Psychopathology

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)

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

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.

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

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

Fragile X Syndrome & ASD 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)

Rett Syndrome: (Graduate) 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:

Rhet Syndrome: Cause & Pathophysiology (Graduate) 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)

Timothy Syndrome (Graduate) 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)

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

Tuberous Sclerosis (Graduate) 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

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

De novo CNVs more common in ASD than in unaffected siblings Sanders et a. (2015), Neuron 87:1215-1233

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

Schizophrenia Failure to embed in reality Problems in thinking (thought disorder) Incoherent speech Flat or inappropriate affect Loss of motivation Delusions Hallucinations

Schizophrenia: Important facts Lifetime risk c. 1% Onset: mostly late teens through 20s, but can occur in childhood and after 40 1.4 males to 1 female Wide variation in course: some recover, but usually poor prognosis No cure but treatment can help psychotic symptoms Very high cost to society; major cause of disability

Current favored model: Two-threshold multifactorial -3 -2 -1 1 2 3 4 Total Liability Frequency Schizotypal Schizophrenic Relatives of Schizophrenics General Population

and CNVs (microdeletions, indels) Mendelian forms and CNVs (microdeletions, indels)

Problem with Mendelian “forms” and CNVs for psychopathology In Alzheimer’s, if you get APP, PSEN1, PSEN2, you get AD; you do not get Pick’s disease, Wernicke-Korsakoff syndrome, or Parkinsons With BRCA1, BRCA2, you get breast or breast/uterine cancer; you do not get lung or pancreatic cancer With HNF1A (hepatic nuclear factor 1 alpha), you get diabetes and possibly its consequences; you do not get other disorders With single gene disorders for psychopathology (including intellectual deficiency), you always get “something else” and do not always get the syndrome

Example 1: 22q11.2 deletion syndrome (AKA DiGeorge syndrome, velocardiofacial syndrome) Immunodeficiency (75%) Congenital cardiac anomalies (75%) Cleft palate and other palatal abnormalities (75%) Endocrine abnormalities (50%) Feeding, swallowing problems (30%) Genitourinary anomalies (30%) Developmental delays in motor, language, speech Mean IQ of c. 70. learning disabilities Higher prevalence of ADHD and ASD in childhood Psychosis/schizophrenia (25%) Microdeletion in chromosome 22, band q11.2 Common signs and symptoms (McDonald-McGinn et al., 2015) Is this gene specific for ASD, AHDH, and schizophrenia?

Example 2: Cortical dysplasia-focal epilepsy (CDFE) syndrome Single gene, autosomal recessive disorder “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) Is this a Mendelian form for ASD or is ASD one of many behavioral outcomes?

Conclusions: In a strict sense, there are few, if any, Mendelian forms or CNVs specific for psychopathology In a loose sense, there are a number of Mendelian disorders and CNVs that have forms of psychopathology as one of several outcomes.

Summary of Results in Psychopathology: (oversimplified) All forms have moderate heritability (h2 = c. 50) with some (schizophrenia) having a high heritability (c. .70 - .80) No single gene, Mendelian forms detected (strict definition) Some Mendelian forms and CNV/indels have psychopathology as one of several symptoms De novo mutations increased Hardly any major loci found Few established phenocopies GWAS data suggest hyperpolygenic Cannot predict risk very well

Fertility Paradox Most forms of psychopathology have reduced fertility (e.g., fertility of schizophrenics = 50% that of normals) Given that all psychopathology runs in families, the prevalence of these disorders should be decreasing But they are not and some, e.g., ASD, are increasing

Possible Reason = Hyperpolygenicity Perhaps there are so many genes involved in schizophrenia that new mutations in several of these genes could replenish the loss from selection. Paraphrase of Erlenmeyer-Kimling lecture, c. 1972 trying to explain the paradox of high heritability and low fitness in schizophrenia. See Keller (2006) Brain & Behavioral Science.

Frontiers: Endophenotype (“within” phenotype) A phenotype closer to gene action than the phenotype of study; usually an anatomical, physiological, or biochemical variable.

Strategy of Endophenotypes: Detect genes that influence the endophenotype instead of genes for the disorder. Examples for schizophrenia: Ventricular size Abnormal eye tracking

Frontiers: Neuroimaging Endophenotypes

Legend for the next two figures From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.

From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.

From Heinz et al. (2004). Nature Neuroscience, 8, 20-21.

Legend for next Figure From Hariri et al. (2005), Arch gen Psychiat 62:146-152

From Hariri et al. (2005), Arch gen Psychiat 62:146-152

Frontiers: Pathway Analysis What do genes detected in GWAS do? Psychiatric Genetics Consortium (2014), Nature, 511:421-427 Identified 108 susceptibility loci Most within/close by coding regions but few (10) in exons Many expressed in brain Important areas = dopamine, glutamate, synaptic plasticity, immune systems Significant enrichment for enhancers Explains 3.4% of variance in liability