Developmental Disabilities and Pervasive Developmental disorders

1. Developmental Disabilities and Pervasive Developmental disorders Dr. Sophia Hrycko April 22, 2008

2. Objectives • To review Developmental Disabilities • To review Pervasive Developmental Disorders • To discuss comorbidity and treatment options

3. Developmental Disability • Often diagnosed in infancy • Mental retardation is the result of a pathological process in the brain characterized by limitations in intellectual and adaptive function. • Areas of function affected: communication, self-care, independence, functional/academic skills, work, health, leisure, safety

4. DSM-IV-TR • Mental retardation requires intellectual deficits (IQ measured by standardized test) and deficit in adaptive function (use of measure with deficits in at least two areas of deficits, Vineland Adaptive Behavior Scale: communications, daily living skills, socialization and motor skills) • Manifested before age of 18

5. Mild Mental Retardation • IQ between 50 and 70 • 85% of persons with MR • Often not identified before gr 1 or 2 • Can learn academic skills up to about gr 6 by late teens. • Can achieve social and vocational skills with minimal self-support but may require assistance when under stress (social, financial) • “Educable”

6. Moderate Mental Retardation • IQ 35-40 to 50- 55 • 10 % of persons with MR • Can talk or learn to communicate • Unlikely to progress beyond gr2 • May learn to travel alone to familiar places • May function under sheltered conditions in unskilled or semiskilled work. • “Trainable”

7. Severe Mental Retardation • IQ 20-25 to 35-40 • 4 % of persons with MR • Minimal speech, unable to profit from training in self-help (age 0 to 5) • Can learn to communicate or talk, be trained in elemental health habits. • Will require complete supervision.

8. Profound Mental Retardation • IQ below 20 or 25 • 1 to 2% of persons with MR • Most have an identifiable cause for their condition. • May be taught some self-care skills. • Will need nursing care.

9. Epidemiology • About 1 % of the population. • 1.5 time more common in men • High mortality rates with severe or profound MR because of complications associated with physical disorders.

10. Etiology • Prenatal • Genetic disorders • Congenital malformations/infections • Exposure: rubella, CMV, Syphilis, Toxoplasmosis, Herpes, AIDS, FAS • Maternal diseases: DM • Perinatal causes • Infections, delivery complications, trauma • Complications of prematurity: ischemia, hypoxia, intra cerebral hemorrhage • Postnatal causes • Environmental/Social (deprivation, malnutrition) • Infections, toxins, trauma, inborn errors of metabolism

11. Genetic • Genetic disorders account for 55% cases of moderate to severe MR, 10-15% of cases of mild MR • Mutation of single genes: Fra X and Rett syndrome with absence of single protein FMRP and MECP2 • Microdeletion syndromes: result from the deletion of multiple genes: Smith-Magenis syndrome, addition or absence of entire chromosomes such as Down syndrome, X and Y chromosome aneuploidies (47 XXY/Klinefelter syndrome, 45,X/Turner syndrome) leading to overexpression or imbalance of many genes and subsequent neurodevelopmental abnormalies. • About 25% more males have MR than females (males are uniquely vulnerable to genetic mutations on the X chromosome, they have only 1)

12. Comorbidity • Up to 2/3 of individuals with MR have comorbid mental disorders. • The more severe the MR, the higher the risk for other mental disorders. • Disruptive and conduct-disorder behaviors are more frequent in Mild MR • Autistic disorder more common with severely retarded individuals.

13. Evaluation • Complete history and physical exam • Will need to evaluate Intellectual function (WISC or WPPSI) and Adaptive function (Vineland Adaptive Behavior Scale) • Sensory screening ( speech, hearing) • Laboratory studies: • Genetic testing, metabolic testing, thyroid/lead screening, imaging

14. Practice Parameters: Evaluation of child with Global Develop. Delay • Metabolic screening NOT indicated in initial evaluation (yield 1%) • Routine cytogenetic studies and molecular testing for FRA X mutation recommended (yield 3.5-10%) • Consider Rett syndrome in girls with unexplained moderate to severe delay • Serum lead when identifiable risk • EEG NOT recommended initially unless features of epilepsy • Imaging with MRI > CT if physical findings • Shevell et al Neurology 2003 60: 367-380

15. Down Syndrome Down syndrome. Note depressed nasal bridge, epicanthal folds, mongoloid slant of eyes, low-set ears, and large tongue. • Trisomy 21, 95% nondisjunction • 1 in 1000 live births • 1 in 80 at 40 yrs • Hypotonia, upward slanted palpebral fissures, midface depression, flat wide nasal bridge, simian crease, short stature, increased incidence of thyroid anomaly and congenital heart disease. • Passive, affable • 25% ADHD • Verbal processing > auditory processing • Increased risk of depression and dementia as adult

16. Down Syndrome • A boy with Down syndrome at age A. 2 • B. age 5 • C. age 11 • D. age 14

17. Fragile X • Mutation of the FMRI gene at Xq27.3. Full mutation: CGG trinucleotide repeat > 200 to 230 repeats • Prevalence 1/1000 male births and 1/3000 female birth • Second most known cause of MR of genetic origin (10-12% MR in men) • long face, large ears, midface hypoplasia, arched palate

18. Fragile X • Macroorchidism • Short stature, strabismus, joint laxity • ADHD, anxiety, speech/language delays, shyness, irritability, stereotypies. LD in some female. • Male: moderate to severe MR • Female: mild MR

19. Fra X • Carriers may show enhancement of verbal comprehension skills, combined with drive for learning can make them exceptional students. • 45% of carrier males have advanced degrees (MS, MD, PhD) • Older carriers (M and F) have problems with tremor and ataxia associated with cognitive decline: Fragile X-associated tremor/ataxia syndrome (seen in 40% of M with premutation)

20. Praeder-Willi Syndrome • Deletion on long arm of chr. 15q11-15q13 (70% paternal, rest maternal uniparental disomy) • 1 in 15 000 birth • Hyperphagia • Obesity • Small hands/feet • Short stature • Microorchidism • Fair hair/light skin • Almond shaped eyes

21. Praeder-Willi Syndrome • Obsessions and compulsions • High rates of behavior problems: aggression, temper tantrums, emotional lability, daytime sleepiness • Increased risk for OCD, affective and impulse control disorders.

22. Phenylketonuria • Autosomal Recessive defect in phenylalanine hydroxylase 12q.24.1 or cofactor 11q22.3-q23.3 • Cause accumulation of phenylalanine if untreated and will result in MR (mild to profound), microcephaly, delayed speech, seizures and behavior problems (self-injury, hyperactivity) • Prevalence 1/12 000 • Fair skin, blue eyes, blond hair

23. Turner Syndrome • XO • Incidence: 1/2500 live births • Patient with Turner’s syndrome exhibiting short stature, low-set ears, webbed neck, shield chest, and widely spaced, hypoplastic nipples. • Cubitus valgus,cardiac defects, gonadal dysgenesis • Mild developmental disability is common • 25% ADHD

24. Tuberous Sclerosis • Autosomal Dominant • Mutation in TSC1 gene (hamartin) 9q34 or the TSC2 tumor suppressor gene (tuberin) 16p13 • Prevalence 1/6 000 • Spectrum of MR, none (30%) to profound • Epilepsy, autism, hyperactivity, impulsivity, aggression, self-injurious behaviors, sleep problems

25. Tuberous Sclerosis Figure 589-2 Tuberous sclerosis. A, CT scan with subependymal calcifications characteristic of tuberous sclerosis. B, The MRI demonstrates multiple subependymal nodules in the same patient (black arrow). Parenchymal tubers are also visible on both the CT and the MRI scan as low-density areas in the brain parenchyma.

26. Neurofibromatosis type 1 • Autosomal dominant • 17q11.2 • Prevalence 1/3 000 • (NF2 1/33 000, 22q) • Café au lait spots • Neurofibromas • Short stature and macrocephaly in 30- 45% • 10 % with moderate to profound MR • ADHD, anxiety, mood problems

27. Velocardiofacial Syndrome • 22q11.2 deletion syndrome • Prevalence 1/ 5900-1/9700 live birth • CATCH 22: Cardiac Anomaly, T-cell deficits, Clefting and Hypocalcemia • LD, pharyngeal hypotonia, slender hands/digits • 25% develop schizophrenia • ADHD 35-46% • anxiety

28. Fetal Alcohol Syndrome

29. Fetal Alcohol Syndrome • Most common preventable cause of MR • 1/3 000 live birth • Microcephaly, short stature, midface hypoplasia, short palpebral fissure • Thin upper lip, micrognatia, hypoplastic long/smooth philtrum • Mild to moderate MR, irritability, memory impairment

30. Mental disorders in Persons with MR • Increased risk (2 to 5) • ADHD, 9 to 18% • Impulse control disorders • Self-injury • Aggression • Anxiety Disorders • Psychosis NOS • Mood Disorders

31. Treatment • Multidisciplinary • Multimodal • Prioritize target symptoms and co-morbid medical conditions • Monitor multiple domains of functioning • Pharmacological interventions target specific symptoms • Family Support Programs: financial, respite

32. Pervasive Developmental disorders • Autistic Disorder • Rett’s Disorder • Childhood Disintegrative Disorder • Asperger’s Disorder • Pervasive Developmental disorder NOS

33. Autistic Disorder • Diagnostic Features • 3 main sets of behavioral characteristics:’ - Social abnormality - Language abnormality - Stereotyped repetitive pattern of behavior • Age of onset: prior to age 3 • Male/Female = 4/1 • Prevalence: 9.5 / 10 000 (range 2.3 to 30.8/ 10 000)

34. Autistic Disorder • Course: variable, strongest predictive factors for adult outcome are IQ (below 70 is strongly indicative of poor social adjustment) and the level of language functioning at age 5 • Etiology: unknown, evidence of strong genetic component; abnormal serotonergic activity, hyperdopaminergic activity

35. Diagnostic Criteria • Qualitative impairment in Social Interaction • Impairment in the use of multiple nonverbal behaviors: eye to eye gaze, facial expression, body postures and gestures to regulate social interaction • Failure to develop peer relationships appropriate to developmental level • Lack of spontaneous seeking to share enjoyment, interests or achievements with other people (not showing, bringing or pointing out objects of interests) • Absence of social or emotional reciprocity

36. Cont. • Qualitative impairment in Communication • Delay in or total lack of, development of spoken language (no attempt to compensate with gestures or mime) • If speech present, marked impairment in the ability to initial or sustain conversation with others • Stereotyped and repetitive use of language or idiosyncratic language • Lack of varied, spontaneous make-believe play or social imitative play appropriate to develop. level

37. Cont. • Restricted repetitive and stereotyped patterns of behavior, interest and activities • Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or in focus • Inflexible adherence to specific, nonfunctional routines or rituals • Stereotyped and repetitive motor mannerisms: hand or finger flapping or twisting, complex whole-body movements • Persistent preoccupation with parts of objects

38. Consider Evaluation if by: • 12 months: No babbling or gesturing (pointing, waving bye-bye) • 16 months: No single words • 24 months: No spontaneous 2 word phrases (i.e. not just echolalia or repeating someone else’s words) • Any age: any loss of any language or social skills

39. Consider Evaluation if • Especially when combined with language delays: • Abnormal eye contact • Aloofness • Not responding to one’s name • Not using gestures to point or show • Lack of interactive play • Lack of interest in other children

40. Autistic Disorder Associated Features • IQ below 70 for 75% of autistics • Uneven cognitive skills • Level of receptive language below expressive language • Behavioral symptoms: hyperactivity, impulsivity, aggressiveness, self-injurious behavior (head banging, finger/hand/wrist biting), temper tantrums • Abnormal mood (giggling or weeping) • Lack of fear

41. Autistic Disorder Associated Findings • Abnormal Imaging Studies: underactivation of fusiform gyrus, abnormality in the medial temporal lobe, increase in brain size in some • EEG abnormalities: varied, non-specific • Non-specific neurological symptoms: primitive reflexes, delayed hand dominance • Medical conditions associated with Autism: encephalitis, neurofibromatosis, PKU untreated, tuberous sclerosis, fragile X, anoxia, maternal rubella • Epilepsy in 10 – 35%

42. Rett’s Disorder (Andreas Rett 1966) • All of the following are required: • 1. Apparently normal prenatal and perinatal development • 2. Apparently normal psychomotor development through the first 5 months after birth • 3. Normal head circumference at birth

43. Rett’s Disorder cont. • Onset of all of the following after the period of normal development: • 1. Deceleration of head growth between ages 5 and 48 months • 2. Loss of previously acquired purposeful hand skills between ages 5 and 30 months with the subsequent development of stereotyped hand movements (e.g. hand-wringing or hand washing) • 3. Loss of social engagement early in the course • 4. Appearance of poorly coordinated gait or trunk movements • 5. Severely impaired expressive and receptive language development with severe psychomotor retardation

44. Rett’s Disorder cont • Prevalence rate: 1/ 15000 – 22 000 females • 26% incidence of sudden and unexpected death • X-linked dominant mutation with lethality in hemizygous males • Mutation in the transcription regulatory gene MECP2 • Stages: • Normal prenatal/perinatal development • Period of developmental stagnation • Gradual, insidious delay in development, decelerated head and body growth, lack of interest in the environment, loss of previously acquired skills (purposeful hand movements)

45. Rett’s Disorder cont • Developmental plateau (school age) • Severe MR • Seizures • Motor problems • Breathing difficulties (breath-holding spells, air swallowing) • Bruxism • Scoliosis • Final phase • Nonambulatory secondary to motor problems, scoliosis

46. Childhood Disintegrative Disorder (Heller 1908) • Apparently normal development for at least the first 2 years after birth as manifested by the presence of age-appropriate verbal and nonverbal communication, social relationships, play and adaptive behavior • Clinically signif. loss of previously acquired skills (before age 10) in > areas: • Expressive or receptive language • Social skills or adaptive behavior

47. Childhood Disintegrative Disorder cont. • Bowel or bladder control • Play • Motor skills • Abnormalities of functioning in at least 2 areas: • Qualitative impairment in social interactions • Qualitative impairment in communication • Restricted, repetitive and stereotyped patterns of behavior, interests and activities, including motor stereotypies and mannerisms

48. Childhood Disintegrative Disorder • Prevalence: 1.7 per 100 000 • Presence of a period of normal development before the onset of the deterioration and loss of skills • Typical age of onset 3 to 4 y old • Very rare, strong male predominance • Deterioration in self-help and motor skills is often marked • Apparently normal fife expectancy • Has been associated with metachromatic leukodystrophy, Schilder’s leukoencephalopathy

49. Asperger’s Disorder • Impairment in social interactions • Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction • Failure to develop peer relationships appropriate to developmental level • A lack of spontaneous seeking to share enjoyment, interests or achievements with other people • Lac of social or emotional reciprocity

50. Asperger’s Disorder • Restricted repetitive and stereotyped patterns of behavior, interests and activities • Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus • Apparently inflexible adherence to specific, nonfunctional routines or rituals • Stereotyped and repetitive motor mannerisms • Persistent preoccupation with parts of objects