This document provides information on evaluating and investigating children with global developmental delay (GDD) or intellectual disability (ID). It defines GDD and ID and outlines the similar investigations pursued for both, including medical history, physical exam, genetic testing like chromosomal microarray and metabolic testing of blood and urine. The diagnostic yield of investigations is highest when focused on identifying potentially treatable inborn errors of metabolism or single-gene disorders. The document recommends chromosome microarray as the first-line genetic test and discusses other genetic tests, metabolic tests, imaging and neurological evaluation that can help identify underlying etiologies.

1. Global developmental delay &
Intellectual disability
Dr. Dilip Choudhary
Department of Pediatrics
TN Medical College &
BYL Nair Hospital,
Mumbai

2. • Children with GDD often evolve to meet
diagnostic criteria for ID and probably represent
the same population.
• Because the etiological diagnoses of GDD and ID
overlap, it is natural that investigations in pursuit
of a definitive diagnosis for either disorder are
similar.
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3. Definition
Global developmental delay
At least two SD below age appropriate mean
development in at least two of the following areas:
• Gross or fine motor
• Speech/language
• Cognition
• Social/personal
• Activities of daily living
Reserved for children <5 years old
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4. Intellectual disability (intellectual developmental disorder):
The following three criteria must be met:
(1.) Deficits in intellectual functions, such as reasoning,
problem solving, planning, abstract thinking, judgment,
academic learning and learning from experience.
(2.) Deficits in adaptive behavior- conceptual/social/practical
skills.
Without ongoing support, it limit functioning in one or
more activities of daily life, such as communication, social
participation and independent living, across multiple
environments, such as home, school, work and
community.
(3.) Onset of intellectual and adaptive deficits during the
developmental period.
Applies to children >5yr and adults with onset before <18 yrs
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5. Unexplained or non-syndromic GDD/ID
• GDD/ID without any other discernible clinical feature.
• Why diagnosis is critical?
(a) clarification of etiology
(b) Improved prognostication
(c) Accurate genetic counselling regarding recurrence risk and
antenatal genetic diagnosis.
(d) Possible treatment options
(e) Avoidance of unnecessary diagnostic tests
(f) Provision of a link to condition specific family support groups
(g) Access to research treatment protocols
(h) Better access to services in the community
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6. Approach to GDD/ID
History
Prenatal history • Prenatal ultrasound
• Screening for fetal aneuploidy
• Maternal diabetes or hypertension
• Infections
• Exposure to medications or toxins
Birth history • Weight and height
• Head circumference
• APGAR score
• Hospitalization
Developmental milestones • Regression or lack of milestones
• Timing of parents’ first concern
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7. Family history Physical exam
(Three-generations review, looking for)
• Recurrent miscarriages
• Birth defects
• Infant deaths
• GDD/ID
• Neurologic conditions
• Genetic conditions
• Consanguinity
Psychosocial history Parent language, education, employment
• Parental drug/alcohol abuse
• Child care arrangements
• History of abuse or neglect and
involvement of child protective services
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8. Examination
Physical exam • Growth parameters
• Head shape
• Fontanelle
• Cutaneous stigmata
• Spine
• Heart abnormalities
• Abdomen check for organomegaly
• Limb abnormalities
• Genital abnormalities
Neurodevelopmental exam • Neurological exam
• Congenital abnormalities
• Dysmorphic features
• Current developmental level
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9. Sensory evaluation
• Assessment of their vision
• Hearing assessment
• Identifying a sight or hearing deficit can alter
management course and guide further
investigation
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10. Genetic testing
(A) Chromosome microarray (CMA):
• Also k/as comparative genomic hybridization(CGH)
• Gold standard first line genetic investigation for unexplained
GDD/LD, replacing chromosomal G-banded analysis
(karyotyping)
• Single test with the best diagnostic yield (at 8% to 20%)
• Higher diagnostic yield primarily because of higher
sensitivity for submicroscopic deletions and duplications.
• When multiple congenital anomalies are present, CMA is a
first-line investigation, unless a specific diagnosis is being
considered
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11. Three possible results may be attained from array CGH:
(a) Normal result with no clinically significant variation
(b) Definitely abnormal result with a known pathological
variation
(c) Variation of unknown significance (VUS).
• VUS are often copy number variations (CNVs) that are
variations in the expected number of copies of DNA in
certain segments of the genome.
• Every person has approx 100 CNVs which can affect
numerous genes but are only sometimes pathogenic.
• It may be difficult to establish the significance of some
CNVs and targeted parental array CGHs are usually
recommended in the first instance to help with the
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12. (B) Chromosomal G-banded analysis (Karyotype):
Not recommended as a first line test, because its
sensitivity is less than one-half that of CMA
The resolution is 5 Mb to 10 Mb compared with 0.05
Mb to 0.1 Mb with CMA.
 Recommended as first line genetic investigations if
(a) Chromosomal syndrome is recognised in neonatal or
infant period that will result in GDD or ID such as an
aneuploidy (e.g. trisomy 13, 18 or 21),
(b) Family history of chromosomal rearrangement
(c) Maternal or paternal H/O of multiple miscarriages
(d) Low level mosaicism (<20 %) is suspected.
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13. (C) Whole-exome or -genome sequencing
Permits analysis of coding regions for known
genes and the identification of causal mutations
in up to 40% of patients with severe ID
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14. (D) Fragile X DNA testing
• For children with ID, Fragile X is the most common
genetic cause, representing 2% to 6% of affected boys
and 1% to 4% of affected girls.
• To be added to the first line genetic investigation list:
(a) males with moderatesevere GDD/ID
(b) females with mild/moderate/severe GDD/ID
without profound physical handicap
• Because the clinical phenotype is often nonspecific in
infants and young children with Fragile X, Fragile X
DNA (FMR1) testing be considered as part of first-line
investigation
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15. (E) Rett syndrome testing:
Rett syndrome is found in 1.5% of girls with
moderate-to-severe ID
MECP2 molecular analysis should be ordered
when characteristic symptomatology is present-
• Initially normal development f/b loss of speech
and purposeful hand use
• Stereotypical hand movement
• Gait abnormalities
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16. (F) Additional genetic analysis:
for genomic imprinting disorders eg.
Prader–Willi syndrome,
Angelman syndrome,
Beckwith–Wiedemann syndrome
Silver–Russell syndrome.
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17. Metabolic investigations
Red flags suggestive of inborn errors of metabolism
• Family H/O IEM or GDD or unexplained neonatal or sudden infant death
• Consanguinity
• Intrauterine growth retardation
• Failure to thrive
• Head circumference or stature growth abnormality
• Recurrent episodes of vomiting, ataxia, seizures, lethargy, coma
• Regression in developmental milestones
• Behavioural or psychiatric problems (e.g., psychosis at a young age)
• Movement disorder (e.g. dystonia)
• Facial dysmorphism (e.g. coarse facial features)
• Organomegaly
• Severe hypotonia
• Sensory deficits, especially if progressive (e.g., cataracts, retinopathy)
• Noncongenital progressive spine deformities
• Neuro-imaging abnormalities
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18. Laboratory investigations for unexplained GDD/ID
Blood tests Urine tests
•CBC
•Glucose
•Blood gas with anion gap
•KFT (Urea, creatinine)
•Electrolytes
•AST, ALT
•TSH
•Creatine kinase
•Ammonia
•Lactate
•Amino acids (PAA)
•Homocysteine
•Ferritin, vitamin B12 when dietary
restriction or pica are +nt
•Lead level when risk factors for exposure
are present
• Urine amino acids (UAA)-including
urine orotic acid.
• Creatine metabolites
• Purines, pyrimidines
• Glycosaminoglycans (GAGs)
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19. Full blood count and blood film
Macrocytic anaemia
•Organic acidaemias especially MMA, hereditary orotic
aciduria or in homocystinuria.
Normocytic anaemia
•Organic acidaemias or
•Erythropoietic glycolytic enzyme deficiency.
Predominant/isolated neutropaenia
•Inorganic acidaemias,
•GSDs or Barth syndrome.
Predominant thrombocytopaenia
•Organic acidaemias
•Lysosomal storage disorders (LSDs).
Vacuolated lymphocytes in peripheral blood film
•some LSDs such as classical juvenile neuronal ceroid
lipofuscinoses (NCL)
Plasma glucose
•Reduced: FAODs, mitochondrial disorders and organic
acidaemias.
•Post-prandial elevation : Glycogen synthase deficiency
(GSD), which presents with recurrent hypoglycaemia
and ketosis.
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20. Liver function tests
May be abnormal in tyrosinaemia, UCDs, FAODs,
mitochondrial disorders, galactosaemia, peroxisomal
disorders
and congenital disorders of glycosylation
Plasma urea and electrolytes
May be abnormal in renal tubular dysfunction dehydration.
Urea is frequently low in UCDs and
Creatinine may be low in creatine synthesis disorders.
Paired plasma urate and
urine urate/creatinine
(U/CR) ratio
Low plasma urate and low urine U/CR ratio
Defect in purine metabolism,
Molybdenum cofactor deficiency
Sulphite oxidase deficiency.
High plasma urate and high urine U/CR ratio
Lesch–Nyhan disorder,
Phosphoribosyl pyrophosphate synthetase superactivity or
GSDs.
High plasma urate and low urine U/CR ratio
Renal dysfunction.
Low plasma urate and high urine U/CR ratio
Renal tubular losses.
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21. Plasma amino acids (PAA)
•60 min “pre-prandial” sample
•Diagnostic in aminoacidopathies and helpful
in identifying some mitochondrial disorders
and urea cycle defects (UCDs)
Plasma lactate
• 60 min “post-prandial” sample
• May be elevated in mitochondrial,
biotin responsive, some glycogen storage
(GSDs), metabolism of pyruvate,
gluconeogenic, organic acid, fatty acid
oxidation (FAODs) and amino acid
metabolic disorders.
•For accurate results, lactate should be taken
without a tourniquet and transported on ice.
Venous blood gas with anion gap
•Low pH may indicate metabolic acidosis due
to an organic acidaemia or lactic acidosis,
•High Ph may indicate respiratory alkalosis
due to a UCD and a low bicarbonate level
may indicate an organic acidaemia.
Plasma creatine phosphokinase (CPK)
•Elevated in muscular dystrophies, even
without overt muscle weakness,
mitochondrial disease and FAODs.
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22. Total plasma homocysteine Only if
(a) plasma methionine is elevated to investigate for
classical homocystinuria or remethylation disorders of
homocysteine
(b) plasma methionine is decreased, to investigate for
methionine synthase deficiency or
methylenetetrahydrofolate
reductase deficiency or
(c) MMA is elevated on UAA analysis
to exclude severe vitamin B12/folate
deficiency and cobalamin defects.
Plasma acylcarnitine profile •Not included in first line investigation,
•Should be included to screen for FAODs if there is a
history of hypoglycaemia, prolonged failure to thrive,
hypotonia, cardiomyopathy, an elevated CPK
level or any obvious abnormality associated with energy
metabolism.
Total urine
glycosaminoglycans (GAGs)
•Screening test for MPS and some other LSDs.
•False positive results are commonly observed on
samples analysed from urine collection bags.
•False negative results occur particularly in patients with
Sanfilippo (MPSIII) and Morquio (MPS IV) diseases.
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23. Thyroid function testing:
• Common, reversible cause of GDD/ID, with an
incidence of approx 1 out of 3,500 live births.
• It is included whether or not newborn screening
is performed, so that acquired and central
hypothyroidism cases are not missed.
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24. Iron and vitamin B12
• Complete blood count, ferritin and vitamin B12
• Especially when there is a history of pica or
feeding restrictions.
• Iron deficiency anemia and Vit B12 deficiency is
an easily identifiable and treatable cause of
altered development.
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25. Lead
• Lead poisoning can affect mental and physical
development severely, especially in children
younger than 5 years of age.
• Lading to conditions such as autism spectrum
disorder, loss of milestones (particularly related
to language) and encephalopathy
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26. Testing for congenital infections
• TORCH titre when neurological anomalies,
microcephaly, hearing and/or vision loss are
present.
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27. Neuroimaging (CT/MRI)
• Reveal nonspecific abnormalities in approx 30% of
children with GDD/ID.
• But contributes to understanding the etiology
underlying GDD/ID in only 0.2% to 2.2% of cases.
• The diagnostic yield improves when an abnormal
neurological examination, seizures or macro or
microcephaly are present.
• MRI is preferred because it is more sensitive for
identifying clinically significant structural
abnormalities and anomalies related to
myelination and neuronal migration.
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28. • AAP does not recommend neuroimaging as a
routine investigation for children with GDD/ID.
• While the AAN recommends performing an MRI
on all patients when chromosomal microarray,
Fragile X testing and MECP2 (if indicated) have
been inconclusive.
• Brain MRI with spectroscopy is indicated in all
cases of intractable epilepsy or developmental
regression.
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29. Electroencephalogram
• Uncontrolled epilepsy or epileptic syndromes,
such as Landau-Kleffner syndrome, can be
associated with developmental delays or
regression.
• Seizures are a common symptom of IEMs.
• An EEG is justified when there is clinical suspicion
of seizures, speech regression/ neurodegenerative
disorder
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30. Some treatable IDs
Biochemical category Disease name
Amino acids •HHH syndrome (hyperornithinemia,
hyperammonemia, homocitrullinemia
•Phenylketonuria
•Tyrosinemia type II
•Late onset Non-ketotic hyperglycinemia
Lysosomes •Gaucher disease type III
•Hunter syndrome (MPS II)
•Hurler syndrome (MPS I)
•Metachromatic leukodystrophy
•Niemann–Pick disease type C
•Sanfilippo syndrome A,B,C,D (MPS III)
•Sly syndrome (MPS VII)
Metals •Aceruloplasminemia
•Menkes disease/Occipital horn syndrome
•Wilson disease
Mitochondria •Co enzyme Q10 deficiency
•MELAS
•PDH complex deficiency
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31. Organic acids •Cobalamin deficiency
•Glutaric acidemia
•Maple syrup urine disease
•Methylmalonic acidemia
Urea cycle •Argininemia
•Argininosuccinic aciduria
•Citrullinemia
•Citrullinemia type II
•CPS deficiency
•NAGS deficiency
•OTC Deficiency
Vitamins/co-factors •Biotinidase deficiency
•Biotin responsive basal ganglia disease
•Cerebral folate receptor-α deficiency
•Congenital intrinsic factor deficiency
•Holocarboxylase synthetase deficiency
•Molybdenum co-factor deficiency type A
•Pyridoxine dependent epilepsy
•Thiamine responsive encephalopathy
Neurotransmission •Biopterin deficiency
•Tyrosine Hydroxylase Deficiency
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33. References
1. AAP clinical report “Comprehensive Evaluation of the
Child With Intellectual Disability or Global
Developmental Delays” (2014)
2. Canadian Paediatric Society “Evaluation of the child
with global developmental delay and intellectual
disability” (2018)
3. Unexplained developmental delay/learning
disability: guidelines for best practice protocol for
first line assessment and genetic/metabolic /
radiological investigations (2015)
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