Chapter 5 - Genetic Diseases Flashcards
(92 cards)
1
Q
What is the most common category of human genetic disorders?
a) Single gene with large effect
b) Chromosomal disorders
c) Complex multigenic disorders
A
Complex multigenetic disorders
- caused by interactions between multiple variant forms of genes and environmental factors
egs. include diabetes mellitus, HTN, autoimmune disorders
2
Q
What is a point mutation?
A
Mutation in which a single base is substituted for a different base.
May result in a
-missense mutation
- may be ‘conservative’ with little change in function
- may be ‘non-conservative’ e.g sick mutation of beta globin chain of Hb -> sickle cell anaemia
- stop codon
3
Q
What is a frameshift mutation and the typical result?
A
Deletion/insertion mutation
The number of affected coding bases is not a multiple of 3
Typically the result is the incorporation of a variable number of incorrect amino acids followed by truncation from premature stop codon
4
Q
What are trinucleotide repeat mutations?
A
Amplification of a sequence of 3 nucleotides
Almost always contain a C and a G
Distinguishing feature is that they are dynamic (i.e. the degree of amplification increases during gametogenesis
5
Q
What is meant by codominance?
A
Both of the alleles of a gene pair contribute to the phenotype
e.g. blood group antigens
6
Q
What is the term that implies a single gene may lead to multiple end effects?
A
Pleiotropism
7
Q
What is meant by the term incomplete penetrance?
A
The inherited mutant gene may be inherited while being phenotypically normal.
Expressed as a %
e.g. 50% penetrance implies that 50% of those who carry the gene express the trait.
8
Q
What is meant by the term variable expressivity?
A
The trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals
e.g. manifestations of neurofibromatosis type 1
9
Q
What is the largest category of Mendelian disorders?
A
Autosomal recessive (i.e. occur when both alleles at a given gene locus are mutated)
10
Q
What is the chance that a sibling will be affected by an autosomal recessive condition?
A
1/4
11
Q
What are 5 distinguishing features of Autosomal recessive conditions compared to Autosomal dominant?
A
- Expression tends to be more uniform in AR disorders
- Complete penetrance is common
- Onset is frequently early in life
- New mutations associated with AR disorders are rarely detected clinically
- Many of the mutated genes encode enzymes
12
Q
Which category of Mendelian disorders includes most inborn errors of metabolism?
A
Autosomal recessive
13
Q
What type of Mendelian disorder is G6PD deficiency?
A
X-linked
an enzyme deficiency which predisposes to RBC haemolysis in patients receiving certain drugs
14
Q
What is the inherited defect in Marfan syndrome?
A
Inherited defect in fibrillin-1 (an extracellular glycoprotein)
15
Q
What are the roles of fibrillin?
A
- Fibrillin is the major component of microfilaments found in the ECM
- Fibrillin-1 controls the bioavailability of TGB-beta (and hence limits inflammation)
16
Q
What is Ehlers-Danlos syndrome?
A
Defect in collagen synthesis or assembly
- skin, ligaments and joints frequently involved
- several variants
17
Q
Name 6 types of Ehlers-Danlos syndrome
A
- Classic
- Hypermobility
- Vascular
- Kyphoscoliosis
- Arthrochalasia
- Dermatospraxis
18
Q
What is the most common cause of familial hypercholesterolaemia?
A
Mutation in the gene encoding for the receptor of LDL
19
Q
What are the 3 types of mutations causing familial hypercholesterolaemia (by impairing hepatic clearance of LDL)?
A
- Mutations in LDL receptor (-> defective LDL clearance)
- Mutations in genes encoding Apolipoprotein B (-> reduced binding of LDL to LDL receptors)
- Activating mutation in proprotein convertase subtilisin/kexin type 9 (PCSK9)
(–> reduced LDL receptors on the cell surface due to increased degradation)
20
Q
What are the components of VLDL?
A
- Cholesterol esters
- Triglycerides
- Apolipoproteins on surface: Apo-C; Apo-E and B-100
21
Q
What changes occur when VLDL is converted to LDL?
A
Reduced content of triglycerides compared to VLDL
and Apo-C is lost
22
Q
What are the 2 options/destinations for IDL?
A
- Taken up by liver by receptor mediated transport and recycling to VLDL (approx 50%) OR
- Further metabolic processing that removes remaining triglycerides and APO-E –> LDL
23
Q
Approx what percentage of plasma LDL is cleared by the liver?
A
70%
24
Q
What is the effect of intracellular cholesterol on: cholesterol synthesis?
A
Suppresses cholesterol synthesis within cells by inhibiting enzyme HMG CoA reductase
25
What is the effect of intracellular cholesterol on: acyl-coenzyme A?
Cholesterol activates the enzyme acyl-coenzyme A -> favours esterification and storage of excess cholesterol
26
What is the effect of intracellular cholesterol on: LDL receptors
Cholesterol suppresses the synthesis of LDL receptors --> protecting cells against excessive accumulation of cholesterol
27
What is the effect of intracellular cholesterol on: PCSK9
Cholesterol upregulates expression of PCSK9 which leads to decreased recycling of LDL receptors
https://www.nps.org.au/australian-prescriber/articles/pcsk9-inhibitors-mechanisms-of-action
28
How do statins work?
Inhibition of HMG CoA reductase -> reduced intracellular cholesterole -> greater synthesis of LDL receptor receptors -> greater uptake of plasma LDL by the cell
29
Where are lysosomes synthesised?
In the endoplasmic reticulum
| ad then transported to the Golgi apparatus
30
What happens to lysosomes in the Golgi apparatus?
They undergo a variety of post-translatiomal modifications including attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains
31
What are 2 pathological consequences that occur from an inherited deficiency of a functional lysosomal enzyme?
1. "Primary accumulation" - accumulation of partially degraded insoluble metabolite within lysosomes (as catabolism remains incomplete)
2. Defects in autophagy -> Cellular injury
(autophagy is essential for turnover of mitochondria by a process called mitophagy)
32
What is the name of the lysosomal storage disease caused by a deficiency of hexosominidase A due to a mutation in the alpha subunit -> inability to catabolise GM2 gangliosides?
Tay Sachs Disease
33
What are the similarities/difference between Niemann-Pick Disease Types A and B?
Both are characterised by lysosomal accumulation of sphingomyelin due to an inherited deficiency of sphingomyelinase
- Type A: missense mutation -> almost complete deficiency of sphingomyelinase. Sever infantile form with extensive neurological involvement.
- Type B: organomegaly but generally no CNS involvement.
34
What is the morphology of Niemann-Pick disease (type A/B)?
affected cells become enlarged due to distention of lysosomes and sphingomyelin and cholesterol
35
What is the most common type of Niemann-Pick disease?
Type C
36
What mutations account for most of Niemann-Pick type C disease?
NPC1
-> defect in cholesterol transport and accumulation of cholesterol in CNS
Both NPC1 (membrane bound) and NPC2 (soluble) are involved in transport of free cholesterol from lysosomes to the cytoplasm.
37
What is the most common lysosomal storage disorder?
Gaucher disease
| - refers to a cluster of AR disorders resulting from mutations in the genes encoding glucocerebrosidase
38
Which enzyme is affected in Gaucher disease?
Glucocerebrosidase
| - enzyme that normally cleaves glucose residue from ceramide
39
A mutation of which gene is the most common genetic risk factors for the development of Parkinson disease?
Glucocerebroside gene
| reciprocal relationship between the level of this enzyme and the aggregation of alpha synuclein
40
What are the clinical features of Type 1 Gaucher disease?
Type 1 Gaucher disease presents in adult life
Splenomegaly - pancytopenia / thrombocytopenia or
Bone involvement - pathological #s, bone pain
41
What are the clinical features of type II and III Gaucher disease?
CNS dysfunction
convulsions
progressive mental deterioration
42
What is the most common mode of inheritance of Mucopolysaccharidoses (MPSs)
```
autosomal recessive
(all of MPS clinical variants except Hunter syndrome which is X-linked)
```
43
What are the 3 major subgroups of glycogen storage disease?
1. Hepatic form (liver cells store glycogen due to a lack of hepatic glucose-6-phosphatase)
2. Myopathic form (lack of muscle phosphorylase -> excess glycogen in skeletal muscles)
3. Miscellaneous (e.g. Pompe disease - lack of lysosomal acid alpha-glucosidase)
44
What is aneuploidy?
When an error occurs in meiosis or mitosis and a cell acquires a chromosome complement that is not an exact multiple of 23
(usual causes are nondisjunction and anaphase lag)
45
What is mosaicism?
2 or more populations of cells with different chromosomal complement in the same individual
(affecting sex chromosomes is relatively common. Autosomal much less common)
46
What is the term for a loss of a portion of a chromosome?
Deletion
(most are interstitial - loss between 2 breaks.
occasionally are terminal - single break in a chromosome arm
ring chromosome - special form of deletion)
47
What is the term for a rearrangement that involves 2 breaks in single chromosome with reincorporation of the inverted, intervening segment
Inversion
(may be paracentric - involving only 1 arm or
pericentric - breaks on opposite sides of centromere)
48
What results when 1 arm of a chromosome is lost and the remaining arm is duplicated
Isochromosome
49
What is the term when segment of one chromosome is transferred to another
Translocation
50
What is the most common cause of trisomy?
Meiotic nondisjunction
51
What are the clinical features of Klinefelter syndrome
- male hypogonadism
- common cause of male infertility
- 2 or more X chromosomes; 1 or more Y chromosomes
- increased incidence of metabolic syndrome
- increased risk of congenital heart disease particularly mitral valve prolapse
52
What is Turner syndrome?
complete/partial monosomy of the X chromosome
| charterised by hypogonadism in phenotypic females
53
Name 3 diseases caused by trinucleotide repeat mutations in expansions affecting non-coding regions
Fragile X syndrome
Friedreich ataxia
Myotonic dystrophy
54
Name 2 diseases caused by trinucleotide repeat mutations affecting coding regions
Huntington disease
| Spinocerebellar ataxia
55
What proportion of carrier females are affected (i.e have intellectual disability and other clinical features) in Fragile X syndrome?
30-50%
| This is higher than in other X-linked disorders
56
What are carrier males of Fragile X syndrome referred to as?
Normal transmitting males
| because carrier males transmit the trait through all their phenotypically normal daughters to affect grandchildren
57
What determines the presence and severity of clinical symptoms in Fragile X syndrome?
The amplification of CGG repeats of the FMRI gene
Patients with Fragile X syndrome have an extremely large expansion of 200-4000 repeats
Normal range of CGG repeats is 6-55
Normal transmitting males and carrier females carry 55-200 CGG repeats
58
Which 2 organs is the FMR protein (product of FMR1 gene) most abundant?
Brain and testes
59
What are 2 disorders that CGG premutations in the FMR1 gene can cause that are phenotypically different to Fragile X syndrome and occur through a distinct mechanism involving a toxic gain of function?
- Fragile X-associated tremor/ataxia syndrome
| - Fragile X associated primary ovarian failure
60
What is the "threshold effect" in terms of mitochondrial gene mutations
A minimum number of mutant DNAs must be present in a tissue before oxidative phosphorylation gives rise to a disease
61
What is the mode of inheritance of Leber hereditary optic neuropathy?
Mitochondrial inheritance
62
What is the term for the epigenetic process which involves transcriptional silencing of the paternal or maternal copies of certain genes during gametogenesis?
Genomic imprinting
63
What is maternal imprinting?
Transcriptional silencing of the maternal allele
64
What is paternal imprinting?
Transcriptional silencing of the paternal allele
65
What chromosome is affected in Prader-Willi syndrome?
The deletion affects the paternally derived chromosome 15
66
What is the difference in inheritance between Angelman syndrome and Prader-willi syndrome?
Prader Willi syndrome - deletion affects the paternally derived chromosome gene region
Angelman syndrome - deletion affects the maternally derived chromosome gene region
67
What are the additional clinical features seen in Angelman syndrome (compared to Prader willi)
Microcephaly; ataxic gait; seizures; inappropriate laughter
68
What is the difference between constitutional and somatic genetic markers?
Constitutional - present in every cell of affected person
| Somatic - restricted to specific tissue types or lesions
69
What is the name of sequencing which involves PCR using primers for many different genomic regions performed simultaneously
Next generation sequencing
70
PCR type that is a useful approach for identifying mutations at a specific nucleotide position
Single based primer extension
71
PCR that takes advantage of the digestion of DNA with endonucleases known as restriction enzymes that recognise and cut DNA at specific sequences
Restriction fragment length analysis
72
Single PCR product mixed with a DNA polymerase, a specific primer, nucleotides and four dead-end nucleotides with different fluorescent tags .
Ensuing reaction -> ladder of DNA molecules labeled with different tags
After size separation by electrophoresis, the sequence is "read" and compared with the normal sequence to detect mutations
Sanger sequencing
73
Genotypic array that are routinely used to uncover copy number abnormalities in paediatric patients when the karyotype is normal but a structural chromosomal abnormality is still suspected.
Can identify loss of heterozygosity.
Important in diagnosis of disorders caused by uniparental disomy (e.g. Prader Willi syndorme and Angelman syndrome)
Single nucleotide polymorphisms (SNP) genotyping arrays
74
The most useful types of genetic polymorphismsfor linkage analysis
SNPs (single nucleotide polymorphisms)
| Minisattelite and microsatellite repeats
75
The study of heritable chemical modification of DNA or chromatin that does not alter the protein-encoding DNA sequence itself
Epigenetics
76
Molecular analysis technique that uses DNA probes that recognise sequences specific to particular chromosomal regions
Large fragments of clonal genomic DNA spanning up to 200kb and labeled with fluorescent dyes and applied to metaphase chromosome preparations or interphase nuclei that are pre-treated
Fluorescence in situ Hybridisation
77
Test DNA and a reference DNA are labeled with 2 different fluorescent dyes
Samples mixed and hybridized to an array spotted with DNA probes that span the human genome at regular intervals
Comparison of binding of labelled DNA from the 2 samples
Cytogenomic Array Technology
78
To what category of genetic diseases does Gaucher disease belong? Name some other diseases in this group
Lysosomal storage disease
| Other examples are Pompe disease, Tay-Sachs disease, and the mucopolysaccharidoses.
79
What are the indications for analysis of inherited genetic alterations in newborns or children? (name 5)
- Multiple congenital anomalies
- suspicion of a metabolic syndrome
- unexplained intellectual disability and/or developmental delay
- suspected aneuploidy
- suspected monogenic disease
80
Indications for inherited genetic testing in adult patients? (name 3)
- inherited cancer syndromes (family history or an unusual caner presentation)
- atypically mild monogenic disease (e.g. attenuated cystic fibrosis)
- neurodegenerative disorders (e.g. Huntingon disease)
81
Indications for analysis of acquired genetic alterations? (name 2 common indications)
- Diagnosis and management of cancer
- Diagnosis and management of infectious disease e.g determination of treatment efficacy of HIV; identification of genetic alterations in microbes associated with drug resistance
82
Which two types of genetic polymorphisms are most useful for linkage analysis?
- SNPs
| - minisatellite/microsatellite repeats
83
Why is DNA-based diagnosis generally preferred to RNA analysis?
DNA is much more stable
84
What is a morphological hallmark of trinucleotide repeat disorders of coding regions?
Accumulation of aggregated mutant proteins in large intranuclear inclusions
85
What pattern of inheritance accounts for autosomal dominant conditions where phenotypically normal parents have more than one affected child (e.g. osteogenesis imperfecta)?
Gonadal mosaicism
86
What is the mode of inheritance of G6PD deficiency?
X-linked recessive inheritance
87
What is the most common mode of inheritance of Marfan syndrome?
Autosomal dominant
88
What is an ophthalmological sign characteristic of Tay Sachs disease?
Cherry red spot in the macular
89
Which organ is most affected in Pompe disease?
Heart - cardiomegaly
90
What is Pompe disease?
Glycogen storage diseases associated with deficiency of acid alpha-glucosidase
91
What is von Gierke disease?
Glycogen storage disease (hepatic type) with deficiency of glucose-6-phosphatase
92
What is McArdle disease?
Glycogen storage disease (myopathic type). Deficiency of muscle phosphorylase
