Chapter 5: Genetic Disorders Flashcards
- List and discuss the three broad categories of human genetic disorders.
1. Mutations in a single gene with large effects (Mendelian disorders)
2. Chromosomal disorders
3. Complex multigenic disorders
- List and discuss the three broad categories of human genetic disorders.
[mutations in a single gene]
Description:
Common:
Penetrance:
Example:
- Mutations with single genes are called Menelian disorders. They have:
- large effects
- rare
- high degree of penetrance.
- An example would be: Sickle cell anemia is prominent in the African-American community and has malaria maintains the mutation in the population.
- List and discuss the three broad categories of human genetic disorders.
Chromosomal disorders
Description:
Common:
Penetrance:
Chromosomal disorders are structural or numerical alterations in autosomes and sex chromosomes. They are:
- Uncommon
- High penetrance
- List and discuss the three broad categories of human genetic disorders.
Complex multigenic disorders
Description:
Common:
Penetrance:
Complex multigenic disorders (polymorphic disorders) are caused by multiple interactions between the environment and genes. They are multi/polygenic: maning that each different gene has a small increase in disease risk but no single gene is necessary and sufficient to produce the disease. They are:
More common
Low penetrance
What are examples of complex multigenic disorders?
- 1. Atherosclerosis
- 2. DB
- 3. HTN
- 4. Autoimmune diseases
- 5. Height and weight
What is a mutation?
permanent change in the DNA
- Germ cells mutations give rise to
- Somatic cells give rise to
- Germ cells sex cells) mutations give rise to inherited dz
- Somatic cells give rise to cancer & some congenital malformations
What are point mutations and what types are there?
Point mutations are changes in which a single base is substituted with another base IN a CODING sequence.
-
Missense: change the meaning of squence in protein.
- Acid -> base
- Nonsense: AA substitution results in a stop codon (chain terminator)
Point mutations can be divided into missense mutations or nonsense mutations.
What is an example of both?
- Missense mutation: Sickle cell changes [glutamic acid -> valine] in a B-globulin chain of Hb.
- Nonsense mutation: β0 -thalassemia is a point mutation affecting the codon for glutamine (CAG) creates a s_top codon (UAG)_ if U is substituted for C => deficiency of β-globin chains
- Discuss the effect of mutations involving noncoding sequences.
Mutations in non-coding sequence can alter promotor or enhancer regions .
- May interefere with binding of transcription factors => reduction or total loss of transcription
Mutaion in non-coding sequences can also cause defects of splicing in intervening sequences.
- Causes fa_ilure to form mRNA=_> cannot translate into protein
What transcription factors should we be aware of when a mutation occurs in non-coding sequences?
1. MYC
2. JUN
3. p53
- Describe and discuss the two effects on protein encoding associated with deletions and insertions (figure 5-2, 5-3, and 5-4).
Deletions and insertion can alter the reading frame of a protein.
Non-frameshit mutation: 3/multiple of 3 base pairs are deleted or inserted, the reading frame will remain intact -> abnormal protein gaining/lacking 1 or more AA will be made.
Framshift mutation: if the number of bases deleted/inserted is not a multiple of 3
- What is trinucleotide repeats (figure 5-23).
-
Tri-nucleotide repeats is an amplification of a sequence of 3 nucleotides, almost always containting C & G.
- Tri-nucleotide repeats undergo anticipation: as the genetic order is passed onto generations, the symptoms more severe and m_ore apparent at an earlier age_ with each generation
- Ex. Huntingtons or myotonic drystophy
Cystic fibrosis is an example of what kind of mutation?
Non-frameshift mutation: 3-base deletion in the CF allele that causes lack of AA 508 (phenylalanine)
Anticipation is seen in which of the following?
A. Frameshift mutation
B. Non-framshift mutations
C. Tri-nucleotide repeats
D. Mutations with noncoding sequences
C. Tri-nucleotide repeats
Anticipation: as a genetic disoder that is passed on to the next generation, the symptoms become more apparent at an earlier age and more severe.
What disorders show anticipation?
1. Huntingtons Disease
2. Myotonic dystrophy
What type of mutation is the Tay-Sachs disease, often seen in Ashkenazi Jews?
Frameshift mutation: insertion of 4 bases (TATC) on hexosaminidase A gene.
What leads to the O allele in ABO blood typing?
Frameshift mutation: deletion of 1 base (G of valine)
- Define “de novo” as related to genetic mutations.
It is estimated that every individual is a carrier of 5 to 8 deleterious genes, most that are recessive and have no serious phenotypic effects.
- About 80% to 85% of these mutations are familial.
- The remainder represents new mutations acquired de novo by an affected individual.
Mendelian disorders can be described in terms of:
1. Codominance
2. Pleitropism
3. Genetic heterogeneity
-
Codominance: both alleles contribute to the phenotype
- Ex. AB blood type
- Pleiotropic: mutation of 1 gene => has many phenotypic affects
- Genetic heterogeneity: mutations at several loci produce the SAME phenotype.
- For the autosomal dominant disorders listed in table 5-1, discuss the following;
- manifestation,
- chance of inheritance,
- new mutations
- penetrance
- expressivity
- Manifestion: Heterozygous state (only 1 gene is affected so 1 parent most often affected). However, in every autsomal dominant disorder, there is a prop of pts whose parents do have the disorder.
- Chance of inheritance: Age of onset is delayed in many AD conditions, meaning sx appear in adulthooD!
-
New mutations:
- With every autosomal dominant disorder, some proportion of patients do not have affected parents. Such patients get the disorder d/t new mutations that involve either the egg or the sperm from which they were derived. Their siblings are neither affected nor at increased risk for disease development.
- How the disease affects the reproductive fittness determines who develops the disease as a result of a new mutation
- When a disease causes low reproductive fitness => most cases of the disease arise from new mutations that occur in germ cells of relatively older fathers
-
PResentations in Autosomal Disorders can vary d/t variations in penetrance and expressivity.
-
Penetrance:
-
Incomplete penetrance: Pt has the mutation, but are phenotypically normal
- Ex. 50% penetrance meants that 50% who carry genes express the trait
-
Incomplete penetrance: Pt has the mutation, but are phenotypically normal
-
Expressivity:
- Expressivity can vary: All of those + for the trait can express it differently
-
Penetrance:
Autosomal dominant disorders
Loss of function mutations:
Gain of function mutations:
Loss-of function mutations: more common in AD disorders
- Result in: decreased production of a gene or decreased activity of a protein.
- Ex. Familial hypercholesterolemia
Gain of function: less common
- Cause disease by giving gene toxic properties or increasing normal activity.
- Ex. Huntingtin protein toxic to neuron
- SN: Huntinging trinucleotide repeat that shows anticipation and gain of function
As mentioned, most Autosomal Dominant mutations are loss of function.
What are the 2 main patterns we see?
- Mutations in structural proteins, like collagen and cytoskeleton elements of RBC
- Mutations in metabolic pathways, subject to feedback inhibition.
Age of onset is delayed in many AD conditions, meaning sx appear in adulthooD!
What does a pedigree for somone with an autsomal dominant mutation look like?
- If the parent is heterozygous or the trait: will pass down to 50% of children (M or F).
- If the mutation is spontaneous (new), parents are not affected and will affect 25% of children.
If dominant: will not skip a generation
If automal: will affect M and F equally
What are the 4 diseases that are autosomal dominant and affect the nervous system? (hint: there is a mnemonic)
- Tuberous sclerosis
- Myotonic dystrophy
- Huntington disease
- Neurofibromatosis
Touch My Hurt Nerves
What is the largest category of genetic disorders?
Autosomal recessive disorders
Autosomal recessive disorders
- Manifestation
- Chance of inheritance
- Manifestations: homozygous; both alleles are mutated; parents are not usually affected
- Chance of inheritance
- Siblings have a 25% chance of inheritance
- If the mutation does not occur commonly in the population, there is a strong liklihood of consanguineous marriage.
How are AR and AD disorders different from one another?
In AR:
New mutations:
Expressivity:
Penetrance
Onset:
- New mutations are rarely detected (would occur after several generations
- Expressivity is more uniform
- Complete penetrance
- Onset is early in life
Autosomal recessive disorders usually involve mutations of ______.
Enzymes (inborn errors of metabolism); activity of normal enzyme is decreased or the enzyme is is defected
Cystic fibrosis (aka)
Transmission pattern:
Mutation:
CF= MUCOVISCIDOSIS
Transission pattern: Autosomal recessive.
Mutation: Non-frameshift 3 base deletion (AA 508;
Phenylalanine) mutation CF allele on CFTR (cystic fibrosis transmembrane regulator) gene on chromosome 7, q31.2=> causing abnormal function of Cl- channel
Cystic fibrosis:
Effect:
Main cause of death:
Effect: (Cl-) cannot be pumped into secretion. B/c it usually draws H20 into secretions and thins them out, this will cause thick secretions in exocrine glands and lungs, intestines and reproductive lining.
- Newborns: thick secretions will affect their meconium (first stool) => making it thicc and stick => get stuck intestines and form meconium ileus
- Eary childhood: thick secretions can cause pancreatic insufficiency because the thick mucus will block the pancreatic ducts, preventing pancreatic digestive enzymes from going into intestines => problem absorbing fats and proteins => can cause [failure to thrive, malnutrition and steatorrhea: fatty stools]
- If continue, can damage the pancrease and cause acute pancreatitis/chronic => develop cysts and fibrosis in the pancreas.
- Later in childhood: develop lung problems: it is hard to clear thicc mucus => create perffff env for bacteria (haemophilus inflenzua and pseudonomas aurginosa) => cough and fever
- If cant clear => chronic CF => bronchiectasis and atelactasis
- => overtime, it can cause respitaroy distress and COPD (LEADING COD IN CF)
- Salt-loss syndrome: acute salt depletion
Main cause of death: COPD (80-90% of cases)
Patients with Cystic fibrosis can get __________, secondary to what?
Chronic lung disease, secondary to:
- pancreatic insufficiency
- steatorrhea
- intestinal obstruction
- male infertility
Cystic fibrosis:
Incidence:
Manifestation appear:
Incidence: most common lethal genetic disease that affects whites
Manifestations appear: at any point in life from b4 birth -> later in childhood and adolescence.
Cystic fibrosis is the best-known examples of what? Is this still true?
ONE GENE -> ONE DISEASE AXIOM;
However, there is evidence that genes other than CFTR alter the frequency and severity of organ-specific manifestations.
In children with Cystic Fibrosis, what is the biggest thing for diagnosis at birth?
- Muconium ileus prevents children from having a bowel movement. Thus, children will have abdominal distension, smelly stouls and failure to thrive/
Chronic CF (sinpulomonary disease) is manifested by what two bacteria and causes what?
1. Haemphilus infleunza
2. Pseudomas aeruginosa
Can cause bronchiestasis and atelectasis.
What is the criteria for diagnosis of CF?
- 1 or more characteristic phenotypic feature
- OR history of CF in sibling
- OR a postitive newborn screening test
AND
- sweat cholide test: increased Cl- in sweat on 2 or more occasions, causing bby to taste salty
- OR ID of 2 cystic fibrosis mutations
- OR abnormal epithelial nasal ion transport
PKU (found in articifial sweetners)
Transmittion pattern:
Mutation:
- Transmittion pattern: Autosomal recessive
-
Mutation: PAH (phenylalanine hydroxylase) => decreased of PAH => phenylalanine cannot convert to tyrosine & tyrosine cannot become melanin => hyperphenylalanemia
- High phenylalanine
- Low tyrosine and melanin
PKU
Effect:
Main cause of death:
Effect: High phenylalanine, low tyrosine and low melanin => toxic; severe mental retardation, hypopigmentation of skin and hair, eczema.
- Pt will have a strong, musty odor in urine and sweat
Main cause of death: N/A
PKU
Incidence:
Manifestation appear:
Other:
- Incidence: 1 in 10K Scandanavian caucasians (not AA or jewish)
-
Manifestations appear: Appears early.
- Children are normal at birth
- By 6 months, child has developed severe symptoms.
- Other: Tx with dietary restrictions.
X-linked recessive diseas that affects the MSK system?
Duchenne muscular dystrophy
X-linked recessive disorders that affect the blood system (3 of them)?
- Hemophilia A and B
- Chronic granulomatous disease
- G6PDH defiency
What X-linked recessive disorders affect the immune system?
Agammaglobinemia*
What 2 X-linked recessive disorders affect the metabolic system?
1. Diabetes insipidus*
2. Lesch-Nyan syndrome *
What X-linked recessive disorder affects the nervous system?
Fragile X syndrome*
The most common X-linked disorders are _______.
Recessive.
- Fully expressed in males because they do not have another counterpart (M are XY)
- Heterozygous F, on the othre hand, have another X chromosome so they usually do not express/fully express the disorder.
What is the pattern of transmittance of X-linked dominant conditions?
Caused by dominant alleles on X-chromosome; there are FEW X-linked dominant disorders.
- Affected heterzygous mom -> passes down to 1/2 sons and 1/2 daughters
- Afffected dad and unaffected mom-> passes to ALL of his daughterss and none of his sons
What is an example of X-linked dominant disorders?
Vitamin D-resistant Rickets
How are X-linked recessive disorders expressed in M and F?
Males:
- Affected males are hemizygous for the disorder.
- Affected men -> fully express disorders if they have 1 copy because the gene will not have a Y counterpart.
- Males are usually infertile; meaning that there is no Y-linked inheritance.
Females:
- Heterozygous females do not usually express the disease d/t a paired normal allelle.
Mitochondrial Inheritance
Tranmission pattern
Mitochondrial DNA is only inherited from the mom. Thus, an affected mom will pass down the gene to all of their children. However, an affected dad will NOT pass on the genes.
What does a mT inheritance pedigree look like?
Single Gene (Mendelian )Disorders can cause disease by what 2 ways?
Altering a single gene can cause:
1. Decrease in a production of a normal gene
2. Forming abnormal proteins (enzymes, substrates, receptors, and structural proteins)
What are the 4 main categories of mendelian disorders?
- Production of defective enzymes (which have decreased actiivity) or decreased production of a normal enzyme
- Defects in membrane receptors and transport systems
- Changes in the structure, function or quantity of proteins that are NOT enzymes.
- Mutations that cause unusual reactions to drugs.
Mendelian disorders can cause defects in enzymes.
What are the 3 consequences and give an example of each.
-
Accumulaton of a precursor, intermediate or alternative product that is toxic.
- Ex. Galactosemia: deficiency of galatacote-1 phosphate uridyltransferse
- Ex. Lysosomal storage disease; accumulation of substrated in lysosomes d/t a deficiency of degradative enzymes.
-
Decreased amount of an end product
- Albinism occurs d/t lack of tyroninase causing a decrease in melanin.
- Lesch-Nyhan: decrease in end-products => increase in intermediate products; when they breakdown => TOXIC.
-
Failure to inactivate a substance that damages tissue
- a_1-antitrypsin deficienc_y causes us to not be able to inactivate neutrophil elastase in lung, causing emphysema.
Disorders related to mutations in single genes with large effects are also called?
What is their pentrance and how common?
- Mendelian disorders
- Uncommon, but highly penetrant
Mendelian disorders can cause defects in receptors and transport systems.
What are 2 examples of these?
1. Familial hypercholesterolemia: decrease in synthesis/function of LDL receptor => defectiev transport of LDL into cells => secondary increase of cholesterol => can cause arthersclerosis and cardiac problems
2. CF: Cl-ion transport in exocrine sweat glands, ducts, lungs and pancrease is defective
Mendelian disorders can cause changes in structure, function or quantity of non-enzyme proteins.
What are examples of these?
- HAVE WIDESPREAD SECONDARY AFFECTS
- Sickle cell disease: defect in structure of globin molecule
- Thalassemias: mutation in globin gene => decrease in globin chains
-
collagen –> osteogenesis imperfecta;
* spectrin –> hereditary spherocytosis
* dystrophin –> muscular dystrophies
-
collagen –> osteogenesis imperfecta;
Mendelian disorders can cause adverse reactions to drugs. How?
Silent mutations in a single gene are unmasked after we are exposed to that drug.
What is the most common adverse reaction to a drug?
G6PD deficiency: give pt antimalarial primaquine can cause severe hemolytic anemia.
What disorders are associated with defects in structural proteins?
1. Marfans syndrome
2. Ehlers Danlos syndrome
Marfan Syndrome
Transmission pattern:
Mutation:
Transmission pattern: Autosomal dominant
Mutation: fibrillin-1 on the FBN1 gene on Chr 15q21.1 or FBN2 Chr5q23.31 (less common)
Marfan syndrome
Effect:
Main cause of death:
Normally fibrillin sequesters TGF-B, a growth-factor that causes tissue growth, to prevent overgrowth.
Effect: Decrease in # of dysfunctional fibrillin-1 => causes clinical manfistations via 2 mechanisms
- Decreases structural support and elasticity in microfibrils of CT
- TGF is not seqetered => high TGF-B => more tissue growth => skeletal, eyes and heart problems
* A. Skeletal: Tall; long arms and short legs; arachnodactaly (long digits), Pectus excavatum, flexibile joints
* B. Ocular: Ectopia lentis=> bilateral dislocation of lens
* D. CV: aortic dissection, mitral valve prolapse*, dilation of ascending aorta- *=most common
* E. HIGH lung capacity; they have the lowest levels of lactate ever -> allowing efficient production of NRG
- *=most common
- TGF is not seqetered => high TGF-B => more tissue growth => skeletal, eyes and heart problems
Main cause of daeth: N/A
Marfans syndrome
Incidence:
1 in 5,000; 70-85% familial passdown
Name that disorder:
Heterogenous group of 6 conditions that is due to a defect in the synthesis of fibrillar collagen in CT.
Ehlers-Danlos Syndrome
What are the general manifestation of Ehlers-Danlos Syndrome?
Changes in skin and joints
- Skin is stretchy, fragile and vulnerable to trauma. Small injuries will produce a gaping defect, making repair hard.
- Joints are hypermobility => makes people more vulnerable to clumsiness and joint sprains/dislocations
- Because there is a defect in CT, pts have internal complications:
- Vascular EDS: rupture of colon and large arteries
- Kyphoscooliosis EDS: eye is fragile: causes cornea ruptures and and retina detaches
- Classic EDS: diaphragmatic hernia
What are the autosomal dominant types of EDS?
1. Classic (I/II) EDS
2. Vascular (IV/4) EDS
What is the autosomal recessive (AR) types of Ehlers-Danlos syndrome?
What is the gene defect and clinical findings in each?
Kyphoscoliosis (Type VI)/6 EDS is the most common AR form
- Gene defect: lysyl hydroxylase
- Clinical findings: hypotonia (low muscle tone/floppy), joint laxity, c_ongenital scoliosis, ocular fragility_ (causing the cornea to rupture and retina to detach)
Vascular (IV) EDS
Tranmission pattern:
Gene defects:
Clinical findings:
Tranmission pattern: autosomal dominant
Gene defects: COL3A1
Clinical findings: thin skin, arterial/uterine/colon rupture and easy bruising
Classic (I/II) EDS
Tranmission pattern:
Gene defects:
Clinical findings:
Tranmission pattern: Autosomal dominant
Gene defects: COL5A1, COL5A2
Clinical findings: atrophic scars, easy bruising
Familal Hypercholesterolemia
Transmission pattern:
Mutation:
Transmission pattrn: Autosomal Dominant
Mutation: LDL receptor
Familial Hypercholesterolemia
Effect:
Main cause of death:
Effect: Mutation of LDL receptor -> increase in cholesterol -> premature atherosclerosis -> increases risk of MI
Main cause of death: N/A
Familial Hypercholesterolemia
Incidence:
Manifestions appear:
Other
Incidence:
- Heterozygotes: occur in 1/500 births;
- 1 mutant gene, with 2-3x increase of cholesterol levels,=>
- tendinous xanthomas, xanthelesmas, and arcus cornealis and premature atherosclerosis
- Homozygotes: worse prognosis;
- 2 mutant genes and 5-6x increase of blood cholesterol levels =>
- skin xanthomas coronary, cerebral, and peripheral vascular atherosclerosis at a early age; MI before 20 yo.
Manifestions appear: N/A
Other: N/A
If a patient comes in before 20 yo with an MI, what should we look for problems with?
Cholesterol, vascularity, and skin xanthomas
=> patient could be homozygous in familial hypercholesterolemia.
VLDLs released by liver are rich in ______ and contain lesser amounts of _______
VLDLs released by liver are rich in triglycerides and contain lesser amounts of cholesterol esters
- Undergo lipolysis via lipoprotein lipase-> release TAGs -> stored in fat cells -> used as source of NRG in skeltal muscle
- -> IDL -> LDL
Patients with ______ familial hypercholesteremia present with tendinous xanthomas. How does this process occur?
Heterozyous familial hypercholesteremia
- Tendinous xanthomas manifest as first, the thickening of, then depostings of cholesterol in extensor tendons.
Xanthelasmas and arcus cornealis are most common in ________ familal hypercholesteremia. What are these?
Heterozygous
- Xanthelasmas: deposits of cholesterol around the eye
-
Arcus cornealis: deposits of cholesterol around the cornea
- occur most commonly in ppl younger than 45.
Mutations in the LDL receptor in familial hypercholestermia can be classified as what?
- Synthesis in the ER (I)
- Transport to Golgi (II)
- Binding of apoprotein ligands (III)
- Clusting in coated pits (IV)
- Recycling in endosomes (V)
____ is the major transport form of cholesterol in the plasma
LDL
Which apoprotein is found on LDL and can be recognized by the LDL-recptor for uptake/clearance by the liver?
ApoB-100
How is plasma LDL most cleared?
Uptake by the liver, even though most cells have high affinity receptor for ApoB-100.
If LDL is chemically altered, how is it taken up?
Scavenger receptors on mononuclear phagocytes and other cells can uptake chemically altered LDL.
What disorders are associated with defects in enzymes?
- Lyosomal storage diseases (Tay Sachs, Niemann Pick Disease Type A, B and C, Gaucher disease, MSP (mucopolysaccharidoses I H and II)
-
Glyocogen Storage Disease (hepatic type and miscellaneous type)
*
-
Glyocogen Storage Disease (hepatic type and miscellaneous type)
Storage diseases are also called _______.
Thesaurismoses
Lyosomal storage diseases are d/t the deficiency of _________; this can cause what?
lysosomal enzymes; causing the accumulation of non-metabolized substrates.
- Primary accumulation: breakdown of the substrate of the missing enzyme is incomplete, causing to accumulate in the lysosome -> lysosomes become large and impair cell functions
- Secondary accumulation: lysosome makes substances needed for autophagy. SA is a buildup of substances important in autophagy in the lysosome
What are the 3 general approaches to treatment of lysosomal storage diseases?
- Enzyme replacement therapy*, currenltly used in many diseases
- Substrate reduction therapy: reduce the substrate that would be degraded by the enzyme. The remaining enymze activity may be enough to catabolis and prevent build up.
- Consider molecular basis of the deficiency: use molecular chaperones to help with mutated proteins fold normally
* Ex. Tx in Gaucher diseaes
- Consider molecular basis of the deficiency: use molecular chaperones to help with mutated proteins fold normally
How can we divide lysosmal storage diseases?
Based on the accumulated metabolite:
1. Glycogenases
2. Sphingolipidoses (lipidoses)*
3. MPSs
4. Mucolipidoses
What is an isochromosome?
Isochromosomes occur when 1 arm of a chromosome is lost and the remaining arm is copied, resulting in a chromosome with only 2 short arms or only 2 long arms. The genetic material in both arms is identical.
i(17q).
DESCRIBE PEDIGREE OF FRAGILE X
IN FIRST GENERATION, ALL SONS ARE NORMAL AND ALL FEMALES ARE CARRIERS.
During oogenesis in the carrier female, premutation expands to
full mutation; hence, in the next generation all males who inherit the X with full
mutation are affected. However, only 50% of females who inherit the full mutation are
affected, and only mildly.
Pedrigree for mT dNA
