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Human Bioscience: Impaired Body Function > genetic disorders > Flashcards

genetic disorders Flashcards

1
Q

Prevalence of genetic disease

A

There are over 13,000 known genetic diseases
 30% of all infant deaths have genetic factors
 5% of the population will have a genetic
disease by the age of 25
 60% of individuals will have a genetic or
genetic-related disease during their lifetime

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2
Q

Common genetic disorders in NZ

A

Familial Cancer (Breast, Bowel)
 Huntington’s Disease
 Muscular Dystrophies
 Chromosomal abnormalities
 Cystic Fibrosis (Not often seen in clinic)
 Haemochromatosis (Not often seen in clinic)

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3
Q

Understanding genetics is important for:

A

 Patient diagnosis/treatment
 Accelerated screening of relatives
 Family counselling/reproduction decisions

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4
Q

Genotype

A
  • the genetic information that is stored in the genetic code
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5
Q

DNA (deoxyribonucleic acid)

A

a stable macromolecule of the genetic information
 Double helix containing nucleotides [cytosine (C), guanine (G), adenine (A)
and Thymine (T)]

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6
Q

Chromosomes

A
  • contain the genome (genetic material) of an organism
     Tightly wound and condensed DNA and proteins
     Located in nucleus of cell (in eukaryotes)
     Humans have 46 chromosomes that come in pairs
     22 autosomal pairs and 1 pair of sex chromosomes
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7
Q

Genes

A

segments of DNA responsible for a particular trait
 Distributed among chromosomes in a specific locus (location)
 Code for proteins that determine the structure and function of our cells

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8
Q

Alleles

A
  • different DNA sequences of the same gene in a
    population
     Differences arise due to mutations
     Alleles of paired (homologous) chromosomes may be the same or different
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9
Q

Alleles on homologous

chromosomes may be

A 
the same (homozygous) or
different (heterozygous)
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10
Q

Alleles at a gene locus carry

A

recessive or dominant traits

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11
Q

Dominant trait expressed with

A

either homozygous or
heterozygous pairing of the
alleles

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12
Q

Recessive trait expressed only

when

A 
two copies (homozygous) of the recessive
allele are present
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13
Q

Genetic mutations

A

 Biochemical events leading to accidental errors in
duplication, rearrangement, or deletion of parts of the genetic code
 Occur all the time in every cell in the body
 Smallest mutation is a point mutation that is the change of 1
base for another

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14
Q

Most mutations are corrected by

A 
DNA repair mechanisms in
the cell (or the cell is eliminated)
Not all mutations have an effect
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15
Q

Gene mutations can be either

A

inherited from a parent or

acquired

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16
Q

A hereditary mutation (germ line mutation) is:

A

 Present in the DNA of all body cells and can be passed from
parent to newborn
 Copied every time body cells divide
 Effects depend on how much and what type of genetic
material is interrupted, missing, or extra

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17
Q

Genetic disease is the

A

pathologic result of an alteration of

the genetic code (genes or chromosomes)

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18
Q

The size of the mutation is

A

not a measure of the severity of the disease

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19
Q

Main types of genetic mutations

A 
 Single gene
     -Autosomal
     -Sex-linked
 Chromosomal
     -Alterations in chromosome structure
     -Alterations in chromosome number
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20
Q

Single gene disorders

A

 Conditions that are caused by a mutation in a single gene in
one copy or in both copies of the gene
 May be present on an autosome or sex-linked chromosome (X)
 Lead to formation of an abnormal protein or decreased
production of a gene product

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21
Q

 Several mutated genes can lead to the

same disorder Example

A

Childhood deafness: Can be
caused by 16 different autosomal
recessive mutations

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22
Q

One mutated gene can affect many

different parts of the body Example

A 
Marfan syndrome
 An estimated prevalence of 1 per
10,000
 Pathogenesis related to mutations in a
gene on chromosome 15 leading to a
defect in connective tissue → affects
various structures (e.g., skeletal,
ocular, and cardiovascular
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23
Q

Autosomal disorders

A

 Caused by mutations in alleles on autosomes
 Male and female parents are equally affected (since the
mutation is not in a gene on a sex chromosome)
 Male and female offspring are equally affected (since the
mutation is not in a gene on a sex chromosome)
 Can be autosomal recessive (more common) or autosomal
dominant (less common)

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24
Q

Autosomal recessive

A 
 Need 2 mutated alleles to be
affected (carriers with one allele
may have ‘mild’ symptoms)
 Each male child and each female
child with two recessive carrier
parents has a 25% (1 in 4) chance
of inheriting the disease
 Each male and each female child
with one recessive carrier parent
has a 25% chance of being a
carrier
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25
Q

Autosomal recessive Examples

A

sickle cell anaemia
(1:600); cystic fibrosis (1:2000);
phenylketonuria (1:12,000)

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26
Q

Autosomal recessive disorders

A

 Mutation on one allele may be “trait” with minimal
health issues
 Mutation on both alleles is “disorder” with true health
issues
 One mutation on one allele and another mutation on
the other allele may be additive!

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27
Q

Autosomal recessive disorders Example

A

qualitative haemoglobin
mutations (such as sickle cell
anaemia

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28
Q

Autosomal recessive disorders: Mutation on one allele (heterozygote/carrier/ ‘trait’ form) is generally

A

asymptomatic and actually
protects against malaria  in
malarial (Arab/SE Asia) countries, up
to 70% of the population are carriers

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29
Q

Autosomal recessive disorders: Mutation on both alleles causes

A

severe anaemia

Mutation S on one allele and
mutation C on the other allele also
causes severe anaemia  genetic
testing and family counselling

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30
Q

Phenylketonuria

A 
 A metabolic disorder caused by
elevated levels of phenylalanine
that are toxic to the brain
 Mostly due to deficiency in
phenylalanine hydroxylase (PAH)
as it leads to accumulation of
phenylalanine and derivatives
 ~400 mutations in the gene that
encodes PAH have been identified,
with variability in their effects 
 Incidence of 1 per 10,000 in the
white and Asian populations with
some geographical variation
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31
Q

Phenylketonuria: Severity of disease rely on

A

amount of deficiency in PAH
 Symptoms develop gradually
 If not treated can cause irreversible brain damage. (“Untreated,
PKU can lead to intellectual disability, seizures, behavioral
problems, and mental disorders. It may also result in a musty
smell and lighter skin.”)
 Babies with elevated phenylalanine need to be treated as early as possible
(even as early as 7-10 days)
 May require dietary intervention

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32
Q

Autosomal dominant

A 
 Only needs 1 mutated allele to
be affected
 Each male child and each female
child with one affected parent
has a 50% (1 in 2) chance of
inheriting the disease
 Penetrance is not always 100%
(can have the mutated gene but
not develop the disease)
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33
Q

Autosomal dominant: Examples

A 
familial
hypercholesterolemia (1:500);
Marfan syndrome (1:10,000);
Huntington’s disease (1:15,000
of European descent)
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34
Q

Huntington’s Disease

A

 Degenerative brain disorder
 Causes gradual nervous system deterioration and eventually death
 Symptoms include: clumsiness, involuntary movements/loss of muscle
coordination, depression, memory loss and loss of ability to speak
 Initial symptoms by the age of 40 → People often pass allele on to their
offspring before they are diagnosed
 Death likely to occur within 12-20 years of onset of symptoms

35
Q

Autosomal dominant disorders

A

 Can also occur without having an affected parent due to
new mutations involving germ cells
 Mutation will be passed on based on the reproductive
capacity of affected person
 Can have reduced penetrance – carrying the mutation but
failing to express it
 Variable expressivity – can be expressed differently among
individuals (e.g., polydactyly or supernumerary digits)

36
Q

X-linked recessive conditions

A

 Sex-linked disorders in which an unaffected mother carries
one normal and one mutant allele on the X chromosome,
or an affected father carries the mutant allele on his (only)
X chromosome.
 Condition occurs more frequently in males than females
 Females have 2 X chromosomes, therefore female heterozygotes
are rarely affected (need 2 altered alleles to express trait)
 Males have only one X chromosome (only one copy of affected
allele)

37
Q

X-linked recessive conditions:Examples

A

colour blindness; haemophilias A and B; Xlinked agammaglobulinaemia;

 Sons of a carrier mother have a 50% chance of being
affected; daughters of a carrier mother have a 50% chance
of being a carrier.
 Sons of an affected father have a 0% chance of being
affected; daughters of an affected father have a 100%
chance of being carriers.
 Sons of an affected mother (herself the daughter of a carrier
mother + affected father) have a 100% chance of being
affected; daughters of an affected mother have a 100%
chance of being carriers.

38
Q

Red-green colour blindness

A

 Most common types of hereditary colour blindness
 ~8 percent of men and 0.5 percent of women with
Northern European ancestry
 Results from loss or limited function of red or green
photopigments (colour-detecting molecules) that are
located in cone-shaped cells within the retina

39
Q

Haemophilia

A 
 Bleeding/clotting disease
Type A, incidence of 1:10,000 males
Type B, incidence of 1:50,000 males
 1/3 have no previous family history
 X-linked recessive trait - passed on by silent carriers
(females)
40
Q

 Rare cases of haemophiliac females, due to:

A

 Random point mutation in FVIII or F IX gene
 random inactivation of a single X chromosome
(“lyonisation”)
 the daughter of a carrier mother + haemophiliac father

41
Q

X-linked dominant conditions

A

Sex-linked disorders in which an affected female carries one
normal and one mutant allele on the X chromosomes, or an
affected male carries the mutant allele on his (only) X
chromosome.
 Sons and daughters of an affected mother have a 50% chance of
being affected.
 Sons of an affected father have a 0% chance of being affected;
daughters of an affected father have a 100% chance of being
affected.
 Many are “atypical” (not simple Mendelian inheritance)

42
Q

X-linked dominant conditions: Examples

A

Vitamin D resistant rickets (1 in 20,000); X linked dominant porphyria (often miscarried)

43
Q

Atypical single-gene disorders

A

 Do not follow the Mendelian pattern of inheritance
 Triplet repeat mutations
 Mutations in mitochondrial genes
 Genomic imprinting

44
Q

Triplet repeat mutations

A

 Characterized by a long repeating sequence of 3 nucleotides in a gene that disrupts its function

45
Q

Triplet repeat mutations:  Huntington’s disease:

A

the normal gene contains 10 – 35 repeats
of a CAG segment. In HD, there will be 36 – 120 CAG repeats.
(36 – 39 is usually asymptomatic; 40+ develops Huntington’s.)
As HD is passed on through generations, the number of repeats
increases, and the higher number of repeats often causes even
earlier onset of the disease.

46
Q

Triplet repeat mutations: Fragile X syndrome:

A

: Normal FMR1 gene on the X chromosome has 5 to 44 trinucleotide repeats. Premutation carriers have 55
to 200 trinucleotide repeats. People with fragile X syndrome full mutation have over 200 repeats and experience severe
intellectual impairment.

47
Q

Mutations in mitochondrial genes

A

Mitochondria are cellular organelles responsible for
generating energy (ATP) for the cell
 Mitochondrial DNA is different than DNA in the nucleus
 Each mitochondrion copies its own mtDNA during mitosis
 Random mutations can occur during mtDNA replication, but
unlike nuclear DNA the mitochondria can’t repair the
mistakes
 When the mistakes accumulate and reach a certain
threshold, the effect of the mutation will become clinically
apparent

48
Q

Mutations in mitochondrial genes

A

Mitochondrial DNA has an almost exclusively maternal
form of inheritance:
 if a father has the trait, none of his children will inherit it (his
sperm’s mitochondria do not get into/survive in the fertilised egg).
 If a mother has the trait, all of her children will inherit it (her ova
have mitochondria that become part of the fertilised egg).

49
Q

Mutations in mitochondrial genes

A

Mitochondrial DNA mutations can affect tissues and organs
that are highly dependant on oxidative phosphorylation
(e.g., brain, neuromuscular system, muscles)
 Difficult to diagnose
 Broad range of diseases such as:
 Liver dysfunction
 Bone marrow failure
 Pancreatic islet cell dysfunction
 Diabetes

50
Q

Chromosomal disorders

A

 Account for a large proportion of early gestational
abortions, congenital malformations, and intellectual
disability
 Approximately 26% of NZ infant deaths are due to
“congenital malformations, deformations and
chromosomal abnormalities”
 Parts of chromosomes are lost or gained or dislocated
 Can result in abnormal gene number or position
 If mutation includes chromosome breakage it may disrupt
gene function
 Effects depend on how much and what type of genetic
material is interrupted, missing, or extra

51
Q

Chromosomal abnormalities:  Alteration in Structure

A 
 Deletion
 Duplication
 Inversion
 Ring
 Translocation
52
Q

Chromosomal abnormalities:  Alteration in Number

A

Monosomy
 Trisomy
 Tetrasomy
 Triploidy

53
Q

Structural abnormalities: Deletion (or deficiency):

A

Simple loss of a chromosomal segment

54
Q

Structural abnormalities: Duplication

A

The presence of two

copies of a chromosomal region

55
Q

Structural abnormalities: Inversion

A

A segment of a chromosome breaks off and then reattaches in the reversed direction

56
Q

Structural abnormalities:  Ring chromosome:

A

Breakage and two ends joining to form ring

57
Q

Structural abnormalities: Translocation

A

An exchange of parts

between non-homologous chromosomes

58
Q

Deletion: Cri du chat (cry of the cat)

A

 Incidence of about 1 in 50,000 live births
 Caused by a heterozygous deletion of the tip of the
short arm of chromosome 5
 Changes in structure are usually due to chromosome breakage

59
Q

Deletion: Cri du chat (cry of the cat): Characteristic phenotype

A 
 Microcephaly, moonlike face
 Usually some intellectual disability
 Abnormal development of the glottis
and larynx
 Distinctive catlike mewing cries
made by infants
 Gastrointestinal and cardiac
complications
60
Q

Chromosomal duplications:

A 
 Extra copy of a chromosome
region
    -Can be located adjacent to each
other on a different part of the same
chromosome or even on another
chromosome
 Most duplications consist of an
extra chromosomal arm or part
of an arm
 Hard to detect and are rare
 Duplications supply additional
genetic material capable of
evolving new functions
61
Q

Chromosomal inversion

A 
 A segment of the chromosome is
reversed (end to end)
 The chromosome breaks, flips
around, and then re-joins
 Usually does not cause
abnormalities if no DNA is
missing (or added)
 Most common occurs on
chromosome 9
   -Generally not harmful
   -May increase risk of infertility or
miscarriage
   -Genetic counselling recommended
62
Q

Chromosomal ring formation

A 
 Both tips of the chromosome are
usually missing
 Can occur in any of the
chromosomes
 Overall occurs very rarely
 Causes marked delay in growth;
usually microcephaly and mental
disability
63
Q

Chromosomal translocation

A 
 Occurs in ~1:500 newborns
 Usually harmless, but can cause the person’s gametes to be
unstable
    -Infertility
    -Miscarriages
    -Children with abnormalities
64
Q

Trisomy 21 - Down syndrome

A

An abnormal chromosome number (47 instead of 46 chromosomes)

A karyotype of a male with an extra copy of chromosome 21

65
Q

Down syndrome

A

 The most common chromosomal disorder
 Occurs once in about every 691 births
 ~95% caused by nondisjunction or error in cell division
during meiosis
 Risk of trisomy 21 increases with maternal age (1 in 25
births at 45 yrs)
 Great improvements in treatment allow to achieve full
potential and independence

66
Q

Down syndrome

A 
 Usually apparent at birth
 Causes a combination of
birth defects including
intellectual disability and
characteristic facial
features
67
Q

Numeric disorders of sex chromosomes

A 
 Turner syndrome
 Absence of all or part of one of
the female’s X chromosome
(45,X/0)
 The more of the chromosome(s)
is/are absent, the more serious
the symptoms - usually includes
missing ovaries & infertility
 Affects ~1 of 5,000 live births
 Nearly all TS foetuses
spontaneously aborted or
stillborn (~15% of all
miscarriages have TS)
68
Q

Turner syndrome

A 
 Diagnosis is often delayed until late
childhood/early adolescence
 Early diagnosis is important for
ongoing assessment and treatment
   -Growth hormone
   -Oestrogen therapy for secondary sexual
characteristics
 Women with Turner syndrome have
increased morbidity due to
cardiovascular disease and
gastrointestinal, renal, and endocrine
disorders
69
Q

Multi factorial disorders

A

Usually several genes are involved and no clear pattern
of inheritance within a family
 Often environmental contribution
 Difficult to predict
 Risks of recurrence are somewhat increased for close
relatives of an affected individual and with severity of
disorder

70
Q

Multifactorial disorders

A

Can be expressed during:
 Foetal life and be present at birth (congenital): cleft lip or
palate, clubfoot, congenital heart disease
 Later in life (environmental contribution is likely greater):
Alzheimer’s, psychiatric disorders, diabetes, obesity, cancer

71
Q

Environmental contribution

A

 Teratogen - environmental agent that produces
abnormalities during embryonic or foetal development
 Can act via:
- Direct exposure of the pregnant women, foetus or embryo
 Exposure to an agent with a slow clearance rate prior to
pregnancy
 Exposure to a teratogenic agent that caused damage to
reproductive cells prior to pregnancy
 Teratogenic agents include: radiation, environmental
chemicals (cigarette smoke), drugs (thalidomide, alcohol),
infectious agents (rubella)

72
Q

Period of vulnerability: Organogenesis

A

Time interval of differentiation and
organ development
 In humans from day 15 to day 60 after conception
 Insult during the first 2 weeks after fertilization may interfere
with implantation → abortion or early resorption
 Each organ has a critical period of development and higher
susceptibility to environmental derangements
 An insult (teratogen) can affect multiple organs at a specific
timing or different organs at different time points

73
Q

Epigenetics

A

 Regulate activation and repression of genes
 Flexible mechanisms
 Occur during development as stem cells
 Also in response to environmental signals
 Two main kinds of epigenetic information
 DNA Methylation (e.g., genetic imprinting)
 Histone modifications
 Result in changes in gene expression without
changes in the actual gene sequence

74
Q

Epigenetics and cell differentiation

A 
 Critical for cell fate during
development
 All cells have same DNA - but epigenetic marks act to
program the cell to express
gene if relevant to tissue
type
 e.g. a neuronal cell will
express genes enabling it
to develop axon and
dendrites - this will be
suppressed in same genes
in liver cell
75
Q

Epigenetic activating marks

A 
 Modifications such as
acetylation,
phosphorylation and
methylation on histone
tail can cause DNA to
unwind
 This releases genes so
they are accessible to
the transcriptional
machinery
 Results in increased
transcription
76
Q

Epigenetic inactivation

A 
 Other modifications
including DNA
methylation and
methylation on histone
tail (at different sites) can
cause DNA to be more
tightly wound
 This makes genes less
accessible to the
transcriptional machinery
 Results in decreased
transcription
 Epigenetic changes can be a temporal or tissue specific effect
 Evidence suggests that some may be heritable (transgenerational)
77
Q

Prenatal tests - screening

A

 Give an estimate of the chance a disorder will occur
 Identify women < 35 years old with higher risk
pregnancies who can be offered diagnostic testing
 Less invasive than diagnostic testing
 Not a “Yes” or “No” answer
 False positives and false negatives can occur

78
Q

Maternal serum screen

A

 Maternal blood test measures the level of specific
proteins (e.g., α-fetoprotein) produced by the foetus
& placenta
 Maternal age + protein levels are combined to
produce an estimated risk for chromosome
abnormalities and neural tube defects
 Not applicable for all pregnancies e.g., a diabetic
mother, or a multiple pregnancy

79
Q

Prenatal ultrasound

A 
 Used for screening (and diagnostic)
 Non-invasive
 Higher detection rate when
combined with other screening
methods (e.g., blood tests)
80
Q

Prenatal ultrasound: Nuchal translucency

A

 Measurement of the thickness of the fluid
that accumulates under the skin at the back
of the neck
 Helps with detecting Down syndrome

81
Q

Prenatal tests - diagnostic

A

 Give a clear answer (usually) about whether or not the
foetus has a particular condition
 Provide the most accurate results
 Involve invasive procedures which carry a risk of
miscarriage
 Are only routinely offered to those at higher risk
 e.g., women >35 yrs; women with an “increased risk” result on
a screening test; significant family history

82
Q

Amniocentesis

A

 Performed after 14 weeks of gestation
 Karyotype from a sample of amniotic fluid
 Identifies major chromosome anomalies
 Does not identify gene mutations, very small chromosome
changes, or structure and development of the foetus
 Risk of miscarriage associated with the test is 1/200
 Accuracy ~ 99.5%
 Funded by NZ healthcare

83
Q

Chorionic Villus Sampling (CVS)

A

 Performed between 10-12 weeks of gestation
 Karyotype analysis from a sample of the placenta
 Identifies major chromosome anomalies
 Does not identify gene mutations, very small chromosome
changes, or structure and development of the foetus
 Risk of miscarriage associated with this test is 1/100
 Accuracy ~ 96%
 Funded by NZ healthcare

84
Q

Non-Invasive Prenatal Testing (NIPT)

A

 Performed anytime after 10 weeks of gestation
 Uses cell-free foetal DNA (cffDNA) present in the circulating
maternal blood
 cffDNA fragments are significantly smaller than maternal DNA fragments
 Identifies major chromosome anomalies – Trisomy 21, 18, and 13; Turner,
Klinefelter, XXX and XYY syndromes
 Does not routinely identify gene mutations, very small chromosome
changes, or structure and development of the foetus
 New testing allows for identification of selected point mutations, foetal
sex determination, and prenatal DNA paternity testing, as well as fetal
RhD status
 Risk of miscarriage associated with this test is 0%
 Accuracy ~ 98%
 Cost ~NZ$800 (overseas testing; not NZ health funded)

Human Bioscience: Impaired Body Function (2 decks)

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