Genetics, Neuroscience, and Imaging

Question 1

What percentage of children with ASD have a co-morbid genetic disorder?

Answer 1

15%

Question 2

What genetic syndrome has the highest rate of co-morbid Autism?

Answer 2

Tuberous Sclerosis (25-50%)

Question 3

What is the inheritance pattern of tuberous sclerosis and what are its signs?

Answer 3

1) Autosomal dominant
2) Benign tumors throughout body, ashleaf spots (HYPOpigmented macules), shagreen patches (thick, leathery skin patch usually on the lower back). Also has a facial rash

Question 4

What is the most common INHERITED cause of intellectual disability?

Answer 4

Fragile X syndrome

Question 5

What is the most common CHROMOSOMAL cause of intellectual disability?

Answer 5

Down syndrome

Question 6

What is the most common autosomal trisomy?

Answer 6

Down syndrome

Question 7

What is the rate limiting step in serotonin synthesis?

Answer 7

Tryptophan hydroxylase

Question 8

What gene is showing evidence of linkage to OCD?

Answer 8

Gain of function polymorphisms in the SLC6A4 promoter

Question 9

What is the preferred imaging modality to localize seizure foci when considering surgery for medically intractable seizures (and why)?

Answer 9

PET scan (able to show interictal hyPOmetabolism around seizure foci)

Question 10

What are MRI brain findings of individuals with ASD? What about postmortem studies? What about early growth and development? What about neurochemical differences?

Answer 10

1) Larger brains and abberations in white matter tract development
2) Limbic system abnormalities
3) Decreased formation of purkinje cells in the cerbellum AND accelerated head growth during infancy
4) Abnormalities in serotonin synthesis

Question 11

What are examples of neuropeptide neurotransmitters?

Answer 11

Hyopthalamic releasing factors (somatostatin, GnRH), pituitary hormones (GH, TSH), opiate peptides (endorphins, enkephalins), neurohypophyseal peptides (oxytocin, vasopressin), neuronal (ANF, VIP), GI/brain/pancreas peptides (CCK, glucagon, gastrin), endocrine (insulin, PTH, calcitonin), circulating (angiotensin, bradykinin)

Question 12

What are some examples of conventional (small-molecule) neurotransmitters?

Answer 12

Serotonin, dopamine, norepinephrine, GABA, glycine

Question 13

What are features of neurofribromatosis type-1?

Answer 13

– Café-au-lait spots (large, hyperpigmented skin patches)
- Cutaneous neurofibromas, optic gliomas, and PHEOCHROMOCYTOMAS
- Cognitive difficulties
- Seizures
- Yellow, dome-shaped growths on the iris (iris hamartomas –> Lish nodules)

Question 14

What gene has been linked to the development of depression in those with stressful life events and childhood maltreatment?

Answer 14

BDNF

Question 15

What gene has been proposed to lead to development in PTSD in those with history of childhood maltreatment?

Answer 15

FKBP5

Question 16

Advanced paternal age is associated with increased risk for what?

Answer 16

Sporadic (non-familial) schizophrenia

Question 17

What is the best imaging modality to assess for a TBI?

Answer 17

Diffusion Tensor Imaging (DTI)

Question 18

1) What syndrome dramatically increases the risk of developing schizophrenia more than any other genetic illness? 2) How high is the risk? 3) What chromosome is it associated with?

Answer 18

1) Velocardiofacial syndrome (also know as DiGeorge Syndrome or 22q11.2 deletion syndrom)
2) Up to 20x increased risk
3) Deletion on chromosome 22

Question 19

What are the symptoms of Velocardiofacial syndrome?

Answer 19

CATCH-22
- Cardiac abnormalities
- Abnormal facies
- Thymic aplasia
- Cleft palate
- Hypocalcemia and Hypothyroidism
- 22: Deletion of chromosome 22

(remember - Velocardiofacial syndrome is the new name for DiGeorge syndrome or 22q11.2 deletion syndrome)

Question 20

1) What does magnetic resonance spectroscopy (MRS) measure? 2) What do you use MRS to evaluate?

Answer 20

1) Uses the signal from hydrogen protons to measure biochemical concentrations of brain metabolites
2) Differentiate between brain tumor types. Evaluation of degenerative disorders, HIV, radiation injury, encephalopathy, and ischemia

Question 21

1) What is the heritability pattern of Lesch-Nyhan syndrome? 2) What is the deficiency? 3) How does it present?

Answer 21

1) X-linked recessive
2) Disorder of purine and pyrimidine metabolism (deficiency in hypoxanthine-guanine phosphoribosyl transferase –> leading to HYPERURICEMIA)
3) CHOREOATHETOSIS, hyperreflexia, hypertonia, dysarthria, behavioral disturbances (AGITATION), cognitive impairment, SELF-MUTILATORY (biting) BEHAVIOR

Question 22

What is the mutation that causes NF1 (chromosomal location, gene name, and what the gene encodes for)?

Answer 22

Chromosome 17, mutation of NF1 tumor suppressor gene, encodes for Ras GTPase activating protein neurofibrin

Question 23

What is the mutation that causes NF2 (chromosomal location, gene name, and what the gene encodes for)?

Answer 23

Chromosome 22, mutation of NF2 gene, encodes for merlin/schwannomin protein

Question 24

What are the genes suspected to play a role in ADHD (4)?

Answer 24

COMT (Catecholomine-O-methyl transferase)
SLC6A3 (a dopamine transporter)
DRD4 (Dopamine D4 receptor)
SNAP-25 (synaptosomal-associated protein)

Question 25

What gene influences the development of psychosis after cannabis use?

Answer 25

AKT1

Question 26

1) What to beta waves indicate on EEG?
2) What to theta waves indicate?
3) How do these two relate to ADHD?

Answer 26

1) Activation of frontal lobe (by dopamine) –> concentration
2) Inactivity of frontal lobe –> relaxation
3) State of day dreaming or drowsiness and difficulty concentrating or problem solving is due to increase in theta and decrease in beta waves (increased theta to beta wave ratio)

Question 27

What is an animal model used to study the genetic risk of developing OCD in children?

Answer 27

SAPAP3 synaptic protein mouse model AND Slitrk5

Question 28

What is an animal model used to study the genetic risk of developing ASD in children?

Answer 28

Pten (phosphotase and tensin) mutant mouse model

Question 29

Increased prenatal stress is a risk factor for schizophrenia due to epigenetic downregulation of what gene?

Answer 29

Reelin gene (extracellular matrix protein responsible for regulating and positioning neurons in the developing brain)

Question 30

1) What is the heritability pattern of ADHD? 2) What about between siblings?

Answer 30

1) 70%
2) Siblings of children with ADHD have a 2-3 fold increased risk

Question 31

What is the purposed neurobiological mechanism involved in the cause of Disruptive Mood Dysregulation Disorder (DMDD)?

Answer 31

Disrupted amygdala-prefrontal cortex circuitry that leads to dysfunctional face emotion processing. Children with DMDD tend to associated ambiguous facial expressions with anger rather than positive emotions.

Question 32

What is the purposed neurobiological mechanism involved in the cause of mania and depression, respectively, in Bipolar Disorder?

Answer 32

1) Mania: Catecholaminergic disruption
2) Depression: Cholinergic dysfunction

Question 33

What genetic variation has been associated with the development of panic disorder with agoraphobia?

Answer 33

Polymorphisms in the long alleles of the MAOA-uVNTR promoter (also implicated in fear conditioning, avoidance behavior, and influences effectiveness of CBT)

Question 34

What growth factor is implicated in the development of depression? How does it result in brain changes leading to depression?

Answer 34

1) Brain-derived neurotrophic factor (BDNF)
2) Decreased expression of BDNF leads to neuronal atrophy and loss of synaptic connections in PFC and hippocampus

Question 35

What is the characteristic EEG finding in Lennox- Gastaut syndrome?

Answer 35

Slow-spike waves

Question 36

What are advantages to SPECT as compared to PET scans? Disadvantage?

Answer 36

1) Advantage: Cheaper, uses isotopes that have a longer half-life
2) Disadvantages: SPECT has poor spatial resolution compared to PET

Question 37

At what age does synaptogenesis in the brain peak?

Answer 37

Age 2-3 years old

Question 38

What are the typical neuroimaging findings seen in schizophrenia (4)?

Answer 38

1) Reduced brain volumes
2) Cerebral atrophy
3) Enlarged ventricles
4) Smaller hippocampus