Chapter 5 Flashcards
what is polymorphism?
Variations in genes within a population
what does it mean when a disease is said to be polygenic?
That it takes multiple different polymorphisms for the disease to present.
Define mutation.
Permanent change in the DNA.
What is a point mutation and what is the consequence?
A change in which a single base is substituted with a different base. It may alter the code in a triplet of bases and lead to the replacement of one amino acid by another in the gene product.
What is a missense mutation?
A point mutation where the meaning of the sequence of the encoded protein has been altered.
What is a conservative missense mutation?
If the substituted amino acid due to a point mutation is biochemically similar to the original, typically causing little change in the function of the protein.
What is a nonconversative missense mutation?
When the a point mutation replaces normal amino acid with a biochemically different one.
The type of mutation seen in sickle cell anemia is an example of what kind of mutation?
nonconversative missense mutation
In biochemistry of sickle cell anemia, explain what the nucleotide triplet change is, what the amino acid change is, and what the protein change is.
within a coding sequence when the normal CTC (or GAG in mRNA) which encodes glutamic acid is changed to CAC (or GUG in mRNA) which encodes valine. This single amino acid substitution alters the physiochemical properties of hemoglobin protein.
What is a nonsensse mutation?
When a point mutation within a coding sequence changes the amino acid codon to a terminator, or stop codon.
What is the type of mutation seen in the disease beta-thalassemia?
nonsense mutation (type of point mutation) within a coding sequence
In beta thalassemia, explain the biochemistry in terms of nucleotide change, codon change, and resulting protein change.
Due to the nonsense mutation within a coding sequence, the codon for glutamine (CAG) creates a stop codon (UAG) where the C was substituted with a U. This change leads to premature termination of beta-globin gene translation, and the short peptide that is produced is rapidly degraded.
Cystic fibrosis is an example where a deletion of a multiple of three AA such that reading frame is kept intact. Deletion of what amino acid leads to the disease? What chromosome is involved?
Amino acid 508 (phenylalanine) on chromosome 7.
Deletion at the ABO (glycostransferase) locus is an example of a _ mutation responsible for the O allele.
Frameshift mutation.
Four-base insertion in the _ gene leading to a frameshift mutation is the major cause of Tay-Sachs disease in Ashkenazi Jew
Hexosaminidase A
In trinucleotide-repeat mutations, almost all affected sequences share what nucleotides?
G and C
In Fragile X syndrome, there are about 250-4000 tandem repeats of _ sequence within a gene called _.
CGG
familial mental retardation 1 (FMR1)
The type of mutation seen in the Factor V Leiden disorder is a _ mutation and what amino acid is switched?
Point mutation. CGA (Arg) is switched to CAA (Gln).
Virtually ALL Mendelian disorders are the result of mutation in _ that have large effects
Single genes
Explain what is meant by sickle cell trait.
The idea that in mendelian disorders, some autosomal mutations produce partial expression in the heterozygote and full expression in homozygote. In sickle cell anemia, homozygous for the mutant gene, all of the hemoglobin is of the abnormal HbS type, but individual who are heterozygous only a proportion of the hemoglobin is HbS and the rest are normal HbA and therefore red cell sickling occurs only under unusual circumstances like exposure to lowered oxygen tension.
What is pleotropism? Give an example of this type.
single mutant gene leading to many end effects. Example Sickle cell anemia, where the bad RBC causes other problems like splenic fibrosis, organ infarcts, bone changes
what is genetic heterogeneity? Give an example.
Mutations at several genetic loci producing the same trait. Example: Profound childhood deafness results from many different types of autosomal recessive mutations
What are the typical pattern of inheritance of mutations involving single genes?
Autosomal dominant, autosomal recessive, and X-linked
What are some characteristics of autosomal dominant disorders?
- manifested in heterozygous state (at least one parent is affected)
- both males and females are affected and both can transmit
- if affected marries unaffected, every child has 1/2 chance
- some cases, don’t have affected parents
- variations in penetrance and expressivity (e.g. neurofibromatosis type I)
What is the general biochemical mechanisms of autosomal dominant disorders?
- depends on nature of mutation and type of protein affected, but most mutations leads to reduced production of gene product or give rise to a dysfunctional or inactive protein or receptor
Many autosomal dominant disease arising from deleterious mutations fall into one of few familar patterns. Give examples of some of such patterns.
- those involved in regulation of complex metabolic pathways that are subject to feedback inhibition. example: LDL receptor in familial hypercholesterolemia
- Key structural proteins, esp when gene encodes one subunit of a multimeric protein the product of the mutant allele can interfere with the assembly of the functionally normal multimer.
- Gain of function - as seen in Huntington disease
Explain what is meant by dominant negative
dysfunction of one component of a multimer protein leading to the impairment of the normal allele. Example: osteogenesis imperfecta where collagen is deficient
Cystic fibrosis, thalassemias, EDS are all examples of what kind of disorders. (autosomal dominant, recessive, X-linked)
Autosomal dominant
what are some characteristics of autosomal recessive disorders?
- trait does not usually affect parents of the affected individual but siblings may show disease
2 siblings have one chance in four - mutant gene occurs with low frequency in population, it could be due to consanguineous marriage
what are some differences that distinguish autosomal recessive from dominant?
- expression of the defect tends to be more uniform than in autosomal dominant
- complete penetrance is common
- onset is early in life
- new mutations are rarely detected clinically. generations may pass before it shows up in kids
- affects enzymes
- include almost all inborns error of metabolism
what are some characteristics of X linked recessive disorders?
- almost all are recessive
- males are hemizygous for X linked mutant genes so these disorders are expressed in males.
- affected male does not transmit to son, but all daughters are carriers
- sons heterozygous women have one chance in two
- heterogygous female does not express full phenotype due to possible x inactivation
- heterozygous usually expresses disease partially as exemplified by G6PD
What is the inheritance pattern for X linked dominant?
-transmitted by an affected heterozygous female to half her sons and half her daughter and by an affected male parent to all his daughter but none of his sons. Example: vitamin D resistant rickets
Single-gene (Mendelian) disorders can be classified into four categories:
- enzyme defect and consequences
- defect in membrane receptors
- alteration in structure, function or quantity of nonenzyme protein
- Mutations resulting in unusual reaction to drugs
Red-green color vision defects and blue cone monochromoacy are inhertied in an 1 pattern. Genes responsible are 2
- X-linked recessive
2. OPN1LW and OPN1MW
Blue-yellow color vision defects are inherited in an 1 pattern which means one copy of the altered 2 genes in each cell is sufficient to cause the condition
- X-linked recessive
2. OPN1SW
An example of the biochemical consequence of an enzyme defects where an substrate accumulates is seen in galactosemia. The accumulated product is 1 and due to deficiency of 2.
- galactose
2. galactose-1-phosphate uridyltransferase
An enzyme defect which can lead to a metabolic block and decreased amount of end product is seen in albinism where deficiency of 1 results from lack of the enzyme 2 which is ncessary for the biosynthesis of melanin from its precursor.
- melanin
2. tyrosinase.
Explain the general mechanism leading to Lesch-Nyhan syndrome.
The end product of an enzymatic pathway is a feedback inhibitor of the enzymes involved in the early reaction. In Lesch-Nyhan the deficiency of the end product due to deficiency of the enzyme HGPRT permits overproduction of intermediates and their catabolic products, uric acid.
A1-antitrypson deficiency is characterized by failure to inactivate a tissue-damaging substrate where inherited deficiency of serum 1 are unable to inactivate 2 in their lungs and thus leads to destruction of elastin in the walls of lung alveoli, leading to pulmonary emphysema.
- a1-antitrypsin
2. neutrophil elastase
_ is a disorder of connective tissues, manifested principally by changes in skeleton, eyes, and cardiovascular system, transmitted mainly by autosomal dominant inheritance.
Marfan’s syndrome
What is the pathogenesis of Marfan’s syndrome?
Inherited defect in an extracellular glycoprotein called fibrillin 1 which leads to loss of structural support in microfibril rich connective tissues and excessive activation of TGF-beta signaling
Fibrillin is a major component of microfibrils found in ECM where the fibrils provide a scaffolding on which _ is deposited to form elastic fibers
tropoelastin
Fibrillin is widely distributed but is abundant in what organs, which is also the organs that are mainly affected in marfan’s syndrome?
Aorta, ligaments, cilliary zonules that support the lens of the eye.
What gene encodes Fibrillin, mutation of which is the cause of Marfans? What kind of mutation is it?
FBN1.
Missense mutation which inhibits polymerization of fibrillin fibers via dominant negative effect.
What are the clinical signs of Marfan’s syndrome?
- Skeletal abnormalities (tall, long extremities, long tapering fingers toes, lax joint ligaments, kyphosis, scoliosis,, chest deformiteis mainly pectus exavatum.
- Ocular changes (bilateral subluxation of lens = ectopia lentis) - THIS IS USUALLY INDICATIVE OF MARFANS
- cardiovascular lesions (Mitral valve prolapse, dilation of ascending aorta, excessive TGF-beta signaling in adventitia leading to aortic dilation , Flappy valve, valvular lesion)
Ehlers-Danlos syndromes comprise a clinically and genetically heterogenous group of disorders that result from some defect in the synthesis or structure of _
Fibrillar collagen
A patient presents after uterine rupture. On questioning and PE you notice that she has very thin skin, easily bruises, and you also notice that she has hyperextensibility of her thumb. You diagnose her with Vascular ( Type IV) EDS. what is the gene defect leading her condition?
COL3A1
Your patient presents with hypotonia, joint laxity, congenital scoliosis, and ocular fragility. You diagnose him with Kyphoscoliosis (type VI EDS), what this the likely gene defect?
Lysyl hydroxylase which is needed for cross linking of collagen fibers and so a deficiency of lysyl hydroxylase results in synthesis of collagen that lacks normal structural stability
What is the gene defect seen in classic ( Type I/II) and arthrocholasia (type VIIa,b) of EDS?
Type I/II = COL5A1, COL5A2
Type VIIa,b = COL1A1, COL1A2
What is the gene defect in dermatosparaxis (VIIc)
procollagen N-peptidase
What are the general clinical signs of EDS?
- Skin hyperextensible/stretchable, fragile and easily traumatized
- Ligaments and joints - joints are hypermobile and easily dislocated
- surgical repairs are difficult
- basic connective tissue defects leads to serious internal complication for example: rupture of colon and large arteries (vascular EDS); ocular fragility with rupture of cornea and retinal deteachment (kyphoscoliosis EDS); diaphragmatic hernia (classic EDS)
Vascular EDS results from abnormalities of what type of collagen? gene?
Defect in COL3A1 gene encoding collagen type III
In arthrochalasia type and dermatosparaxis type of EDS, the fundamental defect is int he conversion of 1 to 2, due to mutation in_3_, as a result abnormal pro-a1 or pro-a2 chains that resist cleave of N-terminal peptides are formed.
- procollagen
- collagen
- COL1A1 and COL1A2
Diaphragmatic hernia is a clinical sign seen in classic EDS, due to mutation in genes _ for what type of collagen?
Gene COL5A1, COL5A2 in collagen type V.
Explain the normal process of cholesterol metabolism and transport.
- VLDL (rich in TG and less cholesteryl esters) is made by liver and transported into blood.
- when VLDL reaches adipose or muscle, it’s cleaved by lipoprotein lipase and most of the TG is extracted and VLDL is made into IDL which is has more cholesteryl ester less TG
- IDL has retains two of three apoproteins: B-100 and E. IDL has one of two fates: 50% are taken up by liver to make more VLDL (receptor mediated which recongize the B100 and apoprotein E - LDL receptor); OR IDL under further progress and metabolism and most of the TG is removed and made into LDL. IDL is the immediate and major source of plasma LDL.
- There are two ways plasma LDL is removed, by LDL receptor or by receptor for oxidized LDL
- 70% of plasma LDL is cleared by liver by binding of LDL to cell surface receptors via coated pits. the Coated pits with the LDL is internalzied and taken to lysosomes.
- In the lysosme, LDL is degraded, apoprotein hydrolzed to AA, cholesteryl esteres are broken down to free cholesterol.
- The free cholesterol then goes to cytoplasm where it is used for membrane synthesis and as a regulator of cholesterol homeostasis.
What two proteins are needed for the exit of cholesterol from the lysosomes?
NPC1 and NPC2
Once cholesterol is gets to the cytoplasm from lysosome, what effects does the cholesterol have?
- Suppress cholesterol synthesis by inhibiting HMG CoA reductase
- Activates enzyme acyl-coEnzyme A: cholesterol acyltransferase favoring esterificaiton and storage of excess cholesterol
- Suppress synthesis of LDL receptors thus protecting cells from excessive accumulation of cholesterol.
What is the general cause of familial hypercholesterolemia?
Mutation in the gene encoding the receptor for LDL which leads to defective LDL clearance and also impairs IDL transport into the liver.
In hypercholesterolemia, explain the reasoning behind the appearance of xanthomas and the premature atherosclerosis.
Impaired IDL transport into the liver secondarily divers greater proportion of plasma IDL into the precursor pool for plasma LDL which get transported via scavenger receptors into cells of mononuclear phagocyte system. This normally doesn’t happen but in hypercholesterolemia there is an increase in scavenger receptor-mediated traffic of LDL cholesterol into cells of mononuclear phagocyte system and possibly vascular walls.
Explain the classification of LDL receptor mutations
Its based on abnormal function of the mutant protein.
Class I mutations are uncommon and lead to complete failure of synthesis of the receptor protein
Class II = common, encode receptor proteins that accumulate in ER cuz their folding defects make it impossible for them to be transported to golgi
Class III = affect LDL-binding
Class IV = mutation fail to localize in coated pits and hence bound LDL is not internalized
Class V = pH-dependent dissociation of the receptor and the bound LDL fails to occur. such receptors are trapped in endosome, where they are degraded and hence they fail to recycle to the cell surface.
Explain the rationale for statin
suppress intracellular cholesterol synthesis by inhibiting the enzyme HMG CoA reductase. This in turn allows greater synthesis of LDL receptors
What are general clinical signs of hypercholesterolemia?
elevated serum cholesterol greatly increased which increases the risk of atherosclerosis and resultant coronary artery disease; homozygotes have an even greater increase in serum cholesterol and a higher frequency of ischemic heart disease. Cholesterol also deposits along tendon, sheaths to produce xanthomas which can be detected in periosteum and fascia
what are the two pathological consequences of deficiency of functional lysosomal enzymes?
- Incomplete catabolism leading to accumulation of partially degraded insoluble metabolite –> primary accumulation
- Secondary accumulation - due to accumulation of impaired autophagy. causes accumulation of dysfunctional mt with poor Ca buffering capacity and altered membrane potential. this can trigger generation of free radicals and apoptosis.
GM2 gangliosidoses are a group of three lysosomal storage diseases caused by _
an inability to catabolize GM2 gangliosides.
Tay-sachs is the most common form of GM2 gangliosidosis, which results from mutation in a-subunit locus on chromosome 15 that cause a severe deficiency of this enzyme
hexosaminidase A
In Tay-Sachs, the absence of hexosaminidase A in which tissues is the dominant clinical manifestation?
Neurons in CNS and retina
In histological slides of tissues of one with Tay-Sachs, presence of what findings is diagnostic along with the appropriate clinical manifestation?
Neurons are ballooned with cytoplasmic vacuoles which represents distended lysosomes withed with gangliosides. Stains for Fat are positive. Several types of cytoplasmic inclusions, the most prominent being whorled configuration within lysosomes composed of onion-skin layers membranes seen in cerebellum, neurons of basal ganglia, brain stem, spinal cord, dorsal root ganglia, neurons of ANS.
In patients with Tay-Sachs what clinical manifestations are seen in the eye?
cherry-red macula
List some clinical features and presentations of Tay-Sachs
Symptoms starts at about 6months of age and shows relentless motor and mental deterioration, motor incoordiatnion, mental obtundation leading to muscular flaccidity, blindness and increasing dementia
-deafness, blindness, inability to swallow
speech disorders difficulty swallowing, loss of coordination
- Cherry red macula
-vegetable state by 1-2 years and death within 2-3 years
_ are two related disorders that are characterized by lysosomal accumulation of sphingomyelin due to an inherited deficiency of sphingomyelinase.
Niemann-Pick Type A and B
How can NPA and NPB be dstinguished?
Type A: Classic infantile form. A missense mutation causes almost complete deficinecy of spingomyeinase which blocks degradation of spingomyelin and results in progressive accumulation within lysosomes mainly mononuclear phagocyte system. severe infantile form of extensive neurologic involvement marked visceral accumulation of sphingomyein and progressive wasting and early death within the first 3 years of life
Type B: organomegaly btu generally no CNS involvement. they usually survive into adulthood
How is Nieman-Pick disease inherited?
Most are autosomal recessive, but if mutant allele inherited from mother can develop disease.
What are some morphological findings on tissues of pt with nieman-pick disease?
- sphingomyelin lipids in lysosomes particularly inside mononuclear system cells.
-many small vacuoles, imparting foaminess to the cytoplasm - vacuoles stain for fat
-membranous cytoplasmic bodies resembling concentric lamellated myelin figures called zebra bodies
-lipid-laden phagocytic foam cells in spleen, liver, lymph nodes, bone marrow, tonsils, GI, lungs.
-spleen is usually HUGE
-Brain: gyri are shrunken and sulci are widened
vacuolation and ballooning of neurons
retinal cherry-red spots (similar to Tay Sach)
What are some gross clinical manifestation of Nieman-Pick Type A?
- presents at birth almost invariably become evident by age 6 months
- protuberant abd cuz of hepatosplenomegaly
- progressive failure to thrive, vomiting, fever, generalized lymphadenopathy
- progressive psychomotor function.
- death within 1-2 yrs of life.
Mutations in NPC1 and NPC2 leads to what disease?
Niemann-Pick Disease Type C (NPC). With NPC1 being 95% of cases. Non-enzymatic lipid transport defect.
what is the normal role of NPC1 and NPC2?
Transport of free cholesterol from lysosomes to the cytoplasm
What are some clinical presentation of NPC?
- hydrops fetalis and stillbirth
- neonatal hepatitis
- chronic form characterized by progressive neurologic damage
- marked ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression
_ refers to cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase.
Gaucher Disease, most common lysosomal storage disease
What is the normal function of glucocerebrosidase?
Cleaves glucose residue from ceramide. Defect in the enzyme leads to accumulation of glucocerebroside mainly in phagocytes but in some types in CNS.
What are the clinical subtypes of Gaucher disease?
- Chronic nonneuropathic form (Type I) 99% of cases
- Acute neuronopathic Gaucher disease - Type II - infantile acute cerebral pattern
- Type III, intermediate of type I and II.
In which subtype of Gaucher are you likely to see the following findings: storage of glucocerebrosides limited to mononuclear phagocytes throughout the body without the involvement of brain, bur rather splenic and skeletal involvement dominate. It’s common in Jews of European stock. Can have bone involvement leading to bone erosion.
Type I, nonneuronopathic form
In which type of Gaucher is there no detectable glucocerebrosidase activity in tissues, and has progressive CNS involvement leading to early death?
Type II, acute neuronopathic Gaucher
In what kind of cells do glucocerebrosidases accumulate as seen in Gaucher disease?
Phagocytes. Distended phagocytic cells are seen in liver, spleen, bone marrow, lymph nodes, tonsils, thymus and peyers patches. Gaucher cells look like crumpled tissue paper.
Gaucher patients with cerebral involvement show accumulated cells in _ spaces and arterioles are surrounded by swollen adventitial cells.
Virshow-Robbin spaces
How to clinical signs present in type I Gaucher?
- first appear in adult life and are related to splenomegaly or bone involvement.
- pancytopenia or thrombocytopenia secondary to hypersplenism
- pathologic fractures and bone pain
- progressive into adulthood but is compatible with long life.
How do clinical signs present in type II and III Gaucher?
- CNS dysfunction, confusions and progressive mental deterioration dominate
Mucopolysaccharidoses (MPS) are group of closely related syndromes that result from genetically determined deficiencies of enzymes involved in the degradation of _.
mucopolysaccharadies (glycosaminoglycans) which are long-chain complex carbohydrates that are linked with proteins to form proteoglycans.
What are some types of glycosaminoglycans that accumulate in MPS?
dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin sulfate.
All MPS except for one are inherited as _
autosomal recessive trait
_, a form of MPS is X-linked recessive
Hunter syndrome
What are the general clinical characteristics of MPS?
- Coarse facial features
- Clouding of cornea
- Joint stiffness
- Mental retardation
In MPS, mucopolysacchardies are often found in what type of cells and what tissues?
In mononuclear phagocytic cells, endothelial cells intimal smooth muscle cells and fibroblasts throughout the body, but common sites are spleen, liver, bone marrow, lymph nodes, blood vessels, and heart.
Common to all MPS, what are some consequences of deposition?
- hepatosplenomegaly
- skeletal deformities
- valvular lesion
- subendothelial arterial deposits
- particularly in the coronary arteries and lesion in the brain
What is Hurler syndrome what does it result from?
MPS1-H, due deficiency of a-1-iduronidase. Most severe form and develops hepatosplenomegaly by age 6 to 24 months, growth is retarded . Death by 6 to 10 years of age and is due to CV complications
How is Hunter’s syndrome differentiated from other MPS?
Hunter is X linked recessive. and absence of corneal clouding, and milder clinical course
von Gierke disease or type I glycogenosis) is a prime example of the _ form of glycogen storage disease.
hepatic-hypoglycemic. This form dominated by hepatic enlargement and hypoglycemia.
What causes McArdle disease and what are some clinical presentation?
It is Type V glycogenosis) with deficiencies of muscle phosphorylase. it is the myopathic form of glycogen storage disease.
How does myopathic form of glycogenosis present?
Individuals presents with muscle cramps after exercise and lactate levels in the blood fail to rise after exercise due to a block in glycolysis. Myopathic form includes McArdle disease (Type V with phosphorylase defect; and Type VII with phosphofructokinase defect)
What is Pompe disease?
Type II glycogenosis. It’s associated with deficiency of a-glucosidase (acid maltase) and lack of branching enzyme. Cardiomegaly is the most prominent feature.
What are some clinical features of Hepatic type of glycogenosis? von Gierke disease Type I)
- failure to thrive, stunded growth, hepatomegaly, renomegaly, hypoglycemia and can lead to convulsion,
- hyperlipidemia and hyperuricemia resulting from deranged glucose metabolism; many pts develop gout and skin xanthomas
- bleeding tendency
What are some clinical features of the myopathic type of glycogenosis? (McArdle disease Type V)
Painful cramps with exercise; myogobinuria, failuret o rise lactate levels; serum creatinine kinase always elevated; compatible with normal longevity
What are some clinical features of Pompe disease (Type II)
massive cardiomegaly, muscle hypotonia, cardiorespiratory failure within 2 yrs; mild adult form with only skeletal muscle involvement, presenting with chronic myopathy; enzyme replacement therapy available
what is aneuploidy and what causes it?
Not an exact multiple of 23 due to error during meiosis or mitosis. The usual caused by nondisjunciton and anaphase lag.
What does nondisjunciton and anaphase lag lead to?
Nondisjunction - either loss of one or gain of one chromosome (trisomy or monosomy)
Anaphase Lag - one homologous chromosome one chromatid in mitosis lags behind and is left out of the cell nucleus. the result is one normal cell and one cell with monosomy
What is mosaicism?
Mitotic errors in early development that gives rise to two or more population of cells with different chromosomal complement in same individual. It results from mitotic errors during the cleavage of fertilized ovum or in some cells. Example: Turner’s syndrome. 45,X/47, XXX, Down syndrome
In an inversion how many breaks in a chromosome were there? and is it compatible with normal development?
two breaks within a single chromosome with reincorporation of the inverted, intervening segment.
Yes compatible with normal development since genetic material is not lost.
_ formation results when one arm of a chromosome is lost and the remaining arms is duplicated, resulting in a chromosome consisting of two short arms only or two long arms.
isochromosome
What is robertsonian translocation and what is its significance?
aka centric fusion. a translocation between two acrocentric chromosomes. typically the breaks occur close to the centromeres and transfer of the segmet then leads one very large chromosome and one extremely small. the small one gets lost in the next cell division. It’s compatible with life. It’s significance lies in when those individual tries to have kids. Produces abnormal progeny. ex. Down Syndrome.
which form of Down syndrome is there no maternal age influence?
Mosaici form. which occurs in about 1% of cases.
What are some diagnostic /clinical features of down syndrome?
- Flat face, oblique palpebral fissure, epicanthic fold
- Mental retardation
- 40% have congential heart defect including endocardial cushion, ostium primum, atrial septal defect, atrioventricular valve malformation, ventircular septal defect.
- Atresia of eoshagus and small bowel
What are some increased risk factors associated with Down syndrome?
- 10-20 fold increased risk of developing ALL and AML
- all patients over 40 develop neuropathologic changes like AD
- pts have abnormal immune response and thus increased risk of infection
Explain the gene dosage hypothesis associated with down syndrome.
the idea that 37% of genes on chromosome 21 are overexpressed by 150%
What is 22q11.2 deletion syndrome and what are some clinical signs?
Clinical features: congential heart defect, abnormalities of the palate, facial dysmorphism, developmental delay (Velocardiofacial syndrome)
- Digeorge syndrome (defect of TBX1 gene that targets PAX9 which are involved in development of palate, parathyroid and thymus.
- Higher risk for psychotic illness like schizo, bipolar, ADD
- attributed to deletion of TBX1 gene
What are some clinical signs of Trisomy 13: Patau syndrome
- Micropthalmia, microcephaly and mental retardation
- polydactalyly
- Cleft lip and palate
- cardiac defect
- umbilical hernia
- renal defect
- rocker bottom feet
What are some clinical signs of Trisomy 18 (edwards syndrome)
- prominent occiput
- mental retardation
- micrognathia
- low set ears
- overlapping fingers
- heart defects
- renal malformation
- limited hip abduction
- rocker bottom feet
what is the karyotype of Klinefelter syndrome?
47, XXY
what are some signs of Klinefelter?
- male hypogonadism
- increase in length between soles and pubic bone, appears alongated, long legs, small atrophic testes, small penis, and lack of secondary sex characteristics
- gynocomastic with higher chance of breast cancer
- increased incidence of DM and metabolic syndrome leading to insulin resistance
- mitral valve prolapse
- increased rate of osteoporosi
- Leydig cells prominent, elevated FSH, reduced testosterone,
Explain how androgen receptor in klinefelter is inactivated
androgen receptor is on X chromosome, and contains highly polymorphic CAG repeats. The functional response of receptor to any particular dose of androgen is dictated by number of CAG repeats, as receptors with shorter CAG repeats are more sensitive to androgens than those with long CAG repeats. In Klinefelter, the X chromosome bearing the androgen receptor allele with the shortest CAG repeat is preferentially inactivated.
what are clinical features of Turner syndrome?
- female hypogonadism
- 57% missing an entire X chromosome, 45X; 43% of the remaining either have structural abnormalities or are mosaics
- 5% have a partial Y or full Y they are at higher risk of gonadoblastoma
- webbed neck
- short stature
- at puberty failure to develop normal secondary sex
- congenital heart defect, left sided CV abnormalities esp preductal coarctation of the aorta and bicuspid aortic valve
- primary amenorrhea
- 50% develop antibodies against thyroid leading to hypothyroidism
- streak ovaries
what is the cause of the webbed neck as seen in Turner syndrome?
During infancy, severe edema of dorsum of hands and foot due to lymph stasis and swelling of nape of neck due to distended lymph channels producing cystic hygroma (neck webbing)
What causes short stature, as seen in Turner’s syndrome?
SHOX gene haploinsufficiency
what is the most common karyotypes of Turner’s syndrome?
45, X
Diseases caused by trinucleotide repeat mutation affecting coding regions usually involve what sequence and what does it code for?
CAG, codes for polyglutamine which can lead to polyglutamine disease characterized by progressive neudegeneration.
What effect does polyglutamine expansion have on normal tissue?
leads to toxic gain of function, whereby the abnormal protein may interfere with function of normal protein (dominant negative activity) and acquire a novel pathophysiology toxic activity. it is believed that aggregation leads to suppression of other genes, causing mt dysfunction, trigger unfolded protein stress response and apoptosis.
Fragile X syndrome is caused by a trinucleotide mutation in the _ gene, expansion of which abnormal methylation of the 5’ region leading to loss of function of the FMR protein
familial mental retardation 1 (FMR1)
What are some phenotypical characteristic of Fragile X patient?
- long face with a large mandible, large everted ears, and large testicles (macro-orchidism) which is the present in 90% of cases
- hyperextensible joints, high arched palate, mitral valve prolapse
-flat feet, soft skin
hypotonia
Fragile X like all X linked disease affects males, but there are some atypical patterns associated with Fragile X transmission. Name 4.
- Carrier males - about 20% with fragile x mutation are clinically and cytogenetically normal. These “normal transmitting males” transmits the trait through ALL their phenotypically normal daughters to affected grandkids
- Affected females: 30% to 50% - abnormally higher than usual
- Risk of phenotypic effects: depends on the position of individual in the pedigree. for example brothers of transmitting males are at 9% risk, whereas grandsons incur 40% risk
- Anticipation - fragile X syndrome worsen with successive generation
In fragile X syndrome, CGG trinucleotide repeat within what range is considered premutation?
55-200.
Explain how premutation leads to full mutation as seen in fragile x syndrome.
Full mutation are believed to arise by amplification of CGG. Carrier males transmit the repeats to their progeny with small changes in repeat numbers. when the premutation is passed on by a carrier female, however, there is a high probability of a dramatic amplification of CGG repeats leading to mental retardation in most male offspring and 50% of femal offspring. Thus, it seems like during oogeneiss but not spermatogenesis, premutation can be converted to mutation by triplet repeat amplification.
what is the normal function of FMRP?
- FMRP binds to mRNA associated with polysomes and regulate their intracellular transport to dendrites
- FRMP is a translation regulator. At synaptic junctions FMRP suppresses protein synthesis from bound mRNA in response to signaling through group 1 metabotropic glutamate receptors. thus a reduction in FMRP in the fragile x syndrome results in increased translation of the bound mRNA at synaptic junction. such imbalance in turn causes permanent changes in synaptic activity and ultimately mental retardation
what is the cause of Fragile X tremor/ataxia?
CGG premutation in the FMR1 via a mechanism involving toxic gain of function. Instead of FMR1 gene being methylated and silenced, it is continued to be transcribed and the CGG-containg FMR1 mRNA formed are toxic and accumulates in nucleus and form intranuclear inclusions.
How does Fragile X tremor/ataxia manifest in male and woman?
In female: about 20% carrying premutation (carrier female) have premature ovarian failure before age 40
In male: 50% of premutation carrying males (transmitting males) exhibit a progressive neurodegenerative syndrome starting in their 6th decade.. this is referred to as ataxia which is characterized by intension tremors and cerebellar ataxia and may progress to PD.
what is Leber hereditary optic neuropathy?
Mitochondrial disease, neurodegenerative disease that manifests as a progressive bilateral loss of central vision. Visual impairment is first noted at age 15-35 leading eventually to blindness. Cardiac conduction defects and minor neurologic manifestation have also been observed in some families.
what is genomic imprinting?
the functional differences between the paternal allele and maternal allele. in most cases, imprinting selectively inactivates either the mom or pops allele. one silences the otheres
Explain how genetic imprinting works?
Differential patterns of DNA methylation at CG nucleotides.
- H4 deacetylation and methylation
- marking the maternal or paternal gene for silencing occurs at gametogenesis.
- imprinting genes work in groups that are regulated by common cis-acting elements called imprinting control regions.
What are some characteristics of Prader-Willi syndrome?
- mental retardation
- short stature
- hypotonia
- profound hyperphagia
- obesity
- small hands and feet
- hypogonadism
- 65-70% cases an interstitial deletion of band q12 in long arm of chromosome 15.
- all cases of deletion affects the paternally derived chromosome 15.
what are characteristics of Angelman syndrome?
- all the signs of Prader-willi but in addition:
- ataxic gait, seizure and inapprorpiate laughter. these pts are termed happy puppet
- deletion same chromosomal region of 15 is derived from mom (instead of pop as in prader willi)
Explain the molecular mechanism involved in prader willi and angelman syndromes.
- deletion: Genes on maternal 15q12 is imprinted and only the paternal is used. but when the paternal is deleted, Prader willi results. Conversely distinct gene on the same region is paternally imprinted and maternal ones are used but when the maternal ones are deleted Angelman results. 70% of cases
- Uniparental disomy, when both copies of chromosome comes from the same parent. 20-25% of cases
- deective imprinting, 1-4% of casses. one parent carries the the the imprints of the other parent
In Angelman syndrome, what gene is imprinted?
UBE3A
In Prader Willi syndrome, what genes are believed to be involved?
SNORP family of genes that encode small nuclear RNA which are involved in modification of ribosomal RNA. loss of function is believed to contribute to Prader WIlli syndrome.
What is the inheritance pattern of Marfans syndrome
autosomal dominant
A pt presents with sudden loss of vision On PE there is a subluxation of the right crystalline lens. On auscultation of the chest, a mid systolic click is heard. An ECHO shows a floppy mitral valve and dilated aortic arch. The patent’s brother and cousin are similarly affected. He is prescribed a beta blocker. What is the genetic defect and what is the mode of inheritance?
Pt has marfan’s. It’s autosomal dominant. The defect is in fibrillin-1.
Deficiency of what enzyme lead to defects in types I and III collagen and is inherited an autosomal recessive disorder as seen in a subclass of EDS?
Lysyl hydroxylase.
Familial hypercholesterolemia is inherited via what mode of inheritance?
autosomal dominant
A 3yr old girl presents with progressive severe neurological deterioration. On PE you find marked hepatosplenomegaly. You suspect patient has NPA, a lysosomal storage disease, On bone marrow biopsy presence of what would be confirmatory of this disorder?
- Lysosomal accumulation of sphingomylin (due to deficiency of sphingomylinase),
- numerous foamy vacuolated macrophages
Hunter’s disease results from deficiency of what enzyme?
a-I-Iduronidase leading to accumulation of mucopolysaccharides within macrophages (balloon cells).
what are some clinical presentation of Hunter’s disease?
Coarse facial features, corneal clouding, joint stiffness, hepatosplenomegaly, and mental retardation.
-Deposits can be seen in subendothelial coronary arterial
what is the inheritance pattern for Osteogenesis imperfecta?
Autosomal dominant. This can be recognized if multiple sibling are affected but parents are unaffected.
In antiphospholipid syndrome, autoantibodies are directed towards what?
Anticardiolipin and anti-beta2-glycoprotein
Match the following autoantibodies with the corresponding disease A. Anti-Sm B. Anticentromere C. Antihistone D. Anti-Jo-1 E. Anti-U1-ribonucleoprotein F. Anti-SSA G. Anti-DNA-topoisomerise 1 1. Drug induced SLE 2. Generalized SLE 3. polymyositis/dermatomyositis 4. Mixed connective tissue disease 5. Limited scleroderma (CREST syndrome) 6. Sjogren syndrome 7. Diffuse scleroderma
A-2 B - 5 C - 1 D - 3 E - 4 F - 6 G - 7
_ is characterized by a rash similar to SLE, but with immune complex deposition only in sun-exposed areas of the skin, a positive ANA test result in a few cases, absence of anti-Smith or anti–double-stranded DNA antibodies, and absence of serious renal disease.
Discoid lupus erythematosus
