Intellectual Disability — SAQ

Stem

A 2-year-old boy is referred by his health visitor because of global developmental delay. He sat at 11 months, crawled at 14 months and only began pulling to stand at 22 months; he has no recognisable words and does not consistently respond to his name. He has a long face, large protruding ears, a high-arched palate, hyperextensible joints and postural hypotonia. He avoids eye contact, flaps his hands when excited, is very active and has a short attention span. His mother reports that her brother had 'learning difficulties' and was 'slow at school'. Pregnancy, birth and the early neonatal period were unremarkable; head circumference is on the 50th centile. He has had no seizures.

Questions

a) What is the most likely clinical diagnosis, and which specific test would you order first to confirm the underlying cause? (2 marks)

The clinical picture is of a syndromic intellectual disability with a behavioural phenotype of social anxiety, gaze aversion, hand-flapping and ADHD-type overactivity — strongly suggestive of fragile X syndrome, the commonest inherited single-gene cause of intellectual disability. The family history of a maternal uncle with learning difficulties (the mother is an obligate premutation/full-mutation carrier) supports X-linked inheritance.^[4][9]

The first-line genetic test in any unexplained intellectual disability is chromosomal microarray (CMA), which detects aneuploidies, deletions, duplications and copy-number variants. CMA should be performed first; if negative, the specific confirmatory test is FMR1 CGG trinucleotide repeat testing (PCR for repeat size, and Southern blot for methylation status) — a full mutation is defined as over 200 CGG repeats with hypermethylation and silencing of FMR1, producing deficiency of the FMRP protein.^[1]

b) Explain the molecular pathogenesis of the most likely diagnosis. (2 marks)

Fragile X is caused by an expansion of the CGG trinucleotide repeat in the 5' untranslated region of the FMR1 gene on Xq27.3. Normal alleles carry 5 to 44 repeats; the premutation (55 to 200 repeats) is unstable on maternal transmission and is associated with fragile-X-associated tremor/ataxia syndrome (FXTAS) in adult men and fragile-X-associated premature ovarian insufficiency (FXPOI) in women. The full mutation (over 200 repeats) becomes hypermethylated, silencing FMR1 transcription so that FMRP (Fragile X Mental Retardation Protein) is absent or severely deficient.^[4]

FMRP is an RNA-binding protein that represses dendritic translation of target mRNAs at the synapse. Its absence causes excessive, dysregulated translation and abnormal dendritic-spine morphology (long, immature, tortuous spines), impairing synaptic plasticity and mGluR5 signalling — the basis of the cognitive deficit and of targeted drug trials such as the mGluR5 antagonist AFQ056 (mavoglurant).^[4] Inheritance is X-linked dominant: full penetrance in males; about 50 to 60 percent penetrance in females (milder due to skewed X-inactivation). Anticipation occurs through maternal transmission as the CGG repeat expands.

c) Outline the comprehensive, multidisciplinary management plan you would offer this child. (4 marks)

Management is multidisciplinary, lifelong and individualised. There is no medication that treats the core cognitive deficit of ID; all pharmacotherapy is symptom-targeted.^[1]

• Confirm cause and genetic counselling — complete the CMA + FMR1 testing; offer family cascade testing (mother is a carrier; test siblings; counsel regarding FXTAS in grandfathers and FXPOI in mother); discuss recurrence risk and reproductive options.
• Multidisciplinary early intervention (the core):
  • Speech and language therapy targeting receptive, expressive and pragmatic language, with augmentative and alternative communication (AAC) if he remains minimally verbal.
  • Occupational therapy for sensory integration, fine motor skills and activities of daily living.
  • Physiotherapy for the postural hypotonia, gross motor delay and hypermobility.
  • Special education — an individualised education plan (IEP) with structured, predictable environment.
  • Behavioural support — Positive Behaviour Support (PBS) based on functional analysis; address attention and overactivity.
• Comorbidity surveillance — audiology and vision (mandatory); screen for autism (DSM-5 criterion E); monitor for ADHD, anxiety, seizures (20 to 30 percent comorbid) and sleep disturbance.
• Symptom-targeted pharmacotherapy — if ADHD is confirmed, methylphenidate or atomoxetine (lower response than primary ADHD, may transiently worsen irritability); if severe anxiety, an SSRI (fluoxetine, START LOW, GO SLOW); melatonin 2 to 6 mg PO for sleep; risperidone or aripiprazole only for severe irritability/aggression refractory to behavioural measures, with monitoring of weight, BMI, fasting glucose/lipids, prolactin, EPSE and QTc.
• Family-centred support — parent training, sibling support, respite, signposting to the Fragile X Society, benefits advice, transition planning from age 14.

d) Twelve years later, the young man (now 14) is brought to the emergency department with a 3-day history of new-onset agitation, self-injurious hand-biting and refusing food. He is afebrile, pulse 96, abdomen soft. Outline your immediate management priorities. (1 mark)

This is an acute behavioural disturbance in a person with ID — apply the principle of diagnostic overshadowing: a new behavioural change is a physical-health problem until proven otherwise.^[6][5]

• Safety of the patient and others; reduce sensory and environmental triggers (quiet room, dim lights, remove unnecessary staff; allow trusted caregiver and familiar objects).
• De-escalation with calm predictable language and visual supports.
• Systematically exclude organic precipitant FIRST: pain (dental abscess, otitis, headache, fracture, gastro-oesophageal reflux, corneal abrasion), infection (UTI, chest, skin, ear), constipation (very common and often overlooked), medication side-effect, seizure/post-ictal state, sleep deprivation, thyroid disease, environmental change, abuse.
• Pharmacological intervention only as last resort when there is imminent risk: lorazepam 0.05 mg/kg PO/IM (max 2 mg) or low-dose antipsychotic (risperidone 0.5 to 1 mg, olanzapine 5 mg orodispersible, or haloperidol 2 to 5 mg IM with promethazine); cautions — airway, QTc, EPSE, paradoxical disinhibition.
• Multidisciplinary review (psychiatry, psychology, OT, SALT, paediatrics/adult ID) and a positive behaviour support plan to prevent recurrence.

e) The young man's maternal grandfather, aged 68, has recently developed intention tremor, ataxia and parkinsonism. What is the likely unifying diagnosis, and what does this imply for the family? (1 mark)

The grandfather is a likely FMR1 premutation carrier developing fragile-X-associated tremor/ataxia syndrome (FXTAS) — a late-onset neurodegenerative disorder (intention tremor, cerebellar ataxia, parkinsonism, cognitive decline, white-matter changes on MRI) affecting approximately 40 percent of premutation-carrier men over age 50 and a smaller proportion of women.^[4]

This implies the family carries an FMR1 premutation: the grandfather transmitted the premutation to his daughter (the boy's mother), who is herself at risk of fragile-X-associated premature ovarian insufficiency (FXPOI); the premutation expanded to the full mutation on transmission to her son. The implication is comprehensive cascade genetic counselling and testing of the extended family — siblings, aunts, cousins — with appropriate reproductive and surveillance advice (FXPOI monitoring in female carriers; FXTAS awareness in older male carriers).

References8ShowHide

1. [1]Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine, 2021.PMID 34211152
2. [2]Scheffer IE, Zuberi S, Mefford HC, et al. Developmental and epileptic encephalopathies. Nature Reviews Disease Primers, 2024.PMID 39237642
3. [4]Berry-Kravis E, et al. Effects of AFQ056 on language learning in fragile X syndrome. Journal of Clinical Investigation, 2023.PMID 37651202
4. [5]Robertson J, Hatton C, Emerson E, et al. The impact of health checks for people with intellectual disabilities: an updated systematic review. Research in Developmental Disabilities, 2014.PMID 24984052
5. [6]Cooper SA, McLean G, Guthrie B, et al. Multiple physical and mental health comorbidity in adults with intellectual disabilities: population-based cross-sectional analysis. BMC Family Practice, 2015.PMID 26310664
6. [7]Rafii MS, et al. Down syndrome and Alzheimer's disease: insights into biomarkers, clinical symptoms, and disease mechanisms. Lancet Neurology, 2025.PMID 40818475
7. [8]Leblay Y, et al. From Gene to Hope: Rett Syndrome and the Rise of Molecular Therapies. Molecular Diagnosis and Therapy, 2026.PMID 41975033
8. [9]Glasson EJ, et al. Systematic Review and Meta-analysis: Mental Health in Children With Neurogenetic Syndromes. Journal of the American Academy of Child and Adolescent Psychiatry, 2020.PMID 31945412