PCR (triplet primed PCR identifies expansions and AGG interruptions). This is the first line test and has replaced karyotyping, which is now obsolete for this purpose.
  2. Methylation analysis to distinguish methylated full mutations and mosaics (mosaicism for size or methylation occurs in about 15 to 40% of males).
  3. Chromosomal microarray in the same developmental assessment, since it is first tier for developmental delay.
  4. Prenatal diagnosis by chorionic villus sampling or amniocentesis for carriers (methylation is not established in CVS, so confirm full mutation methylation status by amniocentesis if needed).
  5. Cascade testing of the family, with genetic counselling for carriers, including the risk of expansion, FXPOI and FXTAS.

There is no disease modifying therapy. Care is multidisciplinary and symptom directed.

• Early intervention: speech and language therapy, occupational therapy (sensory integration), physiotherapy, special educational support, and behavioural therapy. Visual aids and consistent routines help hyperarousal.
• ADHD and impulsivity: methylphenidate 0.3 to 1 mg/kg/day in divided doses (a low initial dose of 5 mg with increments; stimulants can worsen anxiety and irritability); guanfacine extended release 1 to 4 mg daily or clonidine 0.05 mg at night for hyperarousal and sleep.
• Anxiety and mood: sertraline 25 mg daily titrated to 100 to 200 mg, or fluoxetine 5 to 10 mg titrated to 20 to 40 mg; buspirone as an alternative.
• Aggression and severe irritability: aripiprazole 2 to 15 mg daily or risperidone 0.25 to 2 mg daily, with metabolic monitoring.
• Sleep: melatonin 1 to 5 mg 30 minutes before bed.
• Seizures: carbamazepine or levetiracetam; avoid unnecessary long term use in benign seizures.
• Surveillance: otitis media and hearing, strabismus and refractive errors (ophthalmology), scoliosis, flat feet, mitral valve prolapse (cardiac auscultation, echocardiography if murmur), and growth (they are usually tall in childhood, with a blunted adolescent growth spurt).
• Targeted agents (mGluR5 antagonists, arbaclofen) have failed phase III trials; trials of zatolmilast (PDE4D inhibitor) continue.
• Genetic counselling: 50% risk to offspring of a carrier mother; preimplantation genetic testing is available. Counsel female premutation carriers about FXPOI, fertility preservation and bone health, and refer male and female carriers over 50 with tremor or gait problems for FXTAS assessment.