Cognitive Disabilities

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)

General Cognitive Disabilities

• Genetics relatively well studied– Especially for serious (IQ<50) cognitive

disabilities– Can now investigate specific disabilities at gene

level

• Mild disabilities (candidates for QTLs) are harder

Quantitative Genetics• Sibs of mildly cognitive disabled have

below average IQ scores

• Sibs of severely cognitively disabled do not– Why?

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?

Single Gene Disorders

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

• Generally quite rare

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

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

X-Linked

• Genes on X chromosome

• Tend to effect males

• Females: X-inactivation --> mosaicism– Females with disorder, often show highly

variable severity depending on how many/which cells affected

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

• 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

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 --> methylation of that portion of DNA --> silences expression of FMR1 protein

• Methylation constricts the chromosome; “fragile” appearance under the microscope

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

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

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

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

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

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

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

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

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

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

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”

Dale & Harley (1980)

Mental Institute Penal Institute Mental-Penal

Men karyotyped 5100 6983 5479

XYY 13 31 104

XYY/1000 2.5 4.4 20.0

Nanko et al. (1979)

Sample Size <100 101-200 201-500 >500Number of Studies 6 9 3 5Karyotypes 326 1287 1199 2838XYYs found 4 10 6 7XYY/1000 12.3 7.8 5.0 2.4

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

Why?

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

intelligence)

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)

Tall

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

Lower Intelligence

• 31,436 men born in Copenhagen in 1944-47

• IQ tested during mandatory military service

• Studied all tall (>184 cm) men

• Karyotyped 4,139 of them

• Used criminal history database and school exam records

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

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

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 population’s traits

DF Extremes Analysis

• Method for estimating heritability of disorders that are defined qualitatively (i.e., either have or don’t have the disorder)

• But disorders depend on an underlying trait that varies quantitatively along a continuum

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

Regression to the Mean

• 1000 individuals tested on some measure

Regression to the Mean

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

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?

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

Regression to the Mean

Pop. mean

Time 1

Time 1

Time 1

Time 2

Time 2

Time 2

Correlation = +1

Correlation = 0

Intermediate correlation

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

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

Visualization

Probands

MZ co-twins

DZ co-twins

Pop. mean

DZco-twin mean

MZco-twin mean

Proband mean

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

Graphically

Proband mean

MZ co-twin mean

DZ co-twin mean

Population mean

1 0

e = unique environmentc = shared environment

e2 h2/2 h2/2 + c2

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

Verbal Ability is Heritable1.0

0.8

0.6

0.4

0.2

0.0

Unique envir.

Shared envir.

Heredity

Earlychildhood

Middlechildhood

Adolescence Adulthood OldAge

Meta-Analysis of recent twin studies (Adapted from: Price (2002))

Specific Language Impairment (SLI)

1.0

0.8

0.6

0.4

0.2

0.0

MZ twins

DZ twins

1st degree relatives

Controls

Risk

Relations

Data from Stromswold (1998) and Stromswold (2001) (Figure adapted from Price (2002))

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

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)

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

QTL Linkage Map for 6p21

DNA markers

Index of statistical significance

D6S105 sig. at p = 0.05 for siblings and 0.01 for DZ twins

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

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

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

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

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

KE Pedigree

Affected male

Unaffected male

Affected female

Unaffected female

Deceased

I

II

III

Adapted from Lai et al. (2001)