Single Cell Disorder

Question 1

PKU

Answer 1

insufficient phenylalanine hydroxylase activity (phenylalanine > tyrosine)

so can’t degrade phenylalanine = intell dis

treat with phenylalanine free diet

autosomal recessive

Question 2

recessive disorders

Answer 2

only homozygous indivs w/ two mutant alleles affected

heterozygous indivs w/ one mutant allele is carrier
-if both parents carriers = 25% kids affected + 50% carrier kids + 25% unaffected

Question 3

recessive inheritance

Answer 3

if loss of one allele can be compensated aka defects in highly regulated processes OR
enzyme defect

inborn errors of metabolism= family of recessive disorders

Question 4

consanguinity

Answer 4

same blood/related

inc risk for recessive dis esp if rare aka homozygous by descent

children of 1st cousin unions F= 1/16

F = coefficient of consanguinity

Question 5

dominant inheritance

Answer 5

cause disease in heterozygous state so one mutant allele is bad (second normal copy not compensate)

affected children have at least one affected parent

Question 6

haploinsufficiency

Answer 6

one intact allele not enough to maintain function

-receptor mutations aka LDL = familial hypercholsterolemia
-when amount of protein matters more than activity
-protein activity not regulated
-paracine/endocrine messangers (sonic hedgehog)

Question 7

dominant negative effect

Answer 7

mutation = protein that interferes w/ normal function , often when protein part of larger structure i.e collagen

1. null (completely destroys)
2. missense (change sequence)

Question 8

gain of function

Answer 8

mutation = protein w/ new function
-signaling proteins so activate cascade w/o ligand binding

dwarfism/achondroplasia from growth factor receptor misfiring (FGFR3)

Question 9

Two Hit Model

Loss of Heterozygosity

Answer 9

1. mutation in tumor suppressor to predispose to cancer
2. somatic mutations disable the second intact copy = lose heterozygosity

cancer i.e retinoblastoma (bilateral, onset before age 5)

Question 10

x-linked recessive inheritance

Answer 10

-skips generations through carrier females
-males > X to all daughters so will be carriers if affected father
-males > Y to all sons so no father-son transmission

Question 11

mosaicism

Answer 11

in females:
one X is inactivated during dev randomlly and fixed SO

mosaic for x-linked traits

Question 12

Duchenne Muscular Dystrophy

Answer 12

mosaicism = carrier females have mix of cells with and w/o hystrophin, will not be fully normal but not meet diagnostic criteria

affected males have no dystrophin in muscles

Question 13

mitochondrial disorders

Answer 13

all mitochondria passed from mother
-not follow mendelian rules so varying fractions in egg + unpredictable severity +

heteroplasmy = uneven distribution of mito w/ mutations during mitosis

Question 14

codominant inheritance

Answer 14

both alleles of a gene produce distinguishable trait and are both expressed

i.e MN glycoprotein on RBCs

Question 15

diagnostic criteria

familial hypercholesterolemia

Answer 15

diagnosed with FH if
1. heterozygous, dominant dis when threshold low, x2 the LDL
2. or homozygous, recessive dis when threshold high, x4 LDL

Question 16

heterogeneity

Answer 16

one disorder caused by diff mutations

can be:
locus: in diff chromosomal loci/genes
allelic: diff mutation in same locus/gene

Question 17

pleiotropy

Answer 17

one mutation cause more than one disorder or affect multi systems so overlap possible

risk of seeing diff providers for the same disease

Question 18

locus heterogeneity

Answer 18

mutations in diff loci/genes cause same disease

-proteins that require processing/trafficking (ECM proteins, collagen) OR
defect in processing

Question 19

allelic heterogeneity

Answer 19

diff mutations on same locus/gene cause same disease

-null mutation = haploinsufficiency
-missense mutation = dominant negative effect

peripheral mutation not as bad as a central

Question 20

Osteogenesis Imperfecta

Answer 20

disorder of type I collagen (mutation in COL1A1 or COL1A2) = deficienccy in bone formation

-type I = blue sclerae, balance issues, bruising, from COL1A1 = haploinsufficient
-type II = perinatally lethal, severe, COL1A2 = dominant negative effect
-type VIII = loss of function mutations in P3H1 gene so recessive inheritance

Question 21

Collagen Assembly Mutations

Answer 21

mutation in collagen processing enzymes = recessive forms of OI
vs
mutation in collagen genes = dominant OI

dominant negative mut can be more severe than null muts

Question 22

Neurofibromatosis type 1

NF1

Answer 22

autosomal dominant disorder (parent > kid)

complete penetrance and variable expressivity

Question 23

penetrance

Answer 23

% of people w/ mutation who dev symptoms

disorders can skip generations when low penetrance so still passed on just not symptomatic

all or nothing

Question 24

expressivity

Answer 24

how patient presents/phenotypes

can lead to missed diagnoses if mild or diff in parents and children

Question 25

achondroplasia | dwarfism

Answer 25

gain of function mut in FGFR3 fully penetrant + narrow variation in expressivity aka all present similar short limbs, enlarged neurocranium, midface hypoplasia

Question 26

new mutations and fitness

Answer 26

new will occur in diseases that affected indivs have low fitness aka low chance of reproducing OR -large genes (broad target) -genes with mutation hotspots if fitness is 0 (all affected indivs die/not reproduce) then any case must be from new mutation | correlated with advanced paternal age

Question 27

Huntington disease

Answer 27

100% penetrance + narrow variation of expressivity aka diagnosis cannot be missed from triplet repeat inc involuntary muscle movements, inc moody/depressive behavior inc severity = earlier age of onset

Question 28

triplet repeats

Answer 28

pre-mutation: 35-40 repeat expansions , risk of having multiple affected children bc expansion during gametogenesis full mutation : dominant mode of inheritance anticipation: children more severly affected than parents

Question 29

anticipation

Answer 29

repeat length inc = severity inc repeats @UTR, exons, introns