Intellectual disability , global developmental delay, disability certification, related disorders, screening , definitive tests, approach to evaluation, prevention and management strategies

1. GLOBAL DEVELOPEMENTAL DELAY
& RELATED DISORDERS
Presented By
Dr. Vaibhav Kumar Somvanshi
2nd yr Senior Resident Neurology
GMC Kota

2. Outline
1. Introduction
2. Developmental milestones
3. Epidemiology
4. Etiology
5. Approach to aChild with Developmental Delay
6. Differential Diagnosis
7. Management
8. Resources

3. Introduction
◦ Child development refers to how a childbecomes ableto do more
complex things asthey get older.
◦ Growth onlyrefers to the child getting bigger in size.
3Ds of Abnormalities of Development
Delay – Performance >/1 domain significant below avg.
Dissociation – Substantial difference in rate between >/2 domain
Deviancy Milestones achieving out of sequence
• IntellectualDisability-deficits of adaptive function(Conceptual
Skill, Social Skill, Practical Skill) and intellectual function
(reasoning, learning, problem solving)with an age of onset
before maturity is reached.

4. Definition
• GDD - children <5 yr of age - significant delay (>2 SD) in
acquiring early childhood developmental milestones in 2
or more domains of development. domains include
• receptive and expressive language,
• gross and fine motor function,
• cognition,
• social and personal development,
• activities of daily living.

5. Transient developmental delay
◦ Premature babies may show a delayin the area of sitting,
crawlingand walkingbut then progress on at a normal
rate.
◦ Other causes - related to physical illness, prolonged
hospitalization, familystress or lack of opportunities to learn.

6. Persistent developmental delay
◦ Delay in development in one or more of the followingareas:
 understanding and learning
 moving
 communication
 hearing
 seeing.
◦ An assessment is often needed to determine what area or areas are
affected.
◦ Disorders which cause persistent developmental delay are often termed
developmental disabilities.

8. Red flag Sign
• GM – Sitting with Support – 9 month
-Standing with support – 12 m
- Walking with support – 18 m
• FM – Pincer Grasp – 12m
-Scribbling – 24m
• Social – Social smile – 6m
- Waves bye bye – 12m
• Language – Babbling – 12m
- Single Word – 15-16m

9. Epidemiology
• Globally, the prevalence of ID
• 16.4 /1,000 persons in low-income countries, 15.9/1,000
middle-income countries,
9.2/1,000 in high-income countries.
• ID occurs more in boys than in girls,
• 2 : 1 in mild ID and 1.5 : 1 in severe ID.

10. Etiology
20%
8% 7%
3%4%
4%
7%

11. INHERITED CAUSES
Gray matter involvement :
A. with visceromegaly
– GM1 Gangliosides
– Niemann pick Disease
– MPS
– Gaucher disease
B. without visceromegaly
– Tay Sach disease
– Rett Syndrome
– Menke’s kinky hair disease
White matter involvement
– Metachromatic
leukodystrophy
– Krabbe disease
– Adrenoleukodystrophy
– Alexander disease

12. Differentiating
features
White matter
disorders
Gray matter
disorders
Age of onset Usually late (childhood) Usually early (infancy)
Head size May have
megalenchepal
y
Usually microcepaly
Seizures Late , rare Early, severe
Cognitive functions Initially normal Progressive dementia
Peripheral neuropathy Early demyelination Late, axonal loss
Spasticity Early, severe Later, progressive
Reflexes Absent(neuropathy)
or exaggerated(long
tracts)
Normal or exaggerated

13. Differentiating
features
White matter
disorders
Gray matter
disorders
Cerebellar signs Early, prominent late
Fundal examination May show optic atrophy Retinal degeneration
EEG Diffuse delta slowing Epileptic form
discharges
EMG Slowed nerve
conduction
velocity
Usually normal
Evoked
potentials
(VEP, ABR)
Prolonged or absent Usually normal
ERG Normal Abnormal

14. Regression
Normal Development
Illness/trauma

15. IMPORTANT CONSIDERATIONS
• Are the clinical features referable only to the central nervous system
or to both the central and peripheral nervous systems?
• – Nerve or muscle involvement suggests mainly lysosomal and
mitochondrial disorders.
• Does the disease affect primarily the gray matter or the white
matter?
• – Early features of
• Gray matter disease - personality change, seizures, and
• dementia/cognitive decline.
• White matter disease - Focal neurological deficits, spasticity,
and blindness.

16. OBJECTIVE OF EVALUATION
• Categorization of domains involved
• Identification of possible underlying etiology
• Referral to appropriate rehabilitation services
• Management of associated co-morbidities
• Multidisciplinary approach
• Counselling

17. History
• Birth history
• Developmental history
• Family history
• H/o of consanguinity
• Gestational history
• Coexisting medical problems
• Past medical history; treatment
• Social history
• Access to rehabilitation

18. Environmental Factors that MayPlace a Child at Risk
◦ Living in families that are at lower socioeconomic levels;
◦ Being born to teenage mothers or mothers more than forty years old;
◦ Being exposed prenatally to viruses, drugs, or alcohol;
◦ Being born into families with other children who have
developmental delays;
◦ Being born to mothers who were malnourished during pregnancy;
◦ Being born to mothers who have diabetes, thyroid disorders,
syphilis, or other viral infections.

19. Physical Examination Findings
Short / Large Stature
Obesity
Macro/Microcephaly
Dysmorphia
Eye Signs
Low set Ears
Structural Heart Anomaly
Organomegay
Macroorchidism/Hypogonad
Neurocutaneous
Hirsuitism
Hypo/Hypertonia
Ataxia

20. Eye Signs
Oil drop Catarct
Galactosemia
Congenital Catarct
Rubella Corneal Opacity
MPS, Lowe syn
Cherry Red Spot on macula
Tay Scahs , Neimann,
Metachromatic
leukodystrophy

21. Seizures
Myoclonic convulsion
Rett Syn, PME, JME

22. Skin
Adenoma Sebasium Hypopigmented
Macule
Ungual Fibroma Shagreen path

23. Organomegaly
Coarse Facies with
hepatospleenomegaly
MPS
Hepatospleenomegaly
Neimann Pick Disease, Tay
sachs , Galactosemia

24. Hair
Hirsuitism
Hurler syndrome Low hairline
Turner
Syndrome
Sparse Hair
Menkes Kinky
hair

25. BELIEVE IN HISTORY AND EXAMINATION !!!
(GLOBAL DEVELOPMENTAL DELAY)

26. Common Presentations of Intellectual Disability by Age
AGE AREA OF CONCERN
Newborn Dysmorphic syndromes, microcephaly
Early infancy (2-4 mo) Failure to interact with the environment
Concerns about vision and hearing
impairments
Later infancy (6-18mo) Gross motor delay
Toddlers (2-3 yr) Language delays
Preschool (3-5 yr) Language delays Behavior difficulties,
Delays in fine motor skills
School age (>5 yr) Academic underachievement Behavior
difficulties (e.g., attention, anxiety, mood)

27. Developmental Assessment
Developmental Age
Developmental Quotient = X 100
(DQ) Chronological Age
Mental Age
Intelligence Quotient = X 100
(IQ) Chronological Age

28. Grading Of ID
IQ
Mild ID  51-70
Moderate ID  36-50
Severe ID  21-35
Profound ID  0-20
IQ
Moron  50-70
Imbecile  30-50
Idiot  <30

29. Disability certification
Disability calculation
(i) VSMS score 0-20 Profound Disability 100%
(ii) VSMS score 21-35 Severe Disability 90%
(iii) VSMS score 36-54 Moderate Disability 75%
(iv) VSMS score 55-69 Mild Disability 50%
(v) VSMS score 70-84 Borderline Disability 25%
Age for certification: 1-5 yrs – GDD >5yrs – ID
Validity of Certificate: <5yrs  maximum 3 yrs/ 5 yrs age
Temporary certificate
>5yrs mention a renewal age( 5,10,18)
Lifelong certificate  Age >18 yrs

30. Screening Test for Development assessment
Below 3yrs
Phatak’s Baroda screening test
Ages & Stages Questionnaire
Revised DDST ( Denever Developmental Screening test)
Trivendrum Dev. Screening test
After 3 years
Binet-Kamath Test
Senguin form Board

31. • The Denver Developmental Screening Test - an efficient
and reliable method for assessing development.
Rapidly assesses 4 different components of development:
• Personal- Social
• Fine motor adaptive
• Language and
• Gross motor.

33. Screening Test for IEM
• TMS – Tendem mass spectroscopy – Dried blood spot
• GCMS – Gas Chromatography mass spectroscopy -
Urine

34. Definitive Test for Dev./Intellectual assessment
• Vineland adaptive behaviour scale – birth – 89 yrs
• Baeyer scale for infant development – 1m – 3yrs
• Stanford binet intelligence scale – 2-85 yrs
• Wechsler intelligence scale for children – 6-17 yrs

36. Treatable Intellectual Disability Endeavor
(TIDE) Diagnostic Protocol
Tier 1:
Blood
S. amino acids
S.homocysteine
S.Copper,
ceruloplasmin
Urine
Organic acids
Creatine metabolites
Tier 2:
Audiology
Ophthalmology
Cytogenetic testing
Thyroid studies
Metabolic testing
Brain MRI
Fragile X
Targeted gene
sequencing/molecular
panel
Tier 3:
Specific biochemical/gene
test
Whole blood manganese
Plasma 7-
dehydroxycholesterol:c
holesterol ratio
Plasma very-long-chain
fatty acids

38. Mimickers
• Severe malnutrition
• Systemic illness
• Progressive hydrocephalus
• Parental misperception of attained milestones
• Side effects of drugs
• Emotional deprivation
• Depression

39. Down Syndrome
• MC cause Of ID- Trisomy 21
• Mc d/t Maternal meiotic non disjunction (95%)
• d/t Translocation (3%)
• d/t mosaicism (1-2%)
• C/F – incurved little finger, ID
• CHD, congenital hypothyroidism
• Attlanto axial instability, absent moros reflex
• Protruding tongue
• Mongoloid face
• Epicanthal fold, flat occiput Simian Crease

40. • Biochemical Markers
• 1st tri – B- HCG PAPP-A (Dual)
• 2nd tri –
Tripple test  AFP , B-HCG, U- Estradiol
Quadruple test  Triple test + Inhibin
‘HI” = HCG & Inhibin level increased in Down

41. Case scenario – A couple already has child with down
syndrome – prediction of recurrence in next pregnancy
Karyotype of
affected child
Trisomy 21
Transloaction
(t21;21)
Transloaction of 21
with other
chromosome
Karyotype of
father
(N)
(N)
Carrier
(N)
(N)
Carrier
(N)
Karyotype of
mother
(N)
(N)
(N)
Carrier
(N)
(N)
Carrier
Recurrence
Risk
1%
1%
100%
100%
1%
1-3%
10-15%

42. Fragile X syndrome
• Gene – FMR1 gene on Chromosome X
• 2nd MC genetic cause for ID (after Down)
• Genetic basis –
• Normal – 5-55 CGG repeats
• Carrier – 55-200 repeats
• Syndrome - >200 repeats
• C/F – Long Face, testes
• Large Mandible, Ears
• Hyper extensible joints
• High Arched palate
• Mitral Valve Prolapse Increased T2 intensity
MCP

43. Rett syndrome
• Females, X-linked Dominant,
• Mutations in the gene encoding methyl-CpG-binding protein-
2, -- on chromosome Xq28
• Normal during 1st year  Decceleration of head growth
• Aquired microcephaly, lack of interest in the environment &
hypotonia, loss of language skills, gait ataxia, seizures, and
autistic behavior.
• Characteristic feature - loss of purposeful hand
movements before the age of 3.
• hand wringing movement, Repetitive blows to the face

44. Parietal grey matter Loss
DTI – Subcortical white
matter loss

45. HOMOCYSTINURIA
• AR inheritance
• complete deficiency of the
enzyme cystathionine- b
synthase
• Two variants –
– B 6 - responsive &
– B 6 –nonresponsive

46. • Affected individuals appear normal at birth.
• Neurological features – Failure to thrive, marfanoid habitus,
mild to moderate ID, ectopia lentis, and cerebral
thromboembolism. Developmental delay ( 50% cases)
• Intelligence generally higher in B 6 –responsive cases.
• The presence of either thromboembolism or lens dislocation
strongly suggests homocystinuria.
• Diagnosis - increased concentrations of plasma, Urine
homocystine.
Enzyme Assay in Liver biopsy/skin fibroblast
Treatment – High Doses B6 and folic acid
Restriction of methionine , Cysteine supplementation

47. TAY SACHS DISEASE
• Initial symptom - between 3-6 months - an abnormal
startle reaction (Moro reflex) to noise or light.
•Delayed achievement of motor milestones or loss of
milestones previously attained.
• Cherry-red spot on macula present
• By 1 year - severely retarded, unresponsive, and
spastic.
• 2nd year - head enlarges and seizures develop.
• Most children die by 5 years of age.

48. • Diagnosis - psychomotor retardation and a cherry-red spot on the
macula.
• Demonstration of absent to nearly absent b -hexosaminidase
Management - Treatment is supportive
Bilateral thalamic
Calcification T1
Hyperintense T2
Hypointense lesion
without contrast
enhancement

49. Organic acidemia
C/F
Lethargy
Poor feeding
Vomiting
Sz
Dev. Delay
Coma
Disorder Urine odour
Multiple Carboxy def. Tom cat
Tyrosinemia Boiled cabbage
Phenylketonuria mousy smell
Maple Syrup Burnt sugar

50. Approach Organic acidemia
Refusal to
Feed/vomiting/Acidosis/Hypoglycemia
Urine Ketones
Elevated Normal
Organic Acidemia NH3 LevelSkin Rash
Multiple
Corboxylase
Deficiency
Specific Odour
MSUD MMA
B- Ketothiolase
Deficiency
Fatty acid
Oxidation
defect
Urea
cycle
Defect
+ (-) (n)
( )

51. Maple Syrup Urine Disease
• Deficiency of Alpha Keto acid Dehaydrogenase
• Accumulation of Branched chain amino acid – Leucine,
isoleucine, valine
• Urine smell – burnt sugar/maple syrup
• Diagnosis- marked increase level – L,I,V in plasma and
urine – detected by Electrophoresis/HPLC
• DNPH test- Yellow color
• FeCl3 – blue color

52. T1 Hypointense T2 Hyperintense DW restriction d/t metabolic crisis in MSUD
B/L cerebellar hemisphaere, Dorsal brain stem, B/L thalami, globus pallidae, posterior
limb of IC

53. Prevention
• Increasing the public's awareness -alcohol and drugs of
abuse
• Encouraging safe sexual practices- preventing teen
Pregnancy
• Focus on preventive programs to limit transmission of
Diseases-syphilis, toxoplasmosis, cytomegalovirus, HIV).
• Preventing traumatic injury by encouraging the use
of guards, railings, and window locks
• Implementing immunization programs - reduce the risk of ID
caused by encephalitis, meningitis

54. MANAGEMENT
Core symptoms of ID itself are generally not treatable
medication useful in the treatment - associated behavioral and
psychiatric disorders
ADHD - (stimulant medication)
self-injurious behavior and aggression (antipsychotics)
depression (selective serotonin reuptake inhibitors)
Supportive Care – speech therapy, occupational therapy
Interdisciplinary Management
(Neurology,paedia,psychiatry,PMR)
Leisure and Recreational activities
Family Councelling

55. Transition to Adulthood
• Transition to adulthood - stressful and chaotic time for
both the individual and the family
• Several domains of transition must be addressed, such
as education and employment, health and living,
finances and independence, and social and community
life.

56. SPECIFIC TREATMENT

58. Prognosis
• life expectancy - mild ID is similar to the general
population, with a mean age at death in the early 70s
• severe and profound ID have a decreased life
expectancy at all ages - associated serious neurologic or
medical disorders, with a mean age at death in the mid-
50s
• For children with mild developmental delays and
absence of any red flags, appropriate stimulation
activities promising.

59. EMERGING THERAPIES
• Genetic manipulations such as adenoviral-mediated gene
therapy, protein replacement strategies
• microRNAs that can inhibit production of specific key
pathway proteins
• Histone deacetylase inhibitors- Histone acetylation appears
to be involved in memory formation and fragile X syndrome
show decreased histone acetylation
• Mesenchymal stem cell administration- fragile X
• Early trials show problems with demonstrating disease
modification as considerable phenotypic heterogeneity exists
and many uncertainties remain about how to show treatment
effects optimally in a clinical trial setting

60. Take Home
• Thorough History will bring down monetary as well as
emotional burden and unnecessary testing
• Pin pointing diagnosis helps in targeted management
and improved outcome
• Diagnosis of an underlying genetic cause is increasingly
important with the advent of new treatments
• More research is needed to elucidate its complex
molecular basis.

61. THANK
YOU

62. References
• Bradley's Neurology in Clinical Practice.2016.7th ed, chapter
8
• Continuum neurology feb 2018 child neurology
• Nelson Textbook of Pediatrics, 21th edition, chapter 53
• Frankenburg, W.K. (1967). "The Denver Developmental
Screening Test". The Journal of Pediatrics. 71 (2): 181–191
• Vasudevan P, Suri M. A clinical approach to developmental
delay and intellectual disability. Clin Med (Lond).
2017;17(6):558-561. doi:10.7861/clinmedicine.17-6-558
• http://disabilityaffairs.gov.in/content/page/guidelines.php

63. COST OF VARIOUS TESTS AT LABS INDIA