Cognitive%20Disabilities

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Cognitive Disabilities
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General Cognitive Disability

• Behaviourally diagnosed
• IQ
• Average 100, standard deviation 15
• Only 5 of population has cognitive disabilities
• Levels
• Mild (IQ 50-70) about 85 of cases
• Moderate (IQ 35-50)
• Severe (IQ 20-35)
• Profound (IQ below 20)

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General Cognitive Disabilities

• Genetics relatively well studied
• Especially for serious (IQlt50) cognitive
  disabilities
• Can now investigate specific disabilities at gene
  level
• Mild disabilities (candidates for QTLs) are harder

4
Quantitative Genetics

• Sibs of mildly cognitive disabled have below
  average IQ scores
• Sibs of severely cognitively disabled do not
• Why?

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Mild Disabilities Genetic or Environmental?

• Genetics seems to be important
• Concordances for mild cognitive disabilities MZ
  75, DZ 46
• High/low IQ equally heritable across age (infancy
  to middle age)
• But few scores in these studies go below IQ 70
• 50 mildly disabled children also have
  behavioural problems
• Quantitative range of normal distribution?

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Single Gene Disorders

• Over 250 known disorders that show low IQ (also
  other, often primary, symptoms)
• Generally quite rare

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PKU

• Single gene autosomal recessive
• Defect in PAH gene (chr. 12) for enzyme
  phenylalanine hydroxylase
• Converts amino acid phenylalanine to other
  essential compounds
• Over 400 disease causing mutations of PAH
• About 1 in 10,000-15,000 births
• Screening of infants at birth since 1961
• Environmental fix restrict access to proteins
  (and some other foods) and supplement amino acids
  lacking from no protein diet

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Neurofibromatosis Type 1

• Member of the neurocutaneous syndromes, all
  producing neurologic and dermatologic lesions
• Autosomal dominant disorder from mutation of gene
  NF1 (chr. 17)
• NF1 encodes neurofibromin protein, involved in
  intracellular signaling
• Cognitive and learning disabilities also common

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X-Linked

• Genes on X chromosome
• Tend to effect males
• Females X-inactivation --gt mosaicism
• Females with disorder, often show highly variable
  severity depending on how many/which cells
  affected

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X-inactivation

• One X copy silenced in early blastocyst
• Packaged into transcriptionally inactive
  heterochromatin
• Prevents twice as many X chromosome gene products
  being produced as in the male
• In placental mammals, which X chromosome
  inactivated is random

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• Default state is inactivation for X chr.
• In XXX individuals, still only one active X
• Autosomally-encoded blocking factor
  hypothesized binds to one X and prevents its
  silencing
• X-inactivation centre (XIC) necessary and
  sufficient for silencing
• Translocating XIC to autosomal chromosome causes
  inactivation of that autosome X lacking XIC not
  inactivated

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Fragile X Syndrome

• About 1 in 3600 males, 1 in 4000-6000 females
• Mutation of the FMR1 gene on the X chr.
• Normal FMR1 6 to 55 repeats of CGG codon.
• Fragile X 230 repeats
• Expansion of CGG --gt methylation of that portion
  of DNA --gt silences expression of FMR1 protein
• Methylation constricts the chromosome fragile
  appearance under the microscope

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Fragile X

• Males have one copy of X chromosome those with
  expanded FMR1 are symptomatic
• Cognitive disabilities and physical features
  (elongated face, large ears, low muscle tone)
• Females two Xs doubles chances of having
  functioning FMR1 allele
• With X-inactivation females with 1 expanded FMR1
  allele can have some symptoms

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Rett Syndrome

• Deceleration of growth of head, hands, and feet,
  cognitive impairment, GI disorders, serious
  verbal deficits
• Sporadic (de novo) mutations to gene MECP2 on X
  chromosome
• Almost always affects females male fetuses
  rarely survive to term or die at very early age
• With one functioning gene, female fetuses can
  produce enough proteins to survive to birth, but
  symptoms manifest between 6-18 months post-birth

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Duchenne Muscular Dystrophy

• Mutation of gene on X chromosome that codes for
  dystrophin protein
• Necessary structural component of muscle tissue
• Progressive muscle weakness and loss of muscle
  mass some cognitive disfunction
• Affects males
• Females can be carriers rarely manifest symptoms
• Fatal by age 30

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Lesch-Nyhan Syndrome

• X-linked recessive rare, 1 in 380,000 live
  births
• Deficiency of enzyme hypoxanthine-guanine
  phosphoribosyltransferase (HGPRT)
• Causes build up of uric acid in all body fluids
• Severe mental and physical deficits
  self-mutilating behaviour common
• Female carriers typically asymptomatic may have
  some difficulties from increased uric acid
  excretion

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Chromosomal Abnormalities

• More common
• Generally moderate to severe disability
• 7 of children with unexplained moderate or
  severe disabilities have detectable deletions vs.
  0.5 of children with mild disabilities
• Additional chromosomes
• More frequent easily detectable
• Deletions of parts of chromosomes
• Use of microarrays identifying more of these
• Might ultimately be more common

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Williams Syndrome

• Small deletion (chr. 7)
• Affects about 20 genes elastin production, LIM
  kinase, and others
• Usually spontaneous mutations
• Connective tissue defects, multiple medical
  problems, generally moderate cognitive
  disfunction some similarities to autism

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Angelman Syndrome

• Genetic imprinting inherited from mother
• Deletion of genes at 15q11-13
• E.g., defect/deletion in gene UBE3A, coding for
  an ubiquitin ligase absence results in defects
  in hippocampus and cerebellum
• Usually novel in formation of gametes
• Risk to sibs of proband is 1
• Moderate cognitive disfunction, motor and speech
  impairments, seizures, inappropriate happy demenor

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Prader-Willi Syndrome

• Genetic imprinting from father
• Deletion or defect of up to 7 genes at 15q11-13
• Effect is on some non-coding RNA modifies other
  non-coding RNAs and mRNA processing
• Low IQ, compulsive overeating

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Down Syndrome

• Most common cause of cognitive disability (about
  1/1000 births)
• Trisomy 21
• Over 300 symptoms physical, behavioural, and
  cognitive
• Mean IQ 55 dementia commonly sets in by age 45

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Sex Chromosome Abnormalities

• XXY male
• 1/750 low testosterone in adolescence
• Small testes, enlarged breast tissue,
  infertility, low IQ, poor speech and language
• XXX
• 1/1000 females
• Mean IQ 85, poor on verbal tasks

• XYY
• 1/1000 males
• Speech deficits, language and reading
  difficulties tendency to be tall
• X0
• 1/2500 females
• 99 miscarry accounts for 10 of spontaneous
  abortions
• Short stature, abnormal sexual development,
  verbal IQ normal but performance IQ 90 after
  adolescence

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XYY Males

• 1961 first described case, karyotype of man
  whose son had Down Syndrome
• 1965 7 of 197 inmates in a Scottish maximum
  security prison are XYY unusually tall and
  aggressive. Super-male Syndrome
• 1968 Murderer of Parisian prostitutes found to
  be XYY
• 1968 Richard Speck (murdered 8 nursing students
  in Chicago) reported to be XYY subsequently
  rejected
• 1968 23 studies published examining rates of XYY
  in prisons, 0 studying XYY in the general
  population
• 1969 study screens inmates for XYY (but only
  karyotype tall, violent ones) finds 1 of the 9
  tested is XYY
• 1969 first good study on base rates of
  chromosomal abnormalities conduced (about 1/1000)
• 1970 Newsweek article on XYY Congenital
  Criminals, Y becomes the Crime Chromosome

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Dale Harley (1980)
Mental Institute Penal Institute
Mental-Penal Men karyotyped 5100
6983 5479 XYY 13
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104 XYY/1000 2.5 4.4
20.0
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Nanko et al. (1979)
Sample Size lt100 101-200 201-500
gt500 Number of Studies 6 9
3 5 Karyotypes
326 1287 1199 2838 XYYs
found 4 10 6
7 XYY/1000 12.3 7.8
5.0 2.4
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Guesstimate

• If 1/1000 males is XYY and 5/1000 inmates is XYY,
  then what proportion of XYY males are in jail?
• Rough guess 0.5
• Based on knowing proportion of population which
  is incarcerated in Western countries

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Why?

• Some hypotheses
• 1. They are violent
• 2. They are tall
• 3. They have cognitive disabilities (lower
  intelligence)

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Violent

• No personality or crime differences between XYY
  and XY inmates (Clark et al., 1970)
• XYY actually seem to be less violent than XY
  inmates
• More likely incarcerated for property than
  violent crime
• Also, XXY are disproportionately incarcerated,
  and their crime pattern is like that of XYY
  (Hook, 1979)

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Tall

• Tall XY are not jailed disproportionately to
  other XY (Hook Kim, 1971)

30
Lower Intelligence

• 31,436 men born in Copenhagen in 1944-47
• IQ tested during mandatory military service
• Studied all tall (gt184 cm) men
• Karyotyped 4,139 of them
• Used criminal history database and school exam
  records

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Findings

• Karyotype finds 12 XYY and 16 XXY
• Base crime conviction rate of 9.3
• 5 XYY had records (non-violent offences), 3 XXY
  had records
• Intelligence test scores were low for XYY and
  XXY convicted XYY and XXY even lower
• XY males with records also had lower IQ test
  scores

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Inference

• Cognitive deficits are important
• XYY not necessarily any more violent or dangerous
• Cognitive deficits limit employment options
• May be poor criminals - more likely to get
  caught, miss plea bargain opportunities, etc.,
  possibly due to lower IQ

33
Quantitative Genetics

• Mild cognitive disability likely quantitative,
  not qualitative
• Polygenic
• QTL hypothesis
• Many genes making small contributions
• Many disorders, then, may simply be the low end
  of the normal distribution of the populations
  traits

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DF Extremes Analysis

• Method for estimating heritability of disorders
  that are defined qualitatively (i.e., either have
  or dont have the disorder)
• But disorders depend on an underlying trait that
  varies quantitatively along a continuum

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DF Extremes Analysis

• Developed by DeFries and Fulker
• A regression-based method for analyzing twin data
• Designed for proband-selected data
• At least one twin has an extreme score
• Based on regression to the mean

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Regression to the Mean

• 1000 individuals tested on some measure

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Regression to the Mean

• Test same 1000 individuals one month later gives
  a similar profile

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Regression to the Mean

• Focus on people who scored very low at time 1
  (extreme group)
• Can we predict how this group should score at
  time 2?

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Regression to the Mean

• Mean at time 2 for extreme group from time 1
  depends on the correlation between the two time
  points
• Imagine correlations of 1, 0, and something in
  intermediate

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Regression to the Mean
Time 1
Correlation 1
Time 2
Time 1
Correlation 0
Time 2
Time 1
Intermediate correlation
Time 2
Pop. mean
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DF Extremes Analysis

• Considers the differential regression towards the
  mean between MZ and DZ twins
• To parallel the example, time 1 is the proband
  score and time 2 is the co-twin score

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Implementation

• E.g., select individuals in low 5 of a trait
• Look at the scores of their co-twins
• If a trait is influenced by genes, MZ co-twins
  should not regress towards the mean as much as DZ
  co-twins
• Due to higher correlation between MZ twins

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Visualization
Probands
MZ co-twins
DZ co-twins
DZ co-twin mean
MZ co-twin mean
Pop. mean
Proband mean
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Heritability and Non-shared Environment

• Regression to the mean reflects info about the
  correlation between twins.
• Standardize means so population mean becomes 0
  and the proband mean is 1
• Then transformed MZ and DZ co-twin means can be
  implemented just as MZ and DZ correlations are.
• 2 x diff. b/t MZ DZ co-twin mean estimates
  heritability and 1 minus the MZ co-twin mean
  estimates non-shared environment

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Graphically
Proband mean
MZ co-twin mean
DZ co-twin mean
Population mean
e2
h2/2
h2/2 c2
1
0
e unique environment c shared environment
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Learning Disorders

• Dyslexia
• 10 of children have difficulty learning to read
• 80 of diagnosed learning disorders have
  difficulty reading
• Also, math disorder (moderate heritability from
  twin studies) co-occurs with reading disorder
• Sibs and parents of reading-disabled probands do
  worse on tests of reading ability
• Study of 250 twins with one reading disabled 66
  concordance for MZ, 36 for DZ

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Verbal Ability is Heritable
1.0 0.8 0.6 0.4 0.2 0.0
Unique envir.
Shared envir.
Heredity
Early childhood
Middle childhood
Adolescence
Adulthood
Old Age
Meta-Analysis of recent twin studies (Adapted
from Price (2002))
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Specific Language Impairment (SLI)
1.0 0.8 0.6 0.4 0.2 0.0
MZ twins
DZ twins
Risk
1st degree relatives
Controls
Relations
Data from Stromswold (1998) and Stromswold (2001)
(Figure adapted from Price (2002))
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Vernes et al. (2008)

• Rare mutations of FOXP2 transcription factor
  cause some forms of SLI
• Genome screened for regions bound by FOXP2
• Tested for SNPs in set of 184 families with SLI
• FOXP2 binds to and dramatically down-regulates
  CNTNAP2 gene
• One of largest genes in human genome (1.5 of
  chr. 7)
• Role in cell adhesion molecules in developing
  human cortex and axon differentiation
• Significant quantitative association with
  nonsense-word repetition

50
Reading Disability

• Causes of individual variation throughout the
  population may be different from the causes of
  differences between a group with extreme scores
  and the rest of the population
• Genetic contribution to variation in reading
  ability does not mean illiterates are genetically
  different from the rest of the population
• MZ twins correlate 0.9, DZ twins correlate 0.65
• h2 0.5 (group heritability)

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QTLs for Reading Disability

• Can reject various single gene hypotheses
• E.g., autosomal dominant, X-linked
• Sib-paired QTL linkage analysis
• Sib of reading disabled had lower reading ability
  when the two shared the same version of 6p21

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QTL Linkage Map for 6p21
Index of statistical significance
DNA markers
D6S105 sig. at p 0.05 for siblings and 0.01 for
DZ twins
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Developmental Dyslexia

• Galaburda et al. (2006)
• Developmental dyslexia severe and specific
  difficulty in reading acquisition unrelated to
  other cognitive abilities and education
  circumstances
• Phonological deficits with mental representations
  and processing of speech sounds
• Ectopias, nests of neurons, in cortical layer 1
  and focal microgyria affecting language areas
• Neural migration and axon growth, especially in
  first year of life

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Candidate Genes

• Long history of familial occurrence and twin
  studies
• DYX1C1, KIAA0319, DCDC2 and ROBO1 are dyslexia
  candidate susceptibility genes
• Proteins from these genes diverse may be
  functionally linked either directly or by
  similarity to other proteins involved in neuronal
  migration and axon growth
• Coordinating changes in cell adhesion and
  cytoskeletal restructuring

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Protein Function

• ROBO1 and KIAA0319
• Proteins for transmembrane adhesion molecules and
  receptors guiding axons to proper targets
• In vitro assays of KIAA0319 allele linked to
  dyslexia show 40 decrease in expression in vivo
  effects not yet known
• DCDC2 and DYX1C1
• Act as downstream targets that modulate changes
  in cytoskeletal processes involved in motility of
  developing neurons

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Communication Disorders

• DSM-IV four types
• Expressive language disorder
• Mixed receptive and expressive disorder
• Phonological disorder
• Stuttering
• 25 of 1st degree relatives report similar
  disorders
• MZ concordance 90, DZ 50 high heritability at
  2 years

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KE Pedigree

• 3 generation pedigree of family with severe
  speech and language disorder
• Autosomal-dominant monogenic trait
• Linkage pedigree points to responsible locus,
  SPCH1, on 7q31 and FOXP2 gene in particular
• FOXP2 encodes a transcription factor containing a
  polyglutamine tract
• Disrupted by point mutation in affected members
  of KE family

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KE Pedigree
I
Adapted from Lai et al. (2001)
II
III
Affected male
Affected female
Deceased
Unaffected male
Unaffected female