Lecture 3 - Genetic Disorders Potpourri

Question 1

alpha globin gene is on chromosome ____;

beta globin and gamma globin genes are on chromosome ____

Answer 1

16, `11

Question 2

the _____ controls beta globin expression during development. prior to birth, the _____ globin gene is expressed. after birth. the ____ globin gene is expressed. disorders that effect beta globins present _____

Answer 2

locus control region (LCR);
gamma, beta;
post-natally (cuz not really expressed at birth)

Question 3

sickle cell:

conversion of ____ to ____. inheritance?

Answer 3

glu–>val;
autosomal recessive

not bothering with the symptoms

Question 4

beta thal:

_____ mutations in ___ ____ and promoter sequences = reduced levels of ____. heterozygotes get _____

Answer 4

point, splice sites;
beta globin;
thallasemia minor (typically mild anemia)

Question 5

alpha thal:
due to ______, genetically.
reduced levels of _____.

Answer 5

gene deletions;

alpha globin

Question 6

globin deletion can occur with _____, where homologous pairing and unequal crossover occurs

Answer 6

non-allelic homologous recombination (NAHR)

Question 7

marfan syndrome:
FBN1 normally helps sequester ____ ____; decreased FBN1 leads to ____ _____ action/signalling.
marfan syndrome is due to _____ exacerbated by a _____ effect

Answer 7

inactive TGFbeta;
increased TGF-beta;
haploinsufficiency, dominant-negative

apparently helps explain pleiotropy

Question 8

what drug has shown to prevent aortic-root enlargement in mice with marfan?

it is thought to ____ TGF-beta

Answer 8

losartan;

block

Question 9

loeys-dietzy syndrome:

typically due to genes encoding _____. causes very early _____ and pregnancy-related complications (Similar to marfan)

Answer 9

TGFbeta;

arterial aneurysms

Question 10

homocysteinuria:
inheritance = ?
classic form is due to _____ deficiency. increasing vitamin ___ can help treat this
all forms cause an increase in homocysteine, which is pro-thrombotic or anti-thrombotic?

Answer 10

autosomal recessive;
cystathionine synthase, B6;
pro-thrombotic–> thrombotic and heart prpbs

Question 11

other effects of homoecysteinuria besides thromboembolism:

____ (bone thing), marfinoid habitus, _____ lens _____, kyphosis

Answer 11

osteoporosis,

downward lens dislocation

Question 12

other forms of homocysteinuria:
____ synthase deficiency.
different forms causing same disease is an example of _____

Answer 12

methionine synthase;

locus heterogeneity

Question 13

PKU:
inheritance?
classic form is due to decreased ____ ____. various mutations in this gene can cause this = example of ____ ___;
“malignant form” is due to decreased _____

Answer 13

autosomal recessive
phenylalanine hydroxylase;
allelic heterogeneity;
BH4 (ie due to dihydropteridine reductase deficiency)

Question 14

PKU: high levels of Phe inhibit transport of _____ ____ amino acids across the BBB–>intellectual ___. also causes ___ Retardation, ____ body odor, ____ skin, seizures, eczema

Answer 14

large neutral;
disability;
growth;
mousy;
fair

Question 15

PKU:

screening shows increased _____. screening should be done when?

Answer 15

phenyl ketones;

2-3 days after birth (at birth, infant reflects maternal blood levels)

Question 16

PKU diet:
avoid phenylalanine containing foods, such as the artificial sweetener _____. with good diet, all symptoms are reversible other than _____. should diet diet within 4 weeks of age. what cofactor can be supplemented?

Answer 16

aspartame;
mental retardation;
BH4 (aka Kuvan)

Question 17

maternal PKU = due to elevated Phe levels in _____;

causes ____ cephaly, mid ____ hypoplasia, mental retardation, heart probs

Answer 17

mom;
micro, facial;

can be due to mild hyperphenylalanemia

Question 18

Malignant PKU:
better or worse prognosis with treatment than classic PKU?
why?

Answer 18

worse;

BH4 is required for synthesis of other NTs

Question 19

classic galactosemia:
inheritance?
due to absence of _____.
symptoms develop when infant consumes _____

Answer 19

autosomal recessive;
Galactose 1-P uridyltransferase (GALT);
lactose (ie breast milk, formula)

Question 20

classic galactosemia:

___megaly, jaundice, infantile ____, mental probs, _____ (infection)_

Answer 20

hepatomegaly, cataracts;

E. coli sepsis

Question 21

galactokinase defiency:
inheritance?
generally, just causes _____.

Answer 21

autosomal recessive;

cataracts

Question 22

epimerase defeciency = similar to galactokinase deficiency or GALT deficiency?

Answer 22

GALT deficiency

Question 23

galactosemia screening tests:
testing for elevated blood galactose/Gal 1 P can be inaccurate due to ______

GALT measurements can be inaccurate due to _____

Answer 23

requirement for milk ingestion before test (otherwise false neg);

heat denaturation (false positive)

Question 24

cystic fibrosis:
inheritance?
GI probs: causes pancreatic ____, malabsorption with _____, ____ in newborns, liver cirrhosis, pancreatitis

Answer 24

autosomal recessive;
steatorrhea;
meconium ileus

Question 25

CF: | pulm things: recurrent infections, especially ____ in adults. chronic ____ and cough, can cause cor pulmonare

Answer 25

pseudomonas; | bronchiectasis

Question 26

CF: | usually due to defect in CFTR gene on chromosome ____. typically a deletion of ____ which impairs _____

Answer 26

7; | Phe508, post-translational processing-->CFTR retained in rER

Question 27

``` CF other mutations: _____ mutations (G542X, R553X) cause reduction in mRNA transcripts and absence of CFTR. ____ affects activation of CFTR and alters function. ____ is a potentiator thaCt has been approved for treatment of this ```

Answer 27

nonsense (ie nonsense mediated decay); | G551D; Ivacaftor

Question 28

CFTR encodes for a ___ gated ___ channel. | mutation--> in the mucosa, ___ can't exit, causing increased intracellular ___ and ____ --> thick mucus

Answer 28

ATP gated Cl channel; | Chloride, Na, H2O

Question 29

CF: | in sweat glannd, _____ of ___ and ____ is impaired --> very ____ sweat

Answer 29

reabsorption, Na, Cl; salty ie chloride sweat test

Question 30

CF: characterized by polymporphisms in intron ___ of CFTR. people with the ____T genotype produce less CFTR protein. in patients without CF, this genoytype causes increased risk of male ____ due to ______

Answer 30

8; 5T (vs normal 9T genotype); infertility, agenesis of vas deferens (ie congenital absence of vas deferns)

Question 31

newborn CF test: | elevated _____ _____

Answer 31

immunoreactive tyrpsinogen

Question 32

tay-sachs disease: deficiency of ____ --> accumulate ____; inheritance? more common in what population

Answer 32

Hexosaminidase A; GM2 ganglioside; autosomal recessive; ashkenazi jews due to mutation of HexA alpha subunit

Question 33

tay-sachs symptoms: accumulation of GM2 ganglioside in _____ . progressive _____, development delay. _____ spot on macula due to what?

Answer 33

lysosomes; neurodegeneration; cherry red, lipid accumulation

Question 34

tay-sachs carrier testing: | complicated by existence of "_____ alleles". use 2 _____ to identify these alleles

Answer 34

pseudodeficiency; | polymorphisms

Question 35

familial hypercholesterolemia: inheritance? example of a _____ disorder; typically due to absent or defective ______

Answer 35

Autosomal dominant; incompletely dominant/semidominant (ie homozygous is worse than heterozygous); LDL receptors

Question 36

famial hypercholesterolemia: characterized by accelerated _____; tendon ____, corneal _____

Answer 36

atheroscelrosis (Early MI); | xanthomas, arcus;

Question 37

familial h-cholesterolemia: | in addition to LDL receptor probs, can be due to loss of function of apopprotein ____ or gain of function of _____

Answer 37

``` B-100; PCSK9 protease (breaks down LDL receptors) ```

Question 38

LDL receptor problems are an example of _____; | can occur due to non-allelic homologous recombination, aka _____ crossing over

Answer 38

haploinsufficiency; | unequal

Question 39

Charcot-Marie-Tooth (CMT): inheritance is usually ____; due to ______ of PMP-22 aka due to ____ expression

Answer 39

autosomal dominant; duplication, over-expression (chrom 17, can be due to NAHR)

Question 40

CMT: | characterized by ____ demyelination of ____ NS nerves.

Answer 40

segmental, peripheral

Question 41

hemophilia A: | ____ disrupts genes in 45% of cases. happens in ____ meosis and is a type of ______

Answer 41

inversion; | male, NAHR

Question 42

a ____ ___ ____ is a DNA segment 1 kb or larger that is present at a variable number in comparison to reference genome;

Answer 42

copy number variant

Question 43

hemochromatosis: inheritance = classic triad of ____, ____, _____ due to ____ overload

Answer 43

AR; cirrhosis, DM, skin pigmentation; iron

Question 44

hemochromatosis: | mutation in ____ gene, usually due to a ____ to ____ mutation at the 282 position on chromosome _____.

Answer 44

HFE; cysteine to tyrosine; | 6

Question 45

Hemochromotosis: | _____ hepcidin = _____ ferritin = _____ iron

Answer 45

decreased, increased, increased

Question 46

Alzheimers: | name 3 early onset AD genes

Answer 46

APP, presenilin 1, presenilin 2

Question 47

Lesch-Nyhan syndrome: inheritance = due to absent ______, which converts hypoxanthine to ____ and _____ to GMP

Answer 47

X-linked recessive; HGPRT; IMP, guanine

Question 48

``` remember HGPRT for lesch-nyan = H = G = P = R = T = ``` also ____ "Sand" in diapers

Answer 48

``` hyperuricemia gout "pissed off" (self mutilation) retardation (intellectual) dysTonia ``` orange

Question 49

lesch-nyhan; defective ____ salvage; treat with _____

Answer 49

purine; | allopurinol

Question 50

alpha 1 antitrypsin (A1AT) deficiency: | inheritance?

Answer 50

codominant (notes also say AR)

Question 51

A1AT deficiency/phenotype: PiM = PiZZ = PiMZ =

Answer 51

normal; severe disease, early emphysema and jaundice; high risk in smokers

Question 52

adult form of PKD: inheritance = 85% due to mutation in ____ gene on chromosome ___; 15% due to mutation in ____ gene on chromosome ____

Answer 52

AD PKD1, 16; PKD2, 4

Question 53

``` in addition to cysts, ADPKD causes... _____ (CNS); _____ (valve thing); _____ (cardiovascular); _____ in liver ```

Answer 53

berry aneurysms; MVP; HTN; benign cysts

Question 54

PKD1 and 2 mutations = dsrupt ____ signalling --> abnormal _____ mediated proliferation of cystic cells. also due to ____ dysfunction

Answer 54

Ca; cAMP; ciliary