Chapter 5: Genetic Disorders Flashcards
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
What plays an important role in the pathogenesis of complex multigenic disorders/multifactoral disorders?
- Enviornmental factors
- Each polymorphism has a small effect and is of low penetrance, but the more that exist the higher the risk becomes
Atherolsclerosis, diabetes, HTN, autoimmune diseases, and even normal traits such as height and weight are governed by?
Polymorphisms in several genes
The sickle mutation affecting the β-globin chain of hemoglobin is an example of what type of mutation?
What is the change in the AA sequence?
- Non-conservative missense mutation
- CTC (or GAG in mRNA) = glutamic acid —-> CAC (GUG in mRNA) = valine
β0-thalassemia, a rare form of anemia, is due to what kind of point mutation?
What is the change in AA sequence?
- Nonsense mutation (stop codon)
- CAG (glutamine) —> UAG; creates stop codon
- Premature termination of β-globin gene translation = short peptide that is rapidly degraded
What is the distinguishing feature of trinucleotide-repeat mutations?
They are dynamic (i.e., the degree of amplification increases during gametogenesis)
A 4 base insertion in the hemosaminidase A gene, leads to what type of mutation and is the major cause of what disease?
- Frameshift mutation
- Tay-Sachs disease in Ashkenazi Jews
What type of mutation is responsible for the ABO type O?
- Frame-shift mutation
- Single base deletion at the ABO (glycosyltransferase) locus
What differentiates sick cell disease from sickle cell trait?
- Sickle cell disease: homozygote – all the hemoglobin is HbS
- Sickle cell trait: heterozygot – some hemoglobin is HbS and rest is normal HbA – red cell sickling only occurs under circumstances such as exposure to lowered oxygen tension
How is sickle cell anemia an example of pleiotropism?
- Point mutation in gene gives rise to HbS, predisposing red cells to hemolysis, which tend to cause a logjam in small vessels
- Can lead to splenic fibrosis, organ infarcts, and bone changes
- Numerous differing end-organ derangements are all related to the primary defect of Hb synthesis
How can someone have an autosomal dominant disorder, without having at least one affected parent?
Proportion of patients who develop the disease as a result of a new mutation is related to?
Who is more likely to be the contributor of a disease due to a new mutation?
- Mutations involving either the egg or the sperm from which they were derived
- Depends on the effect of the disease on reproductive capability. If disease markedly reduces repro. fitness, most cases would be expected to result from new mutations
- Many new mutations seem to occur in germ cell of older fathers.
A trait seen in all individuals carrying a gene but is expressed differently among individuals is known as?
What controls this variability?
- Variable expressitivity
- Effects of other genes or the enviornment modify the phenotypic expression
Many autosomal dominant disease arising from deleterious mutations affecting what 2 types of biochemical mechanisms/proteins?
- Those involved in regulation of complex metabolic pathways that are subject to feedback inhibition (i.e., membrane receptors – LDL receptor)
- Key structural proteins, such as collagen and cytoskeletal elements of the red cell membrane (i.e., spectrin)
Why does even a single mutant collagen chain have such a large effect?
What is the mutant allele in this case known as?
- Collagen molecules are trimers and require 3 collagen chains arranged in a helical configuration
- Each chain in the helix MUST be normal for the assembly and stability of the collagen molecule
- Known as a dominant negative because it impairs the function of a normal allele
Gain of function mutations are almost always what type of inheritance pattern?
Which disease illustrates this type of mutation?
- Autosomal dominant
- Huntington’s disease gives rise to abnormal protein, huntingtin, that is toxic to neurons, and hence even heterozygotes develop neurologic deficit
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
Autosomal dominant disorders affecting the Urinary and GI systems?
Urinary = Polycystic kidney disease
GI = familial polyposis coli
What are the 4 diseases affecting the skeletal system that are Autosomal Dominant? (hint: there’s a mnemonic)
1) Marfan Syndrome
2) Osteogenesis imperfecta
3) Ehlers-Danlos syndrome (some variants)
4) Achondroplasia
“My Osteology Enters Afterlife”
What are the 2 diseases affecting the metabolic system that are Autosomal Dominant?
- Familial hypercholesterolemia
- Acute intermittent porphyria
What kind of penetrance is common with autosomal recessive disorders?
How are parents and children affected by these disorders?
- Complete penetrance
- Trait does not usually affect the parents (carriers), siblings have 1/4 chance of having trait.
Many of the mutated genes in autosomal recessive disorders affect which proteins?
Enzymes
Almost all inborn errors of metabolism follow what type of inheritance?
Autosomal Recessive
If a male is affected by an X-linked disorder, they are said to be ________ for X-linked mutant genes
Hemizygous
How are X-linked recessive disorders passed down from an affected male?
Carrier mother?
- A male will pass on to all his daughters, and they will be carriers. Will not pass to his sons.
- A heterozygous mother will pass to 50% of her sons and/or daughters
How are X-linked dominant conditions passed to offspring from both males and females?
- Affected heterozygous female will pass to half her sons and half her daughters
- Affected male will pass to all his daughters, but none of his sons, if female parent unaffected
Which condition shows that although a mutant X chromosome may be inactive in some cells, it may be active in other cells?
Affect of drugs?
Who’s at greatest risk (male or female)?
- Glucose 6-phosphate dehydrogenase (G6PD) deficiency
- Predisposes patients to RBC hemolysis when they are treated with certain drugs (i.e., primaquine, anti-malarial) = severe drug-induced hemolytic reaction
- Males more affected because they only have one X chromosome and if gene is mutant they have no functional G6PD. Females have two X chromosomes.
X-linked recessive diseas that affects the MSK system?
Duchenne muscular dystrophy
X-linked recessive disorders that affect the blood system (3 of them)?
1) Hemophilia A and B
2) Chronic granulomatous disease
3) G6PD deficiency
What 2 X-linked recessive disorders affect the immune system?
1) Agammaglobinemia
2) Wiskott-Aldrich syndrome
What 2 X-linked recessive disorders affect the metabolic system?
1) Diabetes insipidus
2) Lesch-Nyhan syndrome
What X-linked recessive disorder affects the nervous system?
Fragile X syndrome
What is the mode of inheritance for Vitamin D-resistant rickets?
X-linked dominant
Galactosemia is due to a deficiency in ________, leading to the accumulation of galactose and consequent tissue damage?
Galactose-1-phosphate uridyltransferase
α1-antitrypsin deficiency leads to what?
- Inability to inactivate neutrophil elastase in the lungs
- Leads to destruction of elastin in the walls of lung alveoli, and eventually pulmonary emphysema
What are the 2 fundamental mechanisms by which loss of fibrillin leads to clinical manifestations of Marfan syndrome?
1) Loss of structural support in microfibril rich CT
2) Excessive activation of TGF-β signalling
Fibrillin occurs in what two homologous forms?
Mapped to which chromosomes?
- Fibrillin-1 (FBN1) mapped to chromosome 15q21.1
- Fibrillin-2 (FBN2) mapped to chromosome 5q23.31
What type of mutations give rise to the abnormal fibrillin-1 seen in Marfan syndrome?
Missense mutations
Mutations of FBN2 are less common and give rise to?
Congenital contractural arachnodactyly
How does loss of microfibrils give rise to abnormal and excessive activation of TGF-β?
What does this excessive activation lead to?
- Normal microfibrils sequester and control the bioavailability of this cytokine
- Deleterious effects on vascular smooth muscle development and increases activity of MMPs, causing loss of ECM
Finding of bilateral ectopia lentis should raise suspicion of which disease?
What is ectopia lentis?
- Marfan Syndrome; since is so uncommon in persons w/o this disease its presence is nearly diagnostic
- Bilateral subluxation or dislocation (outward and upward) of the lens
Most cases of Marfan Syndrome transmitted via what type of inheritance?
Autosomal dominant
What are the most life threatening lesions seen in Marfan Syndrome; what are the 2 most common?
How can they be detected?
- Cardiovascular lesions; 2 most common are mitral valve prolapse and more importantly dilation of the ascending aorta due to cystic medionecrosis
- Echocardiography is extremely valuable in diagnosis
Due to variations, the clinical diagnosis of Marfan syndome is currently based on?
What are the guidelines for using these criteria?
- Revised Ghent criteria
- Takes into account family hx, cardinal clinical signs in absence of family hx, and presence of fibrillin mutation
- In general, major involvement of 2 of the 4 organ systems (skeletal, cardiovascular, ocular, and skin) and minor involvement of another organ is required for diagnosis
What is the mainstay of the medical treatment for Marfan syndrome?
Other treatments being tested?
- Mainstay = β blockers; act to reduce heart rate and aortic wall stress
- Other therapies being tested = block TGF-β signaling and blockade of angiotensin type 2 receptors
Heterogenous group of conditions that result from a defect in the synthesis of fibrillar collagen?
Ehlers-Danlos Syndrome
What are the 2 autosomal recessive types of Ehlers-Danlos syndrome?
What is the gene defect in each?
1) Kyphoscoliosis (Type VI) due to Lysyl hydroxylase defect = most common autosomal recessive form
2) Dermatosparaxis (Type VIIc) due to Procollagen N-peptidase defect
Vascular type (IV) of EDS arises from abnormalities in?
Which gene
- Type III collage
- COL3A1 gene
Which tissues are rich in type III collagen and are affected most by vascular type of EDS?
Blood vessels and intestines
The arthrochalasia type and dermatosparaxis type of EDS arise from defects in?
Which genes is defective for each type
- Conversion of type I procollagen to collagen; through cleavage of noncollagen peptides from the N and C terminus of the procollagen
- Arthrochalasia type = mutations in either COL1A1 or COL1A2
- Dermatosparaxis type = mutation in procollagen-N-peptidase gene
The classic type of EDS arises from mutations in what genes?
Can also be caused by non-collagen related gene abnormalities such as?
Mutations in tenascin-X lead to?
- Genes for type V collagen (COL5A1 and COL5A2)
- Defects that affect the biosynthesis of other extracellular matrix molecules that influence collagen synthesis
- EDS-like condition caused by mutation in tenascin-X, a large multimeric protein, that affects synthesis and fibril formation of type VI and type I collagens
How does familial hypercholesterolemia differ amongst homozygotes and heterozygotes?
Heterozygotes: have one mutant gene, with 2-3x elevation of blood cholesterol levels, leads to tendinous xanthomas and premature atherosclerosis
Homozygotes: have 2 mutant genes and 5-6x elevation of blood cholesterol levels. May develop skin xanthomas and coronary, cerebral, and peripheral vascular atherosclerosis at a early age
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
Which receptor on the liver recognizes IDL and specifically what does it recognize?
- LDL-receptor
- Recognizes apo B-100 and apo-E
What is the immediate and major source of plasma LDL?
IDL
Which apopprotein is found on LDL and can be recognized by the LDL-recptor for uptake/clearance by the liver?
ApoB-100
The exit of cholesterol from the lysosomes requires the action of what 2 proteins?
NPC1 and NPC2
Cholesterol suppresses cholesterol synthesis within the cell by inhibiting?
Also suppresses the synthesis of?
- HMG-CoA reductase = The rate-limiting enzyme
- Suppresses synthesis of LDL receptors, thus protecting cells from excessive accumulation of cholesterol
Statins work by suppressing what?
But increasing?
- Suppress intracellular cholesterol synthesis by inhibiting enzyme HMG-CoA reductase
- Allows greater synthesis of LDL receptors
LDL can also be transported via scavenger receptors, which occurs via what cells?
How does this contribute to the pathogenesis of hypercholesterolemia?
- Cells of the mononuclear phagocyte system; monocytes and macrophages have receptors for chemically altered (i.e., acetylated or oxidized) LDL.
- Impaired IDL transport into liver secondarily diverts more plasma IDL into precursor pool for LDL
- There is marked increased in the scavenger receptor-mediated traffic of LDL cholesterol into the cells of this system and possibly the vascular walls = appearance of xanthomas and premature atherosclerosis
Differentiate class I vs. class II mutations of the LDL receptor gene?
Class I: uncommon; complete failure of synthesis of the receptor protein
Class II: fairly common; encode receptor proteins that accumulate in the ER because folding defects make it impossible for them to be transported to the Golgi
Differentiate class III vs. class IV vs. class V mutations of the LDL receptor gene?
Class III: affect LDL-binding domain of receptor; encoded protein reaches cell surface, but fails to bind LDL
Class IV: bind LDL normally, but fail to localize in coated pits and bound LDL is not internalized
Class V: bind LDL and can be internalized; however pH-dependent dissociation of receptor and bound LDL fails to occur, trapped in endosome, and fail to recycle
What are 3 treatment strategies for lysosomal storage disease?
- Enzyme replacement therapy - currently in use
- Substrate reduction therapy
- Molecular chaperone therapy - exogenous competitive inhibitor that binds mutant enzyme and acts as “folding template.” Tx under investigation for use in Gaucher disease
Tay-Sachs disease is most common form of GM2 gangliosidosis and results from mutations on what chromosome, leading to?
Prevalent in what population?
- α-subunit locus on chromosome 15 causing severe deficiency in lysosomal hexosaminidase A.
- Prevalent among Jews, paticularly Eastern European (Ashkenazic) origin
The enzyme deficiency in Tay-Sachs disease causes accumulation of GM2 gangliosides in many tissues, but which tissues dominate the clinical picture?
What is pictured with an electron microscope?
- Neurons in the central and autonomic nervous systems and retina
- Cytoplasmic inclusions, the most prominent being whorled configurations within lysosomes composed of onion-skin layers of membrane
What constitutes the dominant histological change seen in Niemann-Pick type A?
- Vacuolation and ballooing of neurons
- Concentric lamellated myelin figures called zebra bodies
What is the morphology of Gaucher disease?
Dominant cell type visualized?
What is visualized with electron microscope?
What type of stain is positive?
- Accumulation of phagocytotic cells, known as Gaucher cells, found in spleen, liver, bone marrow, LN’s, tonsils, thymus, and Peyers pathces
- Rarely appear vacuolated but instead have fibrillary type of cytoplasm likened to crumpled tissue paper
- Periodid acid-Schiff staining is intensely positive
Describe the picture on the left vs. the one on the right
Left = normal myocardium with adundant eosinophilic cytoplasm
Right = patient with Pompe disease showing myocardial fibers full of glycogen seen as clear spaces
What are the distinctive clinical features of Trisomy 18: Edwards syndrome?
- Prominent occiput
- Horseshoe kidney
- Low set ear
- Short neck
- Overlapping fingers
- Limited hip abduction
What are the distinctive clinical features of trisomy 13: Patau syndrome?
- Micropthalmia (small or missing eyeballs)
- Polydactyly
- Microcephaly
What are the distinguishing clinical features of Turner’s Syndrome?
- Short stature
- Amenorrhea (single most important cause of primary amenorrhea)
- Streak ovaries
- Cystic hygroma of the neck and hydrops fetalis
- Cubitus Valgus
Where is the FMRP protein found most abundantly?
What are its functions?
- Brain and Testis
- Selectively binds and regulates the transport of mRNA into dendrites
- At synaptic junctions FMRP suppresses protein synthesis of the bound mRNAs in response to signaling through group I metabotropic glutamate receptors (mGlu-R) = translation regulator
What syndrome is characterized by mental retardation, short stature, hypotonia, profound, hyperphagia, obesity, small hands and feet, hypogonadism?
What is the underlying cause of this disease?
- Prader-Willi syndrome
- Deletion affecting the paternally derived chromosome 15 (specifically deletion of band q12 in long arm of chromosome 15)
- Only the functional allele is provided by the paternal chromosome
Mental retardation, ataxic gait, seizures and innapropriate laughter (“happy puppets”) describes what disorder?
Caused by what gene and process?
- Angelman syndrome
- UBE3A gene mapped to maternal chromosome 15 is deleted. This gene is imprinted on the paternal allele, but only the maternal allel is normally active
