Fragile X syndrome — genetics, phenotype and management (MEQ)

(i) Definition and allele classes. FXS is the most common inherited monogenic cause of intellectual disability, caused by pathogenic FMR1 (Xq27.3) variation — classically a full CGG expansion. Working ranges: normal about 5–44; intermediate about 45–54; premutation about 55–200; full mutation greater than 200. This boy's phenotype and maternal-line clues (uncle with ID; maternal POI) make FXS/FMR1 spectrum highly likely.[1][2]

(ii) Mechanisms. Full mutation: expansion with promoter hypermethylation → transcriptional silencing → loss of FMRP (RNA-binding translational repressor). Premutation: elevated FMR1 mRNA / toxic RNA gain-of-function pathway (FXTAS, FXPOI, psychiatric risk) rather than simple childhood FMRP-null FXS. Sherman paradox: increasing penetrance across generations via expanding maternal alleles.[1][3][2]

(iii) Phenotype and differentials. Expect ID (often mild–moderate in males), language delay, social anxiety, ADHD-like symptoms, sensory hyperarousal, possible ASD features; physical clues include long face, prominent ears, later macroorchidism. Anxiety rates are very high on structured assessment.[1][4] Differentials: idiopathic ASD/ADHD, other genetic ID syndromes, FASD, environmental adversity — win with pedigree + molecular test. Mother's early menopause suggests possible premutation FXPOI, not "mild FXS."[5][2]

(iv) Investigations and cascade counselling. Order molecular FMR1 testing (CGG sizing ± methylation per ACMG laboratory standards) — not karyotype alone. Parallel developmental supports. Genetic counselling for parents and at-risk relatives; discuss reproductive implications; screen premutation relatives for psychiatric symptoms, FXPOI and later FXTAS risk.[6][2][5]

(v) Management principles. No approved routine disease-modifying core cure that restores FMRP. Backbone: speech/OT, education, sensory strategies, disability supports, family coaching. Treat comorbidities: environmental + adapted psychological approaches for anxiety; cautious SSRI if indicated (start low, monitor activation/self-harm); ADHD behavioural ± stimulant/non-stimulant with growth/sleep/BP/anxiety monitoring; antipsychotics only for severe risk after functional analysis, lowest dose, metabolic monitoring, time-limited goals. Do not promise experimental mGluR-targeted drugs as standard care.[1][2][4]