Laboratory Studies
The examiner must determine the nature and extent of the laboratory investigation following a history and physical examination. Recommendations have been made by both the American Academy of Pediatrics [24] and the American Academy of Neurology. [3]
Availability of genetic testing, and thus recommendations for work-up, are changing rapidly. Chromosomal microarray and new sequencing techniques have revolutionized genetic testing. [25]
Array-based comparative genetic hybridization (CGH) or "microarray" is increasingly used in the evaluation of intellectual disability (ID) and should be considered in the workup of all children with ID either after or as first-line instead of high-resolution karyotype and fragile-X testing (see below). The yield may be as high as 20%; however, a high false-positive rate can also confound interpretation. [26, 27, 28, 25]
High-resolution karyotype (at the 650 band level of resolution at least) should be completed in all children with ID. [24] Chromosomal abnormalities (trisomy 21 and others) may account for as many as 50% of those affected by severe to profound ID.
Fragile X testing (ie, DNA analysis of the FraX promoter region) should be ordered in all children with ID. [3] In the postpubertal period, the clinical manifestations of Fragile X syndrome are likely to be readily apparent, such that DNA analysis can be ordered with more selectivity in this population. Sex chromosome aneuploidy is seen in as many as 5% of children with mild ID or learning disabilities.
FISH probes are ordered as clinically indicated, as follows:
-
Prader-Willi/Angelman syndrome
-
Smith-Magenis syndrome
-
CATCH 22
-
Williams syndrome
-
Wolf-Hirschhorn syndrome
-
Cri du chat syndrome
-
Langer-Giedion (trichorhinophalangeal) syndrome
-
Miller-Dieker syndrome
Given their low yield, metabolic labs are not routinely ordered unless clinically indicated or newborn metabolic screen was not done or results are not available. [3]
-
Plasma amino acids (aminoacidopathies)
-
Urinary organic acids (organic acidopathies)
-
Urinary mucopolysaccharides and oligosaccharides (mucopolysaccharidoses)
-
Plasma 7-DHC (Smith-Lemli-Opitz syndrome)
-
Thyroid function tests
-
Very-long-chain fatty acids (peroxisomal disorders)
-
Creatine kinase (in the assessment of profound central hypotonia versus myopathy)
Consider lead testing in children with risk factors.
Next-generation sequencing through panels that target genes associated with a specific phenotype (such as epilepsy or autism) or whole exome sequencing are increasingly indentifying genetic etiologies in children and adults with previously unknown etiology for their ID.
Imaging Studies
Brain MRI
Brain imaging should be conducted in any child with global developmental delays or intellectual disability (ID). The yield will be higher in the setting of an abnormal neurologic examination (eg, microcephaly, focal neurologic finding and/or facial dysmorphisms). [3]
Brain MRI is generally preferred over CT scan because the former has greater resolution and enhanced detection of abnormalities in the progression and timing of myelination, demyelination, and heterotopic gray matter.
Head CT scan
This is the preferred imaging study for calcifications that may be identified with TORCH infections (ie, toxoplasmosis, other infections, rubella, CMV, herpes simplex), when tuberous sclerosis is suspected, or if craniosynostosis is a concern.
Skeletal films
These assist with the phenotypic description, syndrome characterization, and assessment of growth.
Other Tests
Detailed assessment by a licensed professional is necessary to confirm the diagnosis of intellectual disability (ID). Some of the most commonly used tests in children include the following:
-
Bayley Scales of Infant Development
Normalized for ages 2-49 months
Subtest scores for receptive and expressive language, gross motor, fine motor, cognitive/problem-solving ability, and sustained attention
-
Stanford-Binet Intelligence Scale
Normalized for ages 2 years to 23 years
Fifteen subtests for assessment of 4 key areas of cognitive proficiency: verbal reasoning, abstract/visual reasoning, quantitative memory, and short-term memory
-
Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R)
Normalized for ages 3 years to 7.25 years
Twelve subtests for assessment of verbal and nonverbal intelligence
-
Wechsler Intelligence Scale for Children–IV (WISC-IV)
For ages 6 years to 16 years, 11 months
Verbal and nonverbal intelligence scores derived from 12 subtests
-
Vineland Adaptive Behavior Scales-II
For neonates to adults
Measures ability to perform daily activities required for personal and social sufficiency; adaptive or functional behaviors rated by interviewing the patient or parent/caregiver
Deficiencies in at least 2 areas of adaptive skills required to meet the ID diagnostic criteria
Electrophysiologic studies
-
Auditory evoked potentials in the context of audiologic assessment
-
Visual evoked potentials in cases of profound delay and suspected cortical blindness
-
EEG is not recommended as part of the routine work-up of ID unless the history is suggestive of seizures or a specific epileptic syndrome. [3] Additionally, even an abormal EEG does not prove that the ID is due to seizures, and the interpretation and decision to treat rests more on the clinical history than the EEG result.
Histologic Findings
Pathologic analysis of cortical tissue by the Golgi method in the 1970s suggested that in cases of profound, unclassified intellectual disability (ID), dendritic spines were decreased and/or had immature morphology. These findings have been confirmed in cortical autopsy material from individuals with Down syndrome and FraX. Dendritic spine morphology is related directly to the intradendritic microtubular components and their organization.
Microtubules in dendrites of cortical neurons often are fragmented or in disarray in cases of developmental failure. In contrast, in some neuronal storage diseases associated with impaired cognition, dendritic spines are sprouted exuberantly beyond the developmental period and in ectopic locations. A relationship is implied, then, between dendritic spine morphology and number and cognitive development in the human.
