What is the recommended diagnostic evaluation and treatment approach for individuals suspected of having Autism Spectrum Disorder (ASD)?

Autism Spectrum Disorder Diagnosis

The diagnosis of ASD must be confirmed by a trained professional using objective criteria and standardized tools, with formal audiometry required before proceeding with genetic evaluation, followed by a tiered genetic workup that identifies an underlying etiology in 30-40% of cases. 1, 2

Initial Diagnostic Confirmation

Diagnostic confirmation requires administration of standardized measures by trained professionals, specifically the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2, sensitivity 91%, specificity 76%) and Autism Diagnostic Interview (sensitivity 80%, specificity 72%). 2, 3

• The diagnosis should include structured parent interviews, direct observation of behavior, and review of developmental history and past records. 1, 4
• Cognitive testing must be performed as part of the pre-evaluation workup. 1, 2
• Every individual with suspected ASD must have a formal audiogram to rule out hearing loss that could mimic ASD symptoms before proceeding with further evaluation. 1, 2, 4
• If clinical suspicion of seizures exists, obtain an electroencephalogram. 1, 2

Establishing a Medical Home

All persons with autism must have a designated primary care physician who coordinates diagnostic testing and ongoing care. 1, 2

• The primary care physician may make the diagnosis if trained and comfortable, or refer to specialists for diagnostic confirmation. 1
• The primary care physician should partner with clinical geneticists in ordering, scheduling, and coordinating recommended diagnostic testing. 1

Tiered Genetic Evaluation

A genetic consultation should be offered to all persons and families with ASD, as this identifies an underlying etiology in 30-40% of individuals. 2, 4

First Tier Testing

• Perform examination by a clinical geneticist with special attention to dysmorphic features, including Woods lamp evaluation for tuberous sclerosis. 1, 2
• Order high-resolution chromosomal analysis (karyotype) if not already performed (3% diagnostic yield). 1, 2
• Order DNA testing for Fragile X syndrome if not already performed (1-5% diagnostic yield). 1, 2
• If specific syndrome is suspected based on examination, proceed with targeted testing. 1
• Consider metabolic screening if clinical indicators are present and the condition was not assessed by newborn screening: urine mucopolysaccharides and organic acids, serum lactate, amino acids, ammonia, and acyl-carnitine profile. 1
• Obtain rubella titers only if clinical indicators are present. 1

Second Tier Testing

• Order chromosomal microarray (comparative genomic hybridization) with 10% diagnostic yield. 2, 4
• Order MECP2 gene testing in females only (4% yield in females with ASD). 2, 4
• Order PTEN gene testing if head circumference is >2.5 standard deviations above the mean (5% yield). 2, 4
• Consider fibroblast karyotype if leukocyte karyotype is normal and clonal pigmentary abnormalities are noted. 1

Third Tier Testing

• Consider brain magnetic resonance imaging. 1
• Measure serum and urine uric acid; if elevated, test for Hypoxanthine-guanine phosphoribosyl transferase (HgPRT) and Phosphoribosylpyrophosphate (PRPP) synthetase superactivity. 1
• If uric acid is low, obtain purine/pyrimidine panel (uracil excretion, xanthine, hypoxanthine). 1

Treatment Approach

Intensive behavioral interventions are first-line therapy, particularly for children 5 years or younger, focusing on improving language, play, and social communication skills with small to medium effect sizes. 2, 4, 3

• Behavioral interventions such as the Early Start Denver Model should be implemented as primary treatment. 3
• Pharmacotherapy is reserved exclusively for co-occurring conditions and specific symptoms, not for core ASD features. 2, 4, 3
• For irritability and aggression, risperidone or aripiprazole can be used (standardized mean difference of 1.1, large effect size), with dosing for risperidone at 0.02-0.06 mg/kg/day or weight-based dosing of 1.25-1.75 mg/day for patients >20 kg. 5, 3
• For co-occurring attention-deficit/hyperactivity disorder, psychostimulants are effective (standardized mean difference of 0.6, moderate effect size). 3
• Monitor for medication adverse effects including changes in appetite, weight, and sleep. 3

Genetic Counseling and Recurrence Risk

Provide genetic counseling to all families regardless of whether an etiology is identified. 2, 4

• For families without identified etiology, provide empiric recurrence risk data: full sibling recurrence risk is 3-10%, modified by sex (7% if affected child is female, 4% if affected child is male). 2
• With two or more affected children, recurrence risk is at least 30%. 2
• Schedule periodic reevaluations for patients without a definitive etiology, as diagnostic technology continues to evolve. 2

Critical Pitfalls to Avoid

• Do not delay diagnosis due to misconceptions about presentation, particularly in adults or atypical cases. 6, 2
• Do not order extensive genetic testing without clinical geneticist evaluation first, as the stepwise approach is more cost-effective and better tolerated by families. 2
• Do not fail to provide recurrence risk information to families, as this is essential for family planning. 2, 4
• Do not proceed with genetic evaluation before confirming the ASD diagnosis with objective criteria, as many neurodevelopmental disorders have overlapping phenotypes. 1