Autism Spectrum Disorder — Viva

Q1: Take me through the DSM-5 criteria for autism spectrum disorder. How is ASD different from social (pragmatic) communication disorder? (2 min)

Autism spectrum disorder is defined in DSM-5 by five criteria, all of which must be met:^[1][9]

• (A) Persistent deficits in social communication and social interaction across multiple contexts (current or by history), in all THREE sub-domains: (1) social-emotional reciprocity (back-and-forth conversation, sharing of interests and affect); (2) nonverbal communicative behaviours (eye contact, body language, facial expression, gesture); (3) developing, maintaining and understanding relationships adjusted for developmental level.
• (B) Restricted, repetitive patterns of behaviour, interests or activities (at least TWO of FOUR, current or by history): (1) stereotyped or repetitive motor movements, speech (echolalia, verbal rituals) or object use (lining up, spinning); (2) insistence on sameness, inflexible adherence to routines, ritualised behaviour; (3) highly restricted fixated interests of abnormal intensity; (4) hyper- or hypo-reactivity to sensory input or unusual interest in sensory aspects of the environment.
• (C) Symptoms present in the early developmental period (may not fully manifest until demands exceed capacity, or be masked by learned strategies).
• (D) Clinically significant impairment in social, occupational or other areas.
• (E) Not better explained by intellectual disability alone — social communication must be below that expected for the general developmental level.

The diagnosis is annotated with specifiers (with/without intellectual impairment; with/without language impairment and the current level; associated with a known medical/genetic condition or environmental factor; associated with another neurodevelopmental/mental/behavioural disorder; with catatonia) and with severity levels 1 to 3 (requiring support; requiring substantial support; requiring very substantial support), graded separately for the social-communication and restricted/repetitive-behaviour domains.

DSM-5 collapsed the historical DSM-IV pervasive developmental disorders (autistic disorder, Asperger disorder, PDD-NOS, childhood disintegrative disorder) into the single ASD umbrella; Rett syndrome was removed to its own code.

Social (pragmatic) communication disorder (SCD) shares the social-communication deficits (criterion A) but lacks the restricted/repetitive behaviours and sensory features (criterion B). The single discriminating feature between ASD and SCD is therefore the presence (ASD) or absence (SCD) of the restricted/repetitive-behaviour and sensory domain — a frequent examination point.

Q2: Walk me through the pathophysiology. What is the evidence for a genetic basis, and what is the role of the environment? (3 min)

ASD is best understood as altered brain wiring beginning prenatally, driven predominantly by polygenic variation with contributions from rare high-effect variants and prenatal environmental/immune factors.^[9][11]

Genetics dominate the aetiology. Heritability estimates are 60 to 90 percent — most precisely quantified by Sandin et al. 2017 (JAMA), a Swedish population twin and family study that estimated heritability at about 83 percent with minimal shared-environment contribution.^[11] Bai et al. 2019 (JAMA Psychiatry), a five-country cohort, confirmed heritability of about 80 percent. The monozygotic twin concordance is 60 to 90 percent versus 0 to 20 percent for dizygotic twins, and the sibling recurrence risk is 10 to 20 percent (rising to 30 to 50 percent with two affected children) — the basis for universal sibling screening.

The genetic architecture is heterogeneous: common polygenic variants (SNPs of small effect, captured by polygenic risk scores) account for the majority of liability; rare de-novo and inherited copy-number variants (CNVs) explain 10 to 20 percent (e.g. 16p11.2 deletion/duplication, 15q11-q13 duplication, 22q11.2 deletion); and single-gene syndromic associations include fragile X syndrome (FMR1 — the commonest inherited cause of intellectual disability and the commonest single-gene ASD association), tuberous sclerosis complex (TSC1/TSC2 — the commonest neurocutaneous cause; 25 to 50 percent of TSC cases meet ASD criteria), Rett syndrome (MECP2), PTEN hamartoma tumour syndrome (with macrocephaly), CHD8, SHANK3, NLGN3/4 and NRXN1.

Brain-level mechanisms. Histologically there is abnormal minicolumn architecture (more numerous, narrower, less well-defined minicolumns), reduced GABAergic interneuron markers (GAD67, GABA-A receptor binding) and patchy heterotopic neurons — a fingerprint of late first- and second-trimester migrational error (8 to 24 weeks gestation). Macroscopically there is early frontal and temporal overgrowth in the first two years (increased total brain volume in about 15 percent), followed by plateau. White-matter tractography shows long-range under-connectivity (fronto-temporal, corpus callosum) producing weak global integration, with local short-range over-connectivity producing detail-focused processing — the biological substrate of weak central coherence. Key regions include the prefrontal cortex, the superior temporal sulcus and temporoparietal junction, the fusiform face area (hypo-active when viewing faces, explaining gaze avoidance), the amygdala (enlarged in early childhood; emotional salience and anxiety), the mirror-neuron system and the cerebellum (Purkinje-cell loss is one of the most consistent findings).

Neurochemistry. Blood (platelet) serotonin is elevated in 25 to 30 percent — the hyperserotonemia of autism (a biomarker, not causal). GABAergic dysfunction and glutamatergic dysregulation underpin the excitation/inhibition imbalance hypothesis. Oxytocin and vasopressin pathways are implicated in social affiliation; dopaminergic reward circuitry in restricted interests.

Environmental contributions are real but smaller than genetic factors — they include advanced parental age (de-novo mutations), prematurity and very low birth weight, perinatal hypoxic-ischaemic injury, maternal infection and fever, maternal autoantibodies to fetal brain proteins, sodium valproate and certain SSRIs in pregnancy, and maternal immune activation — all acting by modifying gene expression and brain development, not by 'causing' ASD in a deterministic sense.

Importantly, vaccines — including MMR and thimerosal — do NOT cause autism. The 1998 Wakefield Lancet paper was retracted as fraudulent, and large cohort studies (Hviid et al. 2019, Annals of Internal Medicine, Danish cohort of over 657 000 children) confirm no association.

Q3: How would you screen a child in primary care, and how do you confirm the diagnosis? (2 min)

The AAP (Hyman 2020) recommends developmental surveillance at every well-child visit (9, 18, 24 and 30 months) and universal autism-specific screening with the M-CHAT-R/F at 18 AND 24 months.^[1][5]

The M-CHAT-R/F (Modified Checklist for Autism in Toddlers, Revised with Follow-up; Robins 2014) is a 20-item parent questionnaire. A child screens positive on the initial screen with a total score of 3 or more (or any two of seven critical items). A positive initial screen triggers the structured Follow-Up Interview, which uses a standard script to clarify each endorsed item. If the child remains positive on the Follow-Up (score of 2 or more), the positive predictive value is about 47.5 percent for ASD and about 95 percent for ANY developmental concern — and the child is referred immediately for diagnostic evaluation AND early intervention (do not wait for diagnostic confirmation to begin services).

Diagnosis is clinical and multidisciplinary. A multidisciplinary team (paediatrician or child psychiatrist, clinical psychologist, speech-language therapist, occupational therapist, special educator, social worker) takes a detailed developmental and family history, observes the child directly, and uses the gold-standard instruments: the ADOS-2 (Autism Diagnostic Observation Schedule, 2nd edition — a standardised, semi-structured, interactive assessment with age/language-stratified modules) and the ADI-R (Autism Diagnostic Interview-Revised — a standardised parent interview covering developmental history). Psychological/cognitive (WPPSI-IV, WISC-V), adaptive (Vineland-3) and communication assessments complete the picture.

I would order audiology in every case (mandatory), chromosomal microarray and fragile X testing in confirmed cases (NICE CG128 and AAP), an EEG if there is regression or seizures (to exclude Landau-Kleffner), and MRI only if there are focal neurological signs or an abnormal head size. The diagnosis is NOT made by blood test, EEG or scan.

Q4: What is your management? How do you choose between behavioural intervention and medication? (3 min)

The pivotal principle is: there is NO medication that treats the core social-communication or cognitive deficits of ASD. The evidence base is for early, intensive, structured behavioural and developmental intervention, ideally starting before age 3 to 5 when the brain is most plastic; medications target comorbid symptoms only.^[1][6][9]

First-line is behavioural and developmental intervention:

• The Early Start Denver Model (ESDM) for children 12 to 48 months — naturalistic, play-based. The Dawson 2010 randomised controlled trial (Pediatrics) showed significant gains in IQ, receptive and expressive language, and adaptive behaviour in toddlers receiving ESDM versus community care.^[6]
• Applied Behaviour Analysis (ABA), Early Intensive Behavioural Intervention (EIBI, Lovaas) at 20 to 40 hours per week, Pivotal Response Training (PRT) and TEACCH structured teaching with visual supports.
• Communication — speech and language therapy targeting pragmatics; PECS and AAC devices for non-verbal children.
• Occupational therapy for sensory processing, motor coordination and activities of daily living.
• Education — an individualised plan (IEP / EHCP / 504) with a structured, predictable environment, visual timetables and movement/sensory breaks.
• Family-centred support — parent training, sibling support, respite, benefits advice.

Pharmacotherapy is symptom-targeted only:

• Severe irritability, aggression, self-injury refractory to behavioural measures — the two FDA-approved drugs for irritability associated with paediatric ASD are risperidone 0.5 to 3 mg/day PO (ages 5 to 16; McCracken 2002 RUPP NEJM trial) and aripiprazole 5 to 15 mg/day PO (ages 6 to 17; Marcus 2011).^[8][7] Both require baseline and periodic monitoring of weight, BMI, waist, fasting glucose and lipids, prolactin, EPSE/AIMS and ECG.
• ADHD comorbidity — methylphenidate or atomoxetine (slightly lower response and more adverse effects than in primary ADHD).
• Anxiety/depression/OCD — SSRI, fluoxetine first; START LOW, GO SLOW.
• Sleep disturbance — behavioural measures first; melatonin 2 to 6 mg PO at bedtime is evidence-based (CARI trial).
• Epilepsy — per seizure type (levetiracetam, lamotrigine; AVOID valproate in girls of childbearing potential).

Treatments NOT recommended — chelation, hyperbaric oxygen, secretin, megadose vitamins, gluten-free/casein-free diet, facilitated communication, MMS — all lack evidence and several are harmful.

The choice between behavioural therapy and medication is therefore not 'either/or': behavioural therapy is first-line and core; medication is reserved for specific symptom targets that have not responded to behavioural measures.

Q5 (examiner's probe): A 4-year-old girl has been referred to you with severe language delay, repetitive hand-flapping and food-texture aversion. Her parents are keen on a gluten-free, casein-free (GFCF) diet they read about online. How do you counsel them?

I would explain that the gluten-free, casein-free diet is NOT recommended for autism spectrum disorder. The AAP and NICE CG128 explicitly list it among the unsupported biomedical interventions to avoid, on the basis of systematic reviews showing no benefit on core ASD symptoms, behaviour or language, alongside real harms: nutritional deficiency (calcium, vitamin D, iron, fibre), restrictive-eating worsening in children who are already food-selective by sensory aversion, family burden and significant financial cost.^[1]

I would also address the underlying assumption — that diet 'treats' autism. There is no medication, diet or supplement that treats the core social-communication or cognitive deficits of ASD; the evidence base is for early intensive behavioural and developmental intervention (ESDM, ABA), speech and language therapy, occupational therapy and individualised education. I would acknowledge the parents' motivation and energy, and channel it into evidence-based interventions — the Early Start Denver Model, parent training, PECS for the non-verbal, OT for the sensory aversion, and a structured routine.

Practically I would: (1) direct the energy into ESDM/ABA and parent-mediated intervention, which is where the evidence lies; (2) work with a dietitian if there is genuine concern about the child's diet — sensory-based selective eating is common in ASD and benefits from structured OT and dietetic input rather than restriction; (3) ensure the child is on a balanced, developmentally appropriate diet with adequate calcium and vitamin D; (4) signpost the parents to reputable resources and parent-led organisations; and (5) explain the broader list of interventions to avoid (chelation, hyperbaric oxygen, secretin, megadose vitamins, facilitated communication, MMS) — several of which are dangerous.

Q6 (final probe): The same girl is found to have a head circumference at the 99.6th centile and an ash-leaf macule on her back. What is the most likely underlying syndrome, and what would you do?

The combination of autism spectrum disorder, a large head (macrocephaly), and an ash-leaf macule is highly suggestive of tuberous sclerosis complex (TSC1/TSC2) — the commonest neurocutaneous cause of ASD, with approximately 25 to 50 percent of TSC cases meeting ASD criteria.^[9] The ash-leaf macule is a hypomelanotic macule best seen under Wood's lamp; other cutaneous stigmata include facial angiofibromas (adenoma sebaceum), shagreen patches, forehead plaques and periungual fibromas.^[1]

Alternatively, the macrocephaly with hamartomatous lesions would raise PTEN hamartoma tumour syndrome (Bannayan-Riley-Ruvalcaba or Cowden syndrome) — PTEN testing is indicated in any child with ASD and a head circumference above 2.5 SD.

My plan would be:

• Clinical genetics referral and targeted genetic testing — TSC1/TSC2 (and consider PTEN) in addition to the chromosomal microarray and fragile X testing recommended for any confirmed ASD case.
• Detailed dermatological examination under Wood's lamp to document the cutaneous features.
• MRI brain to identify cortical tubers, subependymal nodules and subependymal giant-cell astrocytomas (SEGAs).
• Echocardiography (cardiac rhabdomyomas), renal ultrasound (angiomyolipomas and cysts), and fundoscopy (retinal hamartomas).
• EEG — epilepsy is common in TSC, and infantile spasms (West syndrome) are a particular risk; vigabatrin is first-line for TSC-related infantile spasms.
• mTOR inhibitor (everolimus) is now an established treatment for SEGAs and (under specialist guidance) for refractory epilepsy in TSC.
• Genetic counselling for the family — TSC is autosomal dominant with variable expressivity.

The principle: in any child with ASD and macrocephaly or dysmorphism/neurocutaneous features, actively look for a syndromic/genetic cause, because the management, surveillance and counselling differ fundamentally.

References8ShowHide

1. [1]Hyman SL, Levy SE, Myers SM Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics, 2020.PMID 31843864
2. [4]Shaw KA, Bakian AV, Bilder DA, et al. Early Identification of Autism Spectrum Disorder Among Children Aged 4 Years - Autism and Developmental Disabilities Monitoring Network, 2018. MMWR Surveill Summ, 2023.PMID 36952289
3. [5]Robins DL, Casagrande K, Barton M, Chen CM, Dumont-Mathieu T, Fein D. Validation of the modified checklist for Autism in toddlers, revised with follow-up (M-CHAT-R/F). Pediatrics, 2014.PMID 24366990
4. [6]Dawson G, Rogers S, Munson J, et al. Randomized, controlled trial of an intervention for toddlers with autism: the Early Start Denver Model. Pediatrics, 2010.PMID 19948568
5. [8]McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med, 2002.PMID 12151468
6. [7]Marcus RN, Owen R, Kamen L, et al. Safety and tolerability of aripiprazole for irritability in pediatric patients with autistic disorder. J Clin Psychiatry, 2011.PMID 21813076
7. [9]Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet, 2014.PMID 24074734
8. [11]Sandin S, Lichtenstein P, Kuja-Halkola R, Hultman CM, Larsson H, Reichenberg A. The Heritability of Autism Spectrum Disorder. JAMA, 2017.PMID 28973605