1. Autism ASD: Autism spectrum disorder
“There is from the start an extreme autistic aloneness that, whenever possible, disregards, ignores, shuts out anything that comes to the child from the outside. Direct physical contact or such motion or noise as threatens to disrupt the aloneness is either treated “as if it weren't there” or, if this is no longer sufficient, resented painfully as distressing interference.” (Kanner, 1943, p. 242, emphasis in the original)

2. Diagnostic Criteria (ICD)
A) Persistent deficits in social communication and social interaction
B) Restricted, repetitive patterns of behavior, interests, or activities
C) Symptoms must be present in the early developmental period
D) Symptoms cause clinically significant impairment
E) These disturbances are not better explained by intellectual disability

3. Diagnostic Criteria (DSM-V) Autism spectrum disorder
A. Persistent deficits in social communication and social interaction across multiple contexts
B. Restricted, repetitive patterns of behavior, interests, or activities
C. Symptoms must be present in the early developmental period
D. Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.
E. These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level.

4. Autism: Important Facts
Prevalence: used to be considered rare; now 1/68 births (CDC)
Onset: often problems by 6 – 12 months in looking, vocalizing with others; speech and social interactive skills by 12 – 18 months.
Sex ratio: more boys than girls (4:1), but estimates of the ratio vary
Treatment: partial efficacy of early, intense (25 hours a week), structured intervention with highly trained therapists; no cure
Prognosis: generally poor; c. 10% employed as adults but c. 50% still live with parents; worse prognosis with lower IQ

5. Mendelian “Forms” (i.e., single gene disorders associated with ASD)
FMR1 (Fragile X syndrome); most common single-gene disorder associated with ASD
Rett syndrome
Timothy syndrome
Cortical dysplasia-focal epilepsy (CDFE) syndrome
Activity-dependent neuroprotective protein (ADNP) (Helsmoortel-van der Aa) syndrome
Tuberous Sclerosis

6. Mendelian “Form” or ASD as a symptom Problem:
In Alzheimer’s, if you get APP, PSEN1, PSEN2, you get AD; you do not get Pick’s disease, Wernicke-Korsakoff syndrome of Parkinsons
With BRCA1, BRCA2, you get breast or breast/uterine cancer; you do not get lung or pancreatic cancer
With Mendelian “forms” for autism, you always get something else and do not always get autism
Therefore is it a true Mendelian form or a Mendelian disorder that has ASD as one of many possible behavioral outcomes?

7. Fragile X Syndrome Most common single gene associated with ASD
ASD more frequency in FXS boys than girls
FXS with ASD more cognitively impaired; IQ may mediate relation between FXS and ASD
Some maintain the nature of ASD symptoms in FXS is different (e.g., FXS have poor eye contact to avoid social anxiety but still enjoy interacting with people; ASD are disinterested)

8. Cortical dysplasia-focal epilepsy (CDFE) syndrome
“Clinically, patients were reported to develop normally until intractable
focal seizures began in early childhood (1–9 years old), after which
language regression, hyperactivity, impulsive and aggressive behavior,
and mental retardation developed in all children. In addition, nearly
two-thirds of the patients fulfilled the diagnostic criteria for pervasive
developmental delay (PDD), the most generic ASD diagnosis.” Penagarinkano and Geschwind (2013)
Autosomal recessive

9. Rett Syndrome: Symptoms Normal development till 6 months, then:
Slowed cranial growth
Loss of muscle tone, problems walking
Purposeful hand movements replaced by stereotypic movements
Breathing problems
Seizures
Deterioration in language
Marked social anxiety and social withdrawal
Disinterest in other people
Normal development till 6 months, then:

10. Cause & Pathophysiology
Rhet Syndrome:
Cause & Pathophysiology
De novo mutation in MEPC2 (methyl-CpG binding protein 2) gene on the X
Protein called MeCP2
Lethal in males, so virtually all affected are female
Virtually all pathophysiology based on trangenics
MeCP2 may influence chromatin architecture
Interacts with NCOR-SMRT complex (regulatory protein complex)

11. Timothy Syndrome Serious cardiac problems (often lethal)
Webbing of skin between fingers/toes
Seizures
ID, delayed speech & language, impaired communication
De novo mutation in CACNA1C gene (calcium channel)

12. Activity-dependent neuroprotective protein (ADNP) syndrome (Helsmoortel-van der Aa syndrome)
Widespread symptomatology affecting morphology, growth, and the sensory, motor, endocrine, immune, and GI systems
Seizures
Intellectual disability
Hyperactivity
De novo mutation in ADNP gene

13. Tuberous Sclerosis Benign tumors in multiple systems
Most debilitating are CNS tumors but still enormous variable expressivity, anywhere from lethal to normal functioning
Genetic heterogeneity (two loci = TSC1 (hamatrin) gene and TSC2 (tuberin) gene)
1/3 cases autosomal dominant
Rest de novo mutations

14. Chromosomal Anomalies & ASD (not exhaustive)
1) Duplication in 15q11-13 (Dup 15q syndrome)
Prader-Willi/Angelman area
Seizures, delayed motor, language, cognitive development, impaired communication, ID
Most common chromosomal problem with ASD (about 4% of ASD may have this deletion)
2) 22q11.2 deletion syndrome (DiGeorge syndrome, velo-cardio-facial syndrome)
Many physical abnormalities; epilepsy
Delayed growth, speech, learning  ID
ADHD, ASD, sometimes psychosis
3) 16p11.2 deletion and duplication
Some ok; others with marked developmental and behavioral problems including ID and language problems
4) Xp22.3 deletion
Some case histories have ASD
5) Increased number of non-specific de novo CNVs

15. De novo CNVs more common in ASD than in unaffected siblings
Sanders et a. (2015), Neuron 87:

16. GWAS A few suggestive leads but nothing certain
Sample sizes still small