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Autism Spectrum Disorders or Pervasive Developmental Disorders

Autism Spectrum Disorders or Pervasive Developmental Disorders. N. Zelnik – Child Neuology and Development Carmel Medical Center and Clalit Health Services – Haifa district. Autism Spectrum Disorders/PDD. Infantile Autism High Functioning Autism Asperger Syndrome

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Autism Spectrum Disorders or Pervasive Developmental Disorders

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  1. Autism Spectrum DisordersorPervasive Developmental Disorders N. Zelnik – Child Neuology and Development Carmel Medical Center and Clalit Health Services – Haifa district

  2. Autism Spectrum Disorders/PDD • Infantile Autism • High Functioning Autism • Asperger Syndrome • Disintegrative Disorder • PDD not otherwise specified (PDDNOS) • Rett Disorder (not included)

  3. Chromosomes associated with ASD(1/3) • Chr. 1: deletions in 1q &1p.22, • Chr. 2: deletion 2q37 + partial trisomy 6p21-15 • Chr. 3: case report of t (3;12)(p26.3;q23.3) • Chr. 4: case report of t (4q11;10p5.3) • Chr. 5: translocations: 5;Y & 5;11 +several deletions • Chr. 6: parial trisomy 6p21-25, deletion 6q.21-25,… • Chr. 7: t (7;20), del 7p21-inv7p13-21, 7q21, 7q31-33, … • Chr. 8: several trans., deletions or mosaics 8nl/trisomy, • Chr 9: in ASD + TSD (TSC1) hamartin, also del & trans • Chr10: linkage in locus 10q21.2, several translocations, • Chr 11: linkage in locus 11p15.5, HRAS gene, few trans • Chr 12: PAH in PKU & few translocations (incl. TSD) • Chr 13: Trisomy 13 (Patau) MR+autism, few deletions,

  4. Chromosomes associated with ASD(2/3) • Chr. 14: ???? • Chr. 15: locus 15q11-1 (near Angelman):dup, del, others.. • Chr. 16: TSD-TSC2 (tuberin) at 16p13, partial trisomy, tran • Chr. 17: NF-I (17q11), Smith-Magenis synd (17p11), gene of serotonin transporter, other loci of trans or del. Chr. 18: 18q21.1: cases with deletions, dupl, mosaics, … • Chr.19: CTG repeats at 19q3.3 in cases with Asperger synd • Chr. 20: deletions at p11.2, trans. 20;22, …. • Chr. 21: in few cases with Down syndrome • Chr. 22: in few cases with trisomy 22 & ring chromosome • Chr. X: many cases with F-RAX (CGG expansions at FMR1) also in Turner (XO) and other loci on X • Chr. Y: trans 5;Y and patients with XYY syndrome • Mitochondrial DNA: in Leigh, MERRF, tRNA (G8363a), Complex I and COX defects, nuclear DNA mutations

  5. Genetics of ASD(3/3) Studies from 2002-20031. Jamain S et al: Mutations in genes encoding neuroligins NLGN3 & NLGN4 are associated with autism. 2. Weiss LA et al: Sodium channels SCN1A, SCN2A and SCN3A in familial autism. (autism and epilepsy) _____________________ In families: 2-4% in siblings (X 50) Conclusion:many genetic entities, polygenic heredity

  6. Brain anomalies in ASD Developmental variations of brain structure 1. Megalencephaly in 18-37% of patients with ASD. 2. Enlargement of temporal & parietal lobes vs. nonenlarged frontal lobe. 3. Hypoplasia of corpus callosum. 4. Hypoplasia of lobules VI + VII of Cerebellum. 5. Reduced thalamic volume in high functioning ASD. 6. In many of these cases changes in perfusion and metabolism documented with SPECT or PET.Most common Brain Pathology in ASD • Brain tumors (mainly slow growing, in temporal lobe) • Hydrocephalus and bilateral temporal arachnoid cysts • Tubers in TSD

  7. Other pathogenetic factors in ASD Serotonin dysfunction: non-specific alterations in Ser levels ( or ) in ASD patients. Some patients with SIB or OCD features, other patients with serotonin ransporter abnormalities. ß-Endorphins: lower levels in ASD, mainly with SIB and/or increased sterotypies. Catechol amines: reduced CA, mainly in PKU Immunology: non consistent findings: alterations in levels of IL-12, INF-gamma. Alpha-INF, changes in T cell subsets,  IgA,  AB to MBP, and AB to NGF. Also variable reports of (+) AB to viral agents, food allergy ???, Celiac enteropathy -non-proven. Nutritional factors: non-consistent: Mg,  Lead: few cases

  8. Acquired etiologies in ASD • Pre/peri natal events • Postnatal events: Encephalitis, Autistic regression in patients with epileptic encephalopathy, Brain Tumors • Rett syndrome

  9. CONCLUSION Autism is not a medical diagnosis !It is a neuro-behavioral syndrome with a distinctsocial and communicativefeatures; a final commonpathway of multiple bio-logical etiologies.

  10. Historical Aspects • 1911: Bleuler: “Childhood schizophrenia” autism = “autos” (self). Children whose behavior resembles adults with chronic schizophrenia. • 1944: Kanner: Developmental syndrome of infants whose behavior is caused by maternal emotional neglect. They do not manifest positive symptoms of schizophrenia. Accurate description. • 1976 Coleman: } Modern concept of autism • 1985 Gilberg: } which is basicly a neuro- • 1993: WHO: } biological disorder.

  11. Epidemiology of ASD Prevalence: - Lotter, UK, (1966): 4.5:10,000 - Gilberg, Sweden, (1991): 9.5:10,000 - Charman, UK (2002): 6.0: 1,000 - Rice, et al, USA (2003): 3.4: 1,000M/F ratio: 3-5:1(CP: 1-2:1,000, Epilepsy 5-10:1,000)

  12. DIAGNOSTIC CRITERIA(DSM IV-1994) • Significant impairment in social interaction. • Significant impairment in communication. • Restricted repetitive and stereotyped patterns of behavior, interest and activities. • The onset of delay in social interaction and communication or symbolic play prior to age 3 years. • The syndrome is not better accountedby Rett or disintegrative disorders.

  13. CLINICAL PICTURE IN INFANCY • Poor eye contact, absent or dull social smile. • Lack of anticipatory signs when about to be picked up. • Lack of involvement in social game or imitation of adults. No symbolic game. • Stereotyped games rather than explorative. • In contrary to popular belief, many autisticinfants enjoy body contact. • Trend to treat humans as technical tools. • Poor reciprocal babbling. • Delayed acquisition of language; some may acquire 10-20 words, but will regress at the second year of life. Some will acqiure some words but will not use it for communication.

  14. CLINICAL PICTURE IN PRE-SCHOOL CHILDREN • At this age the typical autistic behavior is clearly evident. Most children are diagnosed between 24-36 months of age. • Many autistic children are hyperactive and manifest excessive motor stereotypies. • At this age it is clear that the child has no communication with other children, and failsto develop adeqate speech. • In some cases parents will attribute the autistic behavior to traumatic events. • High-functioning autistic children will develop basic speech, but will fail in social interaction, in joint attention, and will not understand emotions, needs or gestures of others (theory of mind).

  15. CLINICAL PICTURE IN EARLY SCHOOL YEARS • At this age (6-12 y) the social withdrwal and the hyperactive behavior will subside to some extent, and they become more cooperative. • A 1/3 remains severly withdrawn. • Many children will develop some language. Children with high-functioning autism will acquire nearly normal language, but will stillbe “odd” and their abilities to communicate and to “make friends” will stay limited. With some help these children may cope in regular school system.

  16. IMROVEMENT 40% will not change and will continue to acquire higher level of speech.Some high functioning autistic adolescents will even improve in basic social abilities. As adults they wll be able to be independent and study or work. DETERIORATION 12% males, 50% females overall - ~30% - Aggravation of autistic behavior- Depression- Psychosis or catatonia- Epilepsy with regression- problms with sexual maturation PUBERTY & ADOLESCENSE

  17. Abnormal reaction to sensory stimuli Hyperactivity (unpredictable response to stimulants) Mental retardation (65-80% IQ < 70) Abnormal eating behaviors Aggressive behavior or self injury Abnormal sleep patterns (mainly in ages 0-6y) Tics and obsessive-compulsive behavior Visual and hearing impairment Epilepsy (11%-24%, more in females, and MR) Depression COMMON PROBLEMS IN AUTISM

  18. Rett syndrome Sensory deprivation (blindness, deafness) Emotional deprivation(abandoned children in orphanages or retarded children in institutions) Mental retardation with autistic features Autistic regression in epileptic encephalopathy Infantile depression Childhood schizophrenia (rare) Semantic-pragmatic language disorder Non-verbal learning disability ADHD in young children Multi-system developmental disorder (MSDD) Differential Diagnosis of ASD

  19. Tuberous Sclerosis Complex Epilepsy in infancy - Infantile spasms s/p viral encephalitis (HSV, CMV) Fragile-X syndrome Velo-Cardio-Facial-Syndrome (Shprintzen) San-Filippo Syndrome Phenylketonuria Smith-Magenis Syndrome Fetal-Drugs Exposure (alcohol, cocaine, VPA) Down Syndrome Hypothyroidism Medical conditions and syndromes associated with autism (most common)

  20. Full neuro-developmental assessment Language and psychological assessment withfew observations Hearing and ophthalmologic examinations Thyroid function test In cases of megalencephaly – brain imaging In cases of dysmorphism – Genetic consult+ karyotype In cases of regression or suspected SZ – EEG Fragile-X screening In cases of abnormal neurological examination seizures or significant MR – consider brain MRI, and further studies Medical work-up of ASD

  21. Difficulties in non-verbal and social behaviors Failure to develop peer relationships Lack of social-emotional reciprocity Restricted repetitive and stereotyped patterns of behaviors, activities, games, rituals and interests Persistent pre-occupation with parts of objects Normal cognitive and adaptive development Normal and formal “high” language with poor body language, poor pragmatic and communicative skills No sense of humor, irony or symbolic talk ASPERGER SYNDROME

  22. Normal dvelopment (incl. speech and social skills) during the first 2 years of life. Regression in language, symbolic play and social skillsbetween 2-10 years. During the regression process it is common to find restlesness, impairment in sleep cycle, increased motor activities. After the regression is completed the autistic features of the child are identical to those seen in classical autism. In all cases of disintegrative disorder a full neurological work-up for epilepsy or degenerative disease is needed. DISINTEGRATIVE DISORDER

  23. Therapies used in ASD • Special education • Behavioral therapy + modification • Speech and communication therapy • Psychotherapy & parental counseling • Neuroleptics and atypical antipsychotics (Incl. Risperidone and Clozapine) • Serotonin re-uptake inhibitors (Fluoxetine & Fluvoxamine) • Anti-epilpeptic drugs (Sodium Valproate) • Dietary supplements (Mg++, Vit B6) • Non-proven or not-effective (secretin, gluten-free diet)

  24. תודה לכולכם

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