Cognitive disabilities

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Cognitive disabilities
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Mental retardation

• No twin or adoption studies have been done
• Moderate to severe mental retardation has shown
  NO familial resemblance
• Mild mental retardation has a risk for the
  children that is equal to 20 if one parent is
  affected and up to 50 if both are affected
• Other medical disorders tend to co-occur with
  mentally retarded individuals.

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Mental retardation Diagnostic criteria DSM-IV-TR

• Significantly subaverage intellectual
  functioning an IQ of approximately 70 or bellow
  on an individually administered IQ test (for
  infants, a clinical judgment of significantly
  subaverage intellectual functioning)
• Concurrent deficits or impairments in present
  adaptive functioning (ie, the persons
  effectiveness in meeting the standards expected
  for his/her age by his/her cultural group) in at
  least two of the following areas communication,
  self care, home living, social/interpesonal
  skills, use of community resources,
  self-direction, functional academic skills, work,
  leisure, health and safety.
• Onset before 18 years.
• Severity
• Mild 50-55 to 70
• Moderate 35-40 to 50-55
• Severe 20-25 to 35-40
• Profound below 20-25
• Unespecified presumption of MR but intelligence
  is unestable

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Phenilketonuria

• 1 10,000 births
• Single recessive disorder
• Up to 100 mutations that cause milder forms of
  mental retardation
• http//www.dnai.org/lesson/go/7687/

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Fragile X syndrome

• Second most common cause of mental retardation
• 1 in 1250 males and 1 in 2500 females
• Men are moderately or mildly retarded but could
  have normal intelligence
• Girls are affected 1/2 given that one gene is
  inactivated.
• Females show a mosaicism
• The expansion of the CGG is normally 6 to 54
  repeats
• A PREMUTATION includes an expanded section of up
  to 200 repeats
• Mothers pass the premutation which after a few
  generations (four) may expand even more
• http//www.dnai.org/lesson/go/7687/

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Rett Syndrome

• Second most common cause of mental retardation
  amongst females after Downs syndrome
• Severe phenotype appears after age 5
• Gene in long arm X chromosome
• Mutations in MECP2 in 1/3 of cases
• Enzyme responsible for methylation processes to
  silence genes during development

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Duschenne muscular dystrophy

• X linked recessive affects 13500 males
• Lethal by age 20
• Cognitive effects are variable but language is
  severely affected
• Dystrophin is also found in brain tissue
• Mouse dystrophin mutations are not necessarily
  lethal (compensation?)
• http//www.dnai.org/lesson/go/7687/

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Lesch Nyhan Syndrome

• X linked recessive affecting 120,000 births
• Compulsive self-injurious behaviours
• Hypoxanthine phosphorybosyl transferase (HPRT)
  gene affected by many mutations
• Causes pervasive structural defects in
  dopaminergic systems
• KO of HPRT did not affect behaviour due to
  compensation. When compensatory gene is blocked,
  disorder appears

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Neurofibromatosis 1

• Chocolate colored spots (café au lait)
• Tumors in skin and nerves appear in childhood
• IQ in low average range with non-verbal abilities
  being more affected
• NF1 inherited from the father, tumor supressor
• KO models NF1 deficits in learning and memory in
  heterozygous mice (homozygous die), but no tumors
• NF1 and p53 learning disabilities and tumors
• http//www.dnai.org/lesson/go/7687/

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Chromosomal abnormalities

• Due to complete chromosomal additions or
  deletions
• Cause 7 of moderate to severe MR but only 0.5 of
  mild MR
• Angelman and Prader-Willi syndromes
• Spontaneous deletions in 15q11
• Maternal imprinting Angelmans Sx.
• Moderate MR, abnormal gait, speech impairment,
  seizures, inappropriate happy demeanor happy
  puppets
• Ubiquitin ligase UBE3A gene involved crucial in
  brain development

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Chromosomal abnormalities

• Paternal imprinting Prader-Willi sx.
• Overeating, temper outbursts, learning
  difficulties, IQ average low
• Gene involved is tha Small Nuclear,
  Ribonucleoprotein Polypeptide N or SNRPN, which
  is an element in mRNA processing
• Williams Syndrome
• Small deletion Ch. 7
• Absent elastingt connective tissues
• Absent LIM kinase gt expressed in brain and
  manifested as visuospatial constructive
  disabilities

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Chromosomal abnormalities

• Down Syndrome
• 11000 births
• http//www.dnai.org/lesson/go/7687/
• In addition to the usual characteristics two
  thirds have hearing deficiencies and one third
  have cardiopathy
• IQ is 55 avg, but it could be in the low end of
  normal range
• Does not run in families

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Chromosomal abnormalities

• Sex chromosomes abnormalities
• XXY male Sx (Kleinefelters Sx)
• 1750 male births
• Low testosterone after adolescence
• Tall, infertile, small testes, breast
  development, low IQ, language deficiencies and
  poor school performance
• XXX female Sx.
• 11000 female births
• Average IQ 85 but verbal are lower than
  non-verbal scores
• May require speech rehabilitation
• Head circumference is smaller in both XXX and XXY

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Chromosomal abnormalities

• Sex chromosomes abnormalities
• XYY
• 11000 male births
• Taller than average, normal sexual development
• Speech and language difficulties
• Juvenile delinquency, more violent?
• Turners Syndrome XO
• 12500 female births but most are miscarriages
• Short stature and abnormal sexual development
• Hormonal therapy available but no ovulation
  occurs
• Verbal IQ normal but performance IQ is low

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Learning disabilities

• Dislexia
• Up to 10 of children have difficulty reading
• Reading is the primary problem in 80 of children
  with learning disabilities
• Family studies have shown that dislexia runs in
  families
• Twin concordances have shown to be 66 for MZ and
  36 for DZ twins
• DF extreme analysis used to study the genetic
  contribution to dislexia

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DF extremes analysis

• DF extremes analysis
• Assess the concordance in quantitative scores
• by comparing the mean scores of the group (MZ,
  DZ co twins vs probands)
• Correlations for MZ .9 and DZ .65 hence group
  heritability 50
• Difference with liability-threshold is that L-T
  assumes continuity in a discrete trait, while
  DFEA assesses the position of the individual in
  the continuum.
• If all assumptions in L-T are correct, L-T
  resembles DFEA

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Learning disabilities

• Could not be autosomal dominant because there are
  non-familial cases of the disease
• Could not be sex-linked recessive because does
  not skip a generation and is transmitted from
  father to son as often as it is from mother to
  son
• QTL linkage demonstrated for marker D6S105 and
  another marker in chromosome 15q21
• Association studies (TDT) showing significant
  associations with both markers

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Communication disorders

• Include expressive language, mixed receptive and
  expressive, phonological disorder and stuttering
• 25 of first degree relatives of children
  affected, present similar problems in comparison
  to 5 of relatives of controls
• Twin studies present a concordance of 90 MZ vs
  50 DZ.
• Findings have been confirmed in adoption studies
• Linkage to 7q31
• DSM categories may be wrong as expressive and
  receptive disorders overlap genetically, while
  expressive disorders with and without
  articulation problems are genetically different
• Stuttering concordances MZ 77 and DZ 32

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Dementia

• 15 of individuals over 80 years of age suffer
  dementia
• This is the fourth leading cause of death in
  adults
• Initiates with loss of recent memory
• In the advanced stages the individual is
  bedridden and possibly delusional or psychotic
• Pathological features are plaques and tangles
  that accumulate in the cell end lead to its
  destruction
• Various other causes of dementia AIDS,
  multyinfarcts, huntingtons, parkinsons,
  pseudodementia (depression)
• Risk to first degree relative 50 by age 85
• http//www.dnai.org/lesson/go/7687/

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Dementia

• Familial form appears before age 65 and is
  inherited as autosomal recessive
• Associated to presenilin 1 and 2, in chromosomes
  14 and 1 respectively
• They generate lesions that are surrounded by
  beta-amyloid causing neurofibrillary tangles
• Other forms associated to the Amyloid precursor
  protein (APP) in Ch 21

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Dementia

• Late onset Alzheimer is associated to apo-E on Ch
  19 that has 3 alleles, 2,3 and 4
• Allele 4 is associated with the disease in 40
  of cases
• The product of this allele binds to beta-amyloid
  causing it to deposits and plaques
• The other two alleles may act as protective
  factors.
• A polymorphism in the promoter region of apo-E
  has also been suspected to have a role in causing
  Alzheimers
• Other genes may also be implicated given the
  Apo-E explains only part of the variability