Chapter 5 - Genetic Disorders

Question 1

Trisomy 21:

1) what do 40% of patients end up having? why?
2) what do they have a 10-20x increased risk of compared to normal?
3) all patients end up having what? how can you see this histologically?
4) what about their immune systems?
5) what is their usual cause of death?

Answer 1

congenital heart disease –> atrial septal defects of the endocardial cushion (usually osmium primum)

developing acute leukemia

characteristic changes of Alzheimer disease when above 40 yers old

abnormal so they get serious infections usually in the lungs and thyroid. plaques and tangles

cardiac problems

Question 2

Ehlers Danlos Syndrome:

what internal complications can these people have that result in death?

what type leads to blindness?

what. type leads to diaphragmatic hernias?

Answer 2

rupture of the colon and large arteries (vascular EDS)

ocular fragility rupture of cornea and retinal detachment (kyophoscoliosis EDS)

Classic EDS

Question 3

Phenylketonuria

1) what is the incidence of it? what race? be specific
2) what is the inheritance?
3) what’s the problem?
4) because of this problem, what accumulates?

Answer 3

1/10000 live born caucasians of Scandinavian descent

Autosomal recessive

Phenylalanine hydroxyls (PAH) deficiency –> changes phenylalanine to tyrosine

hyperphenylalaninemia

Question 4

What is codominance?

Pleiotropism?

genetic heterogeneity?

Answer 4

both alleles contribute to the phenotype

single mutant gene has many different end effects with it

mutations at several loci produce the same trait

Question 5

Tay Sachs Disease:

1) what is the problem
2) what chromosome is it located on?
3) what is the deficiency?
4) what is the carrier rate and race associated?

Answer 5

you can’t catabolize Gm2 gangliosides

15

hexosaminidase A

1/30, Eastern European –> Ashkenazic Jew

Question 6

Velocardiofacial syndrome:

1) what’s causing it?
2) what is seen on the patient?

Answer 6

Chromosome 22q11 deletion

super long face, super prominent nose (pear shaped), overfolded helix on their nose

Question 7

Other than the “miscellaneous diseases”, What are the different organs that have glycogen storage disease? what’s the mechanism? explain these briefly

what are examples of each?

Answer 7

——- Hepatic forms –> liver is the key to glycogen metabolism, so if you have a deficiency, you’ll have INCREASED STORAGE of glycogen and DECREASED blood glucose concentrations.

Von Gierke

——- Myopathic forms: skeletal muscle –> glycogen storage is INCREASED in the muscle leading to muscle weakness and cramping after exercise.. even after you’re done exercising there’s no increase in blood lactate due to block

McArdle disease

Question 8

Marfan syndrome:

1) what inheritance pattern
2) what things are affected?
3) what chromosome?
4) what does this code for?

Answer 8

1) Autosomal Dominant
2) FBN1 / FBN2 (less common)
3) 15Q21.1 / 5q23.31 (less common)
4) Fibrillin 1

Question 9

What is incomplete penetrance?

What is variable expressivity? What’s the big example?

Answer 9

you have the mutation, but a normal phenotype

we can have the positive trait, but it’s expressed differently. –>

big example is neurofibromatosis type 1.. some have cafe-au-lait spots, skeletal deformities and or neurofibroma.

Question 10

What is the inheritance of most classic Ehlers Danlos syndrome?

what’s the one exception? what is the defect in this case?

Answer 10

Autosomal Dominant

Kyphoscoliosis which is autosomal recessive. –> Lysyl hydroxylase

Question 11

What is a prime example of anticipation?

what is anticipation again?

Answer 11

Huntington’s disease –> passed through the male. so we have an unstable spermatogenesis and adds increase in base pairs.

genetic disorder passed on to the next generation, the symptoms come at an even earlier case.. severity of symptoms is also increased too.

Question 12

How do we know if a baby has CF at birth?

Answer 12

meconium ileus –> first bowel movement you have at birth.

when they have meconium ileus –> children with CF do not have that first bowel movement within the first few days of birth. so it’s DELAYED

when they do have it, it smells awful.

Question 13

For glycogen storage diseases (glycogenesis), what is the general problem?

what’s the result?

Answer 13

deficiency of one of the enzymes involved in synthesis or sequential degradation of glycogen

storage of normal or abnormal forms of glycogen, PREDOMINANTLY in the liver or muscle.

Hepatic forms

Question 14

Explain aortic dissection

1) what is it simply?
2) what is it physically separating?
3) what can it “occlude”?
4) what is the name of the space it creates?

Answer 14

the actual layers of the aorta separate

you have tears through the lining of the endothelium and the blood separates the endothelium from the adventitia from the outer layers of the aorta and dissect that lining away from the rest of the aorta

so as the blood separates it, it occludes the arteries going to the intercostals, or occlude the main trunks to the UE and the brain, or it can occlude off the kidneys if it goes lower.

“false lumen”

Question 15

Fragile X:

1) what’s unique regarding this that doesn’t associate with other diseases?
2) what happens if they transmit to a female, what’s the problem with this?
3) what makes affected females different in this disease vs others?
4) what big process is happening with fragile X?

Answer 15

there are normal Carrier males! –> 20% of males are known to carry fragile X mutation and are COMPLETELY NORMAL –> they only transfer it to their phenotypically normal daughters to affected GRANDCHILDREN.

the female has a high probability of DRAMATIC amplification of CGG repeats that occur during OOGENESIS but not spermatogenesis

most it’s a small chance to be affected, but this is 30-50% chance.

Anticipation –> gets worse with each successive generation FROM THE FEMALE

Question 16

What are examples of alterations in structure, function, or quantity of non-enzyme proteins?

2 clinical stuff

what overarching structural proteins do we see affected?

Answer 16

Sickle Cell disease –> defect in structure of global molecule

Thalassemias –> globin again

Collagen disorders, spectrin problems, dystrophin,

Question 17

Ring Chromosome? How is it going to be denoted?

Inversion? what are the two types?

Answer 17

there’s a break that occurs at both ends of the chromosome with the fusion of the damaged ends

“r(chromosome” –> 46,XY,r(14)

you get two breaks within a single chromosome and it just flips

if inversion of one arm –> paracentric, if breaks are on opposite sides of the centromere –> pericentric

Question 18

What are the three trisomies to know?

Answer 18

Trisomy 21 = Down Syndrome

Trisomy 18 = edwards

Trisomy 13 = Patau syndrome

Question 19

Marfan syndrome

1) what do people with this issue present with vascularly?
2) which one is the cause of death

Answer 19

1) mitral valve prolapse
2) dilation of the ascending aorta
3) AORTIC DISSECTION

aortic dissection!!!

Question 20

What happens if babies have CF?

Answer 20

they have failure to thrive (protein-calorie malnutrition) because of the pancreatic problems and bowel issues.

Question 21

mendelian disorders… what are examples of problems because we have a decreased amount of end product?

what about something where you have an accumulation of an intermediate product?

Answer 21

1) albinism –> we don’t have tyrosinase so we have lower melanin (end product).
2) Lesch-Nyhan –> increased intermediated product and their breakdown is what leads to toxicity.

Question 22

What are two examples of defects in receptors and transport systems? what are two examples and what happens in each?

Answer 22

Familial Hypercholesterolemia –> lower synthesis or lower function of LDL receptor –> leads to defective transport of LDL into cells –> increased cholesterol synthesis because of this –> atherosclerosis

Cystic fibrosis –> chloride ion transport in exocrine sweat glands, sweat ducts, lungs defective and pancreas defective

Question 23

What are the 3 types of Gaucher Disease?

Type 1: what is it? how common is it? what group has it? is it fatal?

Type 2: what is it? what hallmarks? what group has it? is it fatal?

Type 3: what is it? what do they have? when does it present?

what’s the worst, what’s the best?

Answer 23

Type 1: CHRONIC –> 90% of the cases. NO CNS involvement. European Jew. slight decrease in life span

Type 2: ACUTE NEURONOPATHIC –> infantile cerebral pattern –> hepatosplenomegaly and EARLY death. NOT JEWISH

Type 3: intermediate. systemic involvement mostly, but some CNS involvement. presents in adolescence or early childhood.

1 = best
2 = worst

Question 24

When does cystic fibrosis present?

is it treatable?

what race does it affect? what is it considered in this frame?

what genetics?

Answer 24

before birth to early childhood or even in adolescence

pretty much lethal

Caucasian population –> most common lethal genetic disease involving caucasian populations.

autosomal recessive

Question 25

We have an autosomal dominant disorder that has killed someone within a few years of life, what was the cause? who gave it to them?

Answer 25

since the disease had a low reproductive fitness, it would have had to come from a new mutation new mutations occur in germ cells of relatively OLDER fathers.

Question 26

When to suspect a genetic syndrome.. what's the mnemonic?

Answer 26

VACTERL (Vater) ``` Vertebral Anal anomalies Cardiac Trachea-Esophageal fistula Renal anomalies Limb anomalies ```

Question 27

Someone with super thin skin and bruising comes in to give birth. upon giving birth, they end up dying due to a uterine rupture. what is your diagnosis? what is the gene defect in this case? what is the inheritance?

Answer 27

Vascular EDS COL3A1 autosomal dominant

Question 28

What's to know about mitochondrial inheritance? what effect happens because of the mitochondrial inheritance

Answer 28

all the children from the female are going to be + because that's where the mitochondria comes from.. it does NOT come from the male. --> affected males do not pass on their mitochondria, so a positive male and nothing else afterwords. threshold effect --> need a minimum # of mtDNA present in a cell or tissue before oxidative dysfunction gives rise to the disease

Question 29

X-linked disorders: 1) what is the inheritance, where is it located? 2) What's going to happen if a man has it? 3) what about a mother that's the carrier?

Answer 29

1) almost all are recessive 2) all of his daughters will be carriers.. but his sons won't have it (duh, x linked)... 3) if the mother is heterozygote, the son WILL be affected if it gets the X, the daughters will be carriers.

Question 30

What do you see on the physical eyeball of people with familial hypercholesterolemia? what about this same problem in old people?

Answer 30

there's a little arc of white --> this is "arcus Cornelius" --> it's a deposit of this material in the cornea. arcus senilis --> a circular ring around the iris of the xanthoma stuff

Question 31

Tay Sachs: 1) cytoplasmic inclusions stain positive for what? 2) What do we see on an H and E of a neuron? 3) what do we see on EM? ***

Answer 31

the fat stains Oil Red O and Sudan Black B a large lipid vacuole filling up the space of the neuron whorled lysosomes --> look like onions

Question 32

What's mostly happening in lysosomal storage disease? what two things are happening during this?

Answer 32

they're missing the catabolism of the substrate because of the missing enzyme so you have an accumulation of stuff that isn't digested in the lysosome --> PRIMARY ACCUMULATION, so the lysosomes are super large. autophagy is interrupted as well in lysosomal storage diseases, so we also get a "SECONDARY ACCUMULATION" of the autophagic substrates

Question 33

Someone comes in, super tall, long dangly fingers.. they describe a "tearing" feeling. what happened? will they survive? in what scenario?

Answer 33

aortic dissection in marfans usually toast however if it ruptures back into the lumen, blood will come back in and go back to normal processes

Question 34

Turner syndrome: 1) what is the typical genotype? 2) what are the 3 types of karyotypic abnormalities? 3) what is the key feature to Turner syndrome? what happens because of this? 4) as someone with this grows older, what happens to #3?

Answer 34

45X or 45Xo complete or partial monosomy of X chromosome. --> it's gotta be a female - 57% missing entire X, so 45X - partial monosomy of X - mosaic types Cystic hygroma!!! --> infant with edema --> swelling of the nape of the neck due to LYMPH STASIS, can't drain it! the swelling subsides but the skin stays put, so you have bilateral neck webbing

Question 35

Say we have a mendelian disorder, we know that it leads to an abnormal product or decreased normal product.. what increases? what's an example of this? what's the problem?

Answer 35

accumulation of the substrate (or precursor) Galactosemia --> galactose 1 phosphate uridyltransferase deficiency leads to tons of galactose.

Question 36

What are the two most common Mucopolysaccharidoses? 1) which one HAS corneal clouding? when does it present? what is the first sign of presentation? is it fatal? 2) which one does not have corneal clouding? What inheritance? is it fatal? mnemonic?

Answer 36

Hurler (MPS I-H) --> corneal clouding.. Normal at birth, hepatosplenomegaly by 6-24 months, dead at 6-10 years old Hunter --> no corneal clouding, X linked, Milder clinical course Hunter needs to see so no corneal clouding, and the bow and arrow cross making an "X" for x-linked

Question 37

What is the incidence of heterozygote Familial Hypercholesterolemia? what do you see on these people? because of the hypercholesterolemia, what do you see? what does this give you a risk of?

Answer 37

1 in 500 --> they have 2-3 fold increase in cholesterol Tendinous xanthoma (lipid deposits, so you'll see yellowish stuff premature atherosclerosis increased risk of MI

Question 38

Difference between von gierke and drug primaquine?

Answer 38

von Gierke is G6Phosphatase Primiquine is G6PD

Question 39

a 19 year old man comes in complaining of not having a child and thinks it's him. on further inspection, he complains that he has been having some epigastric pain, a chronic cough with sputum, and fatty stools. He complains somewhat of respiratory problems but he says it hasn't bothered him before. what can explain his problem?

Answer 39

Cystic Fibrosis male urogenital abnormalities resulting in obstructive azoospermia (no vas deferens)

Question 40

Klinefelter syndrome: 1) what are they at an increased risk for? (4 things) hints: 50% of people with these have one, and they are 20x higher risk for something. what don't they have that would be characteristic of someone without Klinefelter?

Answer 40

Type 2 DM / metabolic syndrome*** Mitral Valve Prolapse Osteoporosis (because of hormone issues, so fracturing is easy) 20x risk of breast cancer no beard, no deep voice, no male pubic hair

Question 41

What are the differences between niemann-pick disease, type a, b, and C? 1) Start with C. where's the defect at? what do they present with? 2) Type B, what is to know about this? 3) Type A, what's to know about this? 4) which is the best prognosis? worst prognosis?

Answer 41

Type C --> most common. defect in NPC1.. which usually transports free cholesterol from lysosomes to cytoplasm but can't do that --> get progressive neurological damage, ataxia, stuff like that Type B --> NO CNS involvement; they reach adulthood. Type A --> SEVERE infantile form. extensive neuro involvement. it has a COMPLETE lack of sphingomyelinase.. present by 6 months, dead before 3. A is worst, B is best

Question 42

Explain Point mutations: 1) what is it? 2) what are the three types? 3) what is the best example with regards to two of these types? explain why

Answer 42

a change in a single nucleotide base can be silent --> single change but same amino acid missense --> can be a little change in functionality "conservative", or nonconservative where it changes the function. nonsense --> changes to a stop codon Sickle Cell --> B chain is changed from glutamate to valine --> gives rise to sickle cell anemia B - thalassemia (severe form of anemia) glutamine in the B chain is changed to a stop codon.

Question 43

Digeorge syndrome: 1) what's causing it? 2) what are the 2 main problem? 3) what does this result in? (2 things) 4) what is the mnemonic?

Answer 43

Chromosome 22q11.2 deletion 2) thymic hypoplasia and parathyroid hypoplasia 3) T-cell immunodeficiency and hypocalcemia Catch 22 --> Cardiac abnormality, Abnormal faces, Thymic aplasia, cleft palate, hypocalcemia/hypoparathyroidism

Question 44

Ehlers Danlos Syndrome: 1) what's the problem? 2) what about range of motion? 3) what about their skin in general. why is this a problem?

Answer 44

defect in the structure fibrillar collagen for connective tissue hyperextensible skin, joints are hypermobile skin is EXTRAORDINARY stretchable. --> they are super vulnerable to trauma.. so when we get minor injuries they produce GAPING defects and surgical repair is extremely DIFFICULT because it doesn't have the normal tensile strength

Question 45

Robertsonian Translocation? what do we see? what is the rate of robertsonian translocations? what is the most classic robertonian translocation and how does it work?

Answer 45

2 acrocentric chromosomes translocate, typically breaks appear closer to the centromeres of each chromosome. we see 1 very large chromosome and 1 extremely small one. 1/1000 people --> even though its pretty normal Trisomy 21, q arm of chromosome 21 is translocated onto another chromosome.. so the fetus has 46 chromosomes but 3 copies of the long arm of chromosome 21.

Question 46

Von Gierke Disease: 1) what's the deficiency and where is it typically seen 2) what's the type of disease? 3) what do patients present with?

Answer 46

1) G6Phosphatase --> in the liver 2) Hepatic glycogenoses 3) hepatomegaly (more but I don't know if it will be tested)

Question 47

What are the two main patterns of disease with autosomal dominant? examples of each? what is the age of onset usually? why?

Answer 47

1) regulation of complex metabolic pathways --> LDL receptor in familial hypercholesterolemia... we have 50% less receptors, which means increased cholesterol which leads to early atherosclerosis 2) key structural proteins are screwed up --> collagen and cytoskeletal elements of the RBC membrane --> Osteogenesis imperfecta --> people have fractures in utero.. they break their bones super easily. it's a lack of collagen! delayed onset --> we need it to remain silent for it to be passed on.

Question 48

Euploid? Aneuploid? What 2 things can create this? Mosaicism? where is it common most in?

Answer 48

any exact multiple of haploid number (23) NOT an exact multiple of 23 1) nondisjunction (+/- 1 chromosome) 2) anaphase lag --> during meiosis or mitosis one chromatid lags behind and is left out of the nucleus.. so one normal, one monosomy cell --> mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement in the same individual --> sex chromosomes

Question 49

what are the four mutation types that can give inherited disease?

Answer 49

point mutations in coding sequences mutations in noncoding sequences deletions and insertions trinucleotide repeat mutations

Question 50

What does it mean for complex multigenic disorders to be multifactorial? what are the common malformations of these disorders? is it always going to be super severe?

Answer 50

they're going to have two or more genes and environmental influences. clef lip, cleft palate, neural tube defects no. there's a range of severity.

Question 51

Say we have anaphase lag, what would most certainly result in death?

Answer 51

if you have a monosomy of an autosome. we need autosomes to survive.

Question 52

Isochomosome? what can you only get then? Translocation?

Answer 52

One arm of the chromosome is lost, remaining arm is duplicated.. you can have a chromosome with 2 short arms ONLY or 2 long arms ONLY segment of one chromosome is transferred to another one.

Question 53

Trisomy 21: 1) what is the strongest influence on incidence of trisomy 21? 2) 4% of the cases have what cause for Down syndrome? 3) what do the final 1% have? what's to note about this version?

Answer 53

maternal age robertsonian translocation of the q arm of 21 to another acrocentric chromosome (22 or 14) mosaics! mixture of cells with either 46 or 47 chromosomes --> symptoms are variable and generally milder

Question 54

Genomic Imprinting is what? what are the two characteristic syndromes to know for this?

Answer 54

we get selective inactivation of maternal or paternal genes it's deletions of the SAME gene, it's just how the imprinting goes that changes things up Prader Willi and Angelman

Question 55

Prader-Willi syndrome: 1) what's happening? 2) what is it characterized with?

Answer 55

Paternal deletion of chromosome 15 Obesity, mental retardation, short stature, hypotonia (lack of tension in extremities), small hands and feet

Question 56

Marfan Syndrome 1) what physical characteristics do they have? (4) 2) what about flexibility? 3) what about their eyes***

Answer 56

Extremely long arms compared to their legs.. so very disproportionate unusually tall long fingers and toes pectus excavatum Hyperflexibility (double jointed) Ectopia lentis --> dislocation of the lens!!!

Question 57

What are the three broad categories of human genetic disorders? what penetrance does each have? which is the most common? what is the classic for each (if applicable)

Answer 57

Disorders related to mutations in a single gene with large effects --> highly penetrant --> sickle cell Chromosomal disorders --> highly penetrant but uncommon Complex multigenic disorders --> low penetrance complex multigenic is most common --> atherosclerosis, diabetes, autoimmune, height and weight

Question 58

Fragile X: 1) what is the gene affected? what is the sequence that is being repeated and how many repeats can be seen? 2) what's the rate in males and females? who's more affected? 3) what if males are affected 4) phenotypic features? 5) hallmark?

Answer 58

FMR1, CGG repeats, up to 4000 repeats 1 in 1550 for males, in females its 1 in 8000 males are mentally retarded (super small IQ) long face, large mandible, LARGE everted ears, LARGE TESTICLES, hyper extensible problems.. mitral valve prolapse hallmark is macro-orchidism (extremely large testicles)

Question 59

Marfan Syndrome 1) how many people get this? what about familial wise? 2) what are the mechanisms by which this issue leads to clinical manifestations

Answer 59

1) 1 in 5000, 70-85% familial 2) - loss of fibrillin means loss of structural support in the microfibril rich connective tissue - excessive activation of TGF-B signaling

Question 60

Leber hereditary Optic Neuropathy 1) what kind of disease is it 2) what's happening? 3) when does it present? 4) what does it lead to?

Answer 60

mitochondrial disease progressive bilateral loss of central vision --> so people will be doing their head around trying to see what's going on. ONLY THE CENTER IS OUT 15-35 years old complete blindness

Question 61

why do clinicians say "kiss your baby" with regards to CF? what test do we do? how does it work?

Answer 61

the baby will taste salty because of the increased ion transport sweat chloride test --> put a chemical on them and an electrical current, collect the sweat and see how much chloride they have.. obviously if it's higher than normal it's an indication

Question 62

Explain why one sickle cell anemia patient can have full blown sickle cell and another can only exhibit symptoms in lowered oxygen environments like on a mountain?

Answer 62

If you're heterozygous for sickle cell, only a portion of the cells is HbS, the rest being HbA, then you are only going to sickle under unusual circumstances like described if you're homozygous, all of the hemoglobin is abnormal, HbS type, and even with normal saturation of oxygen the disorder is FULLY expressed.

Question 63

Explain Trinucleotide repeat mutations what is in almost all sequences with these mutations? what happens with these mutations across generations? what is this called? what is considered it's "distinguishing feature"? what are two famous trinucleotide repeat mutations to know?

Answer 63

amplification of a sequence of three nucleotides almost all affected sequence share the nucleotides G and C! usually when you get these you have an earlier age when you have an increase in number of nucleotides or repeats --> anticipation (appears at an earlier age with each generation) they're dynamic --> degree of amplification increases during gametogenesis Fragile X syndrome + Huntingtons

Question 64

What is the gene defect in classic EDS?

Answer 64

COL5A1, COL5A2

Question 65

Explain what's happening in CF? 1) what is causing this? 2) what are the two major processes do we see in the lungs? --> what cell type is at a higher presence? 3) what happens in the pancreas? be specific 4) what about the small intestines? 5) what about genitals?

Answer 65

this is due to a chloride ion channel transport issue --> VISCOUS SECRETIONS--> plugs everything up in the body.... called "insipated" these blockages are called Bronchiectasis, where instead of wedging like there would be in infarction, it's instead staying large the whole way. emphysema ends up with one big round wall, we lose a bunch fo surface area so decreased oxygenation increased goblet cell development --> more mucus, even worse breathing. PANCREATIC INSUFFICIENCY --> cystic dilations of those ducts because the mucus is too thick. enzymes aren't going to come out, it leads to fibrosis, chronic pancreatitis, a lot of pain. TONS OF problems distended small intestines because of the mucus --> STEATORRHEA (smelly), INTESTINAL OBSTRUCTION male infertility

Question 66

Phenylketonuria 1) what is tyrosine a precursor of? so people with PKU present with what? 2) when do you see symptoms? why at this point? 3) what's the main characteristic of this besides the above? 4) what's the therapy?

Answer 66

1) melanin, so no melanin, they are super pale --> albinism 2) normal at birth, but severe mental retardation, hypopigmentation and severe eczema at 6 month.. it takes that long for toxic products to start building. 3) diaper smells like a "mouse" or "musty" 4) dietary restrictions (no Diet Coke) to keep them from progressing!

Question 67

Neural tube defects are reduced by intake of what in the diet?

Answer 67

Folic Acid

Question 68

Klinefelter syndrome: 1) what's the genotype 2) what do you see? 3) what's the rate? when does it present 4) clinical stuff

Answer 68

47,XXY (90%) Male Hypogonadism 1/660 live male births, but usually not diagnosed until puberty abnormally long legs, atrophic testes and small penis, enlargement of breast tissue In males

Question 69

in autosomal dominant disorder, what state is usually manifested? how many genes? so how many parents are affected?

Answer 69

heterozygous, one gene affected, so one parent is usually affected

Question 70

Huntington Disease: 1) what is the inheritance of Huntington's? what is degenerating? 2) what do you get eventually? 3) what do they present with? 4) what's the lifespan of the disease? when are you diagnosed? 5) anticipation in this case is through the male or female?

Answer 70

1) autosomal dominant, head of the caudate nucleus --> eventually to the globus palladus eventually we get brain atrophy dance like movements (chorea), and they have 3x more calorie intake because they're constantly moving. later in life, but 15 years male

Question 71

Trisomy 21: 1) what do you see on fish? 2) what are the gross morphologic features we see? 3) what is to note about Down syndrome? what is it the major cause of? 4) what is the incidence? how many cases have this trisomy?

Answer 71

3 red signals flat facial features, epicanthal folds, single palmar crease, wide gap between toes, fissured tongue most common chromosomal disorder + major cause of mental retardation 1/700, 95%

Question 72

What mutations can we see with regards to adverse reactions to drugs? 1) what deficiency? 2) what drug was used? 3) what people were affected? 4) what did they end up getting because they took this drug?

Answer 72

G6PD --> Antimalarial drug called primaquine.. came out in Korean War to prevent malaria.. people of mediterranean and middle eastern descent had this deficiency and didn't know it. as they took this drug they got SEVERE hemolytic anemia

Question 73

What is the problem with being homozygotic for familial hypercholesterolemia? what do you see on these people? what's super significant to know?

Answer 73

you have a 5-6x higher increase in cholesterol than normal instead of tendinous xanthomas, you see skin xanthomas.. deposits often on the eyelids. you also have cerebral, peripheral and vascular atherosclerosis at early age --> MI before 20 y/o

Question 74

Angelman Syndrome: 1) what's happening 2) what are the hallmarks of this? 3) what are people with this called?

Answer 74

maternal deletion of chromosome 15 mentally retarded, but present with ataxic gait, siezures, and INNAPROPRIATE LAUGHTER ***happy puppets***

Question 75

Chromosome 22q11.2 deletion syndrome 1) where's the deletion? 2) what is kind of the hallmark that discerns this from others? 3) what's the incidence? 4) what are the two pathologies associated with it?

Answer 75

small deletion of band q11.2 on the long arm of Chr 22 T cell immunodeficiency and hypocalcemia 1/4000 DiGeorge syndrome, Velocardiofacial syndrome

Question 76

2 basic approaches to treatments of lysosomal storage diseases?

Answer 76

enzyme replacement therapy substrate reduction therapy (don't eat the stuff that we can't eat, then the reduced enzyme activity will be enough to work on its own)

Question 77

Mendelian Disorders encompass what? what does it result in? 2 things what are the 4 main categories?

Answer 77

alterations in a single gene --> leads to an abnormal product or decreased normal product enzyme defects defects in membrane receptors/transport systems alterations in structure, function, or quantity of non-enzyme proteins mutations resulting from reactions to drugs

Question 78

Say you're a carrier for cystic fibrosis but you don't have cystic fibrosis because of its inheritance pattern. are you going to have any issues/

Answer 78

higher incidence of respiratory and pancreatic diseases than a normal individual

Question 79

What are the two glycogen storage diseases that don't necessarily correlate with the liver or skeletal muscle? why don't these correlate?

Answer 79

Acid maltase deficiency (Pompe disease) problems with lack of branching enzyme overlapping symptoms --> they often associate with glycogen storage in MANY organs and death in early life.

Question 80

what's the difference between mendelian problems and sex chromosome problems What is one major process that is happening with Sex chromosome disorders? how does it work? How can we see this inactivated X stain wise?

Answer 80

sex chromosome problems are much better tolerated than autosomal problems. --> not necessarily lethal. 1) lyonization (inactivation) of all but one X chromosome --> we end up with mosaics with two populations of cells going on. (can be maternal or paternal origin that gets inactivated) --> activated early in life. the inactivated x is turned into a Barr body Barr body --> inactive X is going to be a mass connected to nuclear membrane in interphase

Question 81

Tay Sachs Disease: 1) when does it present? 2) is it lethal? 3) what hallmark do we see? 4) what accumulates and where does it accumulate?

Answer 81

1) Normal at birth, at 6 month you have motor and metal deterioration. blindness 1-2 year old vegetative state, death by 2-3 years cherry-red spot in the macula Gm2 gangliosides --> neurons, retina

Question 82

Explain the cherry red spot 1) what disease process 2) why does it look the way it does?

Answer 82

all the ganglion cells around it are swollen and pale, but the macula stays red because no ganglion cells.

Question 83

CF: 1) what's the problem 2) what gene is the problem 3) what chromosome?

Answer 83

chloride channel CFTR gene 7q31.2

Question 84

In CF, what are the three major organisms that we see in this pathology?

Answer 84

two big organisms --> Staph aureus, and Pseudomonas aeruginosa, Haemophilus Influenzae

Question 85

what are the 3 features of autosomal recessive disorders?

Answer 85

25% 1) trait is usually NOT affecting the parent 2) siblings have a 25% risk at birth 3) if mutation is low frequency in a population, it means that it's part of consanguineous marriage (if it's something super rare but all the sudden we see it.. look at family history)

Question 86

Hermaphroditism and Pseudohermapthroditism?

Answer 86

true hermaphrodite --> presence of ovary and testicular tissue pseudo --> disagreement between phenotypic and gonadal sex female pseudo has ovaries, but male external Male has testicular tissue, but female type genitalia

Question 87

What do people with Mucopolysaccharidoses (MPS) usually have morphologically? what's the exception with one of them?

Answer 87

Coarse facial features, joint stiffness, mental retardation, clouding of the cornea hunter syndrome DOES NOT have clouding of the cornea

Question 88

Pompe Disease: 1) what is the deficiency? 2) what is the KEY characteristic in this pathology? how do you see this on a slide? 3) how do they die?

Answer 88

acid maltase deficiency cardiomegaly (die at early age). --> you'll see normal myocardium but in Pompe it's glycogen filled myocardial cells 3) cardiorespiratory failure within 2 years of onset.

Question 89

Mutations with noncoding sequences are found where usually? what happens because of this? what are three transcription factors associated with these mutations?

Answer 89

promotor or enhancer sequences (part of the intron) failure to form mRNA (so no translation) MYC, JUN, p53

Question 90

What is usually the Cause of Death for those with MPS? what is the cell to know? what is this similar to? what do we have on EM?

Answer 90

myocardial infarction and cardiac decomposition. Balloon cells --> clear cytoplasm with multiple vacuoles.. similar to niemann pick lamellate zebra bodies, similar to NP

Question 91

What is the usual pathogenicity resulting of an autosomal dominant disorders? What are the two possible mutations seen in autosomal dominant diseases? examples of each?

Answer 91

lower product, dysfunctional or inactive protein produced loss of function --> familial hypercholesterolemia Gain of function --> Huntington

Question 92

Gaucher Disease: 1) what is the inheritance? 2) what's the deficiency? 3) what results because of this deficiency? 4) because of this problem, what is released?

Answer 92

1) autosomal recessive 2) glucocerebrosidase 3) accumulation of glucocerebrosides in phagocytes primarily, but sometimes CNS too. 4) it activates the macrophages, which leads to IL1, IL6, and TNF

Question 93

Why is sickle cell anemia still in the population? it's kind of its key feature too

Answer 93

it strongly selects for people to not contract malaria (their blood type doesn't allow them to contract malaria)

Question 94

Niemann-Pick Disease, what are the cells going to look like? what is this sometimes called? what are these also called if seen on an EM image? anything to note about their organs? be specific this is important!! what is similar with this and Tay Sachs that you'll need to know how to distinguish? what happens in the brain?

Answer 94

really enlarged because of the sphingomyelin and cholesterol accumulation --> foamy cytoplasm "Zebra bodies" --> lysosomes with concentric lamellations massive splenomegaly! 10x the normal weight of a spleen 1/3 to 1/2 of NPD have cherry red retinal spot we have ballooning of neurons (like tay Sachs) but then brain atrophy

Question 95

Gaucher Disease: 1) what is the distinct morphology seen on a slide? 2) what about organs? what about this vs niemann pick? 3) what happens if these cells are in the bone marrow? (2 things)

Answer 95

you see "Gaucher cells" which are distended phagocytic cells the cytoplasm is elongated distended lysosomes and noted as "CRUMPLED TISSUE PAPER" 2) enlarged spleen, greater than 10kg.. not 10x greater, only above 10kg. 3) if it hits the bone marrow, it leads to bone erosion --> so we have pathological fractures because of weakening of the bones. also because of bone marrow involvement we have pancytopenia and thrombocytopenia (low red and white blood cells, also platelets)

Question 96

What is common between Edwards (trisomy 18) and Patau (trisomy 13) but NOT seen in trisomy 21? What does Trisomy 13 (Patau syndrome) have that 18 and 21 don't have? What does Trisomy 18 (Edwards) have that 13 and 21 don't have? 21 rather than 18 and 13?

Answer 96

rocker bottom feet Cleft lip and palate, microphthalmia, microcephaly, POLYdactyly short neck, OVERLAPPING fingers, micrognathia (small mouth) gap between first and second toe, epicanthic folds, simian crease in hand. INESTINAL STENOSIS

Question 97

Niemann-Pick disease, type A and B: 1) what's the problem? (include the deficiency) 2) what inheritance? chromosome? 3) what population of people? 4) where is it expressed preferentially? why?

Answer 97

accumulation of sphingomyelin due to a deficiency of sphingomyelinase Autosomal recessive, 11p15.4 Ashkenazi Jew on the maternal chromosome due to epigenetic silencing of the paternal gene

Question 98

Say we have a mutation that fails to inactivate a tissue-damaging substrate.. what is an example? what does it lead to?

Answer 98

A1-antitrypsin deficiency --> can't inactivate neutrophil elastase in the lung (decreases surface area, decreases oxygenation) this leads to EMPHYSEMA

Question 99

Turner syndrome: 1) what is common among 25-50% of patients? 2) mortality comes from what? when does this happen? 3) what are the classic gross features they have? 4) What's going on with sexual development? 5) why might 50% of people with Turner syndrome have more weight than a normal person?

Answer 99

Congenital heart disease (LEFT SIDED).. COARCTATION of the aorta cardiovascular abnormalities in children with turner short stature, nipples are farther apart than typical, shield shaped chest, WEBBING OF THE NECK, cubitus valgus "menopause before menarche" --> they have streak ovaries (or fibrotic ovaries), and amenorrhea 50% of Turner syndrome have hypothyroidism

Question 100

McArdle disease: 1) what is the deficiency 2) what kind of disease is it? 3) what is the patient presenting with? 4) when does it present? is it fatal?

Answer 100

Muscle Phosphorylase --> so presents in the muscle Myopathic Glycogenoses Painful cramps associated with strenuous exercise, along with failure to raise lactate levels. in adulthood, no

Question 101

Explain the deletions and insertions seen in gene mutations? what are two famous deletions to know? what kind of deletion? what's a famous insertion to know? what kind of insertion?

Answer 101

if the number of base pairs involved is 3 or a multiple of it --> reading frame is intact and will only involve extra amino acids. if not a multiple of 3 --> it's a frameshift mutation.. not the same reading frame, you screw up the whole protein. usually results in a truncation because of a premature stop codon. cystic fibrosis --> amino acid 508 (phenylalanine), it's only 3 base pairs that are removed so it's not a frameshift. ABO O allele --> single base deletion at the ABO locus --> frameshift mutation) Tay-Sachs --> 4 base pair insertion (so is a frameshift) in the hexosaminidase A gene.

Question 102

What are Mucopolysaccharidoses (MPS)? 1) what are we deficient in? 2) where are these Mucopolysaccharides abundant in? 3) what are all of these inheritance patterns? any exceptions?

Answer 102

deficient enzymes degradign glycosaminoglycans ground substance of connective tissue all autosomal recessive except HUNTER which is X LINKED RECESSIVE

Question 103

Trinucleotide repeat mutations typically cause what kind of disorder? what are the 3 key mechanisms by which these repeats cause disease? examples of diseases pairing with each? what's the morphologic hallmark?

Answer 103

neurodegenerative loss of function (repeats in non-coding) --> fragile X toxic gain of function (repeats in coding) --> Huntington disease toxic gain of function mediated by mRNA --> fragile x tremor-ataxia syndrome all of these diseases accumulate aggregated mutant proteins (misfiled proteins) in large intranuclear inclusions

Question 104

Mutation in germ cells gives rise to what? what about in somatic cells?

Answer 104

inherited disease cancer and some congenital malformations

Question 105

In general, sex chromosome disorders cause what? in general, the greater amount of X chromosomes, what happens? say you have XXXXXY, what's the gender?

Answer 105

subtle, chronic problems related to SEXUAL development and INFERTILITY the more likelihood of mental retardation male, doesn't matter how many X's there are.

Question 106

How do you differentiate AR from AD? (there are 5 things)!

Answer 106

(All AR) expression of the defect is more uniform in Autosomal Recessive --> everyone has a similar trait or phenotype pattern complete penetrance common EARLY onset!! new mutations are RARELY detected --> usually takes several generations many mutations involve ENZYMES (inborn errors of metabolism)