Genetics - Martin Flashcards
Missense
change 1 base = different protein
Nonsense
change 1 base = stop codon
CF is what type of d and how are heterozygote carriers in risk of things
Autosomal recessive
- in risk of pulmonary or pancratic
CF genes mutations that are not the actual gene mutation for CFTR can cause
- in risk of pulmonary or neonatal meconium ileus (thick hard to pass)
PKU common in
scandinavian
NOT AA or jews
PKU deficiency in
causing
when do sx start
Phenylalanine hydroxylase (PAH) deficiency = hyperphenalaniemia
X tyrosin
at 6mo
PKU sx
intellectual disability
hypopigmentation hair, skin, eczema
musty odor
2 X linked DZ
- G6PD deficiency
2. Fragile X syndrome
autosomal dominant
- HD
- neurofibromatosis
- marfan syndrome
- Ehlers-Danlos syndrome
- Osteogenesis imperfecta
- Familial hypercholesterolemia
autosomal recessive 2 DZ
- CF
2. PKU
Galactosemia
X galactose-1-phosphate uridyltransferase = accumulation of galactose
albinism
low TRY = X melanin
Lesch-Nyhan
high intermediate product that breaks down to toxic product
a-antitrypsin deficiency
X neutrophil elastase in lung = emphysema
* avoid smoking
reason for a-antitrypsin deficiency
mutated PIZZ
- in risk of emphysema, hepatocellular carcinoma = liver transplant
Thalassemia
effects amount of globin chains made for Hb
drugs and enzyme deficiency
some drugs can unmark a deficient enzyme in a person
= Antimalarial primaquine = severe hemolytic anemia (from G6PD deficiency)
Marfan Syndrome defected gene and chr
FBN1 = X fibrillin-1 (ECM glycoprotein)
chr 15q21.1
X fibrillin leads to
- loss of structural support
2. excessive activation of TGF-B
high TGF-B SX
- bony overgrowth, myxoid changes in mitral valve
2. inflammation, vascualr SM, high MMPs (metalloproteases)
Marfan Syndrome SX
- congential contractural arachnodactyly
- tall, long extremities
- double jointed, hyperextension
- Dolicocephalic (long- headed), frontal bossing,
prominant supraorbtial ridges - pectus excavatum (depressed sternum)
- ectopic lentis (lens dislocation)*
- mitral valve prolapse, dialted distended ascending aorta = aortic dissection
Ehlers- Danlos Syndromes (EDS) reason
defect in collagen synthesis
Ehlers- Danlos Syndromes (EDS) SX
- hyperextensive skin, hypermobile joints
- fragile skin brusing
- gaping defects (hard to heal surgery)
- colon or Large As rupture,
- rupture of cornea, retinal detachment
classic EDS
diaphragmatic hernia
= AD
vascular EDS
colon or Large As rupture,
=AD
Kyphoscolisis EDS
rupture of cornea, retinal detachment
= AR
= PLODI gene
Dermatosparaxis EDS
= ADAMTS2 gene
Familal Hypercholestrolemia
due to
- mutated LDL Receptor
- ApoB problem (ligand)
- PCSK9 problem : remove LDL form liver
Familal Hypercholestrolemia heterozygoze
2-3 X higher cholesterol + CAD
= Tendinous xanthomas
Familal Hypercholestrolemia homozygous
5-6X higher plasma cholesterol
= skin xanthomas, coronary , cerebral atherosclerosis , MI before 20yo
Lysosomal Storage Disease : Gaucher Disease in risk of getting
Parkinsion’s D
Lysosomal Storage Disease : Niemann- Pick type C in risk of getting
Alzheimer’s D
Autophagy
turnover dysfunctional mitochondria = mitophagy
impaired autophagy gives rise to
2ndaryt accumulation of lysosomes = neurodegenerative link
primary accumulation of lysosomes =
large lysosomes stuffed, due to enzyme not present
TX of lysosomal diseases
- enzyme replacement therapy
- “substrate reduction therapy: reduce substate unable to get degraded
- molecular chaperone therapy: a misfolded enzyme when bound to competitive inhibitor can cause proper folding of it to occur
Gaucher cell looks
crumpled tissue paper
Globoid cells seen in
Krabbe’s disease
Niemann-Pick disease cells
- Zebra bodies
2. Foam cells (bubble appearence)
Tay-Sach’s disease cells
onion skin whorled lysosomal membranes in EM
lipid vacuoles also in neurons
Lysosomal diseases 4
- Tay-Sachs
- Gaucher
- Niemann pick
- MPSs (Hurler)
Tay-Sachs reason and most likely to get it
X Hexosaminidase A (HEXA) from mutation of chr 15
Jews, east euopeans
Tay-Sachs causes
gangliosidosis GM2
Tay-Sachs SX
at 6mo
motor and mental disorientation, flacciditym blind, dementia
= average age is 2-3 yo
Tay-Sachs on eye
Cherry-red spot on macula
Tay-Sachs accumulation of
ganglioside in neurons, eye, heart, liver , spleen
= fat stains oil red O+ Sudan black B
Niemann- Pick DZ reason
common in
X sphingomyelinase
= accumulation of sphingomyelin in lysosomes
(Chr 11p15.4)
Jews
Niemann- Pick Type A :
severe infantile, COMPLETE x spingomyelinase
- neuro issues
- a lot of accumulation
- death before 3yo, sx by 6mo
Niemann- Pick Type B :
least severe
- organomegaly
- NORMAL CNS
- live to adult
Niemann- Pick type C :
intermediate severe, most common
- NPC1 mutation,
- progressive CNS change
- ataxia, palsy, dystonia
zebra bodies are
lysosomes with concentric lamellations
Niemann- Pick eye and 2 other special things you see
- Cherry red retinal spot -type A
- massive splenomegally
- lipid accumulation in cerebellum
Gaucher Disease reason
X Glucocerebrosidase = accumulation of glucocerebroside in phagocytes (involves BM) or CNS
= M ACTIVATION - IL1, IL6, TNF
Gaucher Disease Type 1 :
least severe
- chronic nonneronpathic
- NORMAL CNS
- spleenomegally
- bone sx
- jews
Gaucher Disease Type 2 :
most severe
- acute neuropathic
- infantile cerebral pattern, progressive CNS problems
- early death
- hepatospleenomegally
- NOT JEWS
Gaucher Disease Type 3 :
intermediate
- progressive CNS
- begins at adolescence or early adulthood
Gaucher Disease special things you see 4
- 10Kg spleen
- BM erosion , bone sx
- pancytopenia
- thrombocytopenia
Gaucher cells
distended phagocytic cells
Gaucher Disease TX
allogenic hematopoietic stem cells transplant
Mucopolysaccharidoses (MPS)
reason and 2 types
X glycosaminoglycas
= a lot of ground substance of CT
1. Hurler
2. Hunter
Mucopolysaccharidoses (MPS) SX
coarse facial features, clouding of cornea, stiff joints, intellectually problems
Hepatospleenomegaly, valvular leasions, brain lesions
Hurler specific SX:
MPS I-H : X a-L-iduronidase, -normal at birth -hepatopleenomegaly by 6-24mo - death at 6-10yo (cardiac problems, coronary deposits) - corneal clouding (AR)
Hunters specific SX:
MPS II: X iduronate-2-sulfatase
- NORMAL cornea
- milder then hurlers
(X-linked)
Mucopolysaccharidoses (MPS) are
mononuclear phagocytic cells
Mucopolysaccharidoses (MPS) cells and histology
- lamellated Zebra bodies also
2. balloon cells : clear cytoplasm, many vacuoles = swollen lysosomes —-> PAS +
Mucopolysaccharidoses (MPS) most common cause of death
MI, cardiac decomposition
Glycogenoses, Glycogen storage disease usually involves what organs
liver or muscle
Glycogenoses : Hepatic form
VON- Gierke
high glycogen storage in liver = hypoglycemia
VON- Gierke
X Glucose-phosphatase , no release of glucose from the liver
Glycogenoses : Myopathic form
McArdle
high glycogen storage in muscles
muscle weakness, cramps after exercise
(* NO blood lactate after exercise)
McArdle
X Phosphofructokinase (PFK) , phospholylase in muscles
Glycogenoses : Miscellaneous
Pompe 1. X acid a-glucosidase (acid maltase) 2. X branching enzymes = cant store glycogen - early death
Pompe
X acid maltase (acid a-glucosidase)
= cardiomegaly
low amounts of :
in Von Gierke
in McArdle
low glucose in blood (hypoglycemia)
low energy output
Pompe cells
glycogen filled cardiac cells
most common cause of congenital malformation
environment enhancing genetic problems
= range of severity of disorder due to environment and many factors involved
reducing neural tube defects can be done by
ADD FOLIC ACID in diet of mother
Euploid
exact multiple of haploid 23 number
Aneuploid
chr not multiple of 23
- nondisjunction : +/- 1 chr
- anaphase lag : during meiosis or mitosis, one chr lags behind and left out = 1 normal cell and 1 monosomy cell
Monosomy
too much loss of DNA to have live birth except some trisomies that still do
Mosaicism
mitotic errors in early development = 2 or more populations of cells with different chromosomal complement
Mosaicism usually effect
sex chr
ring chr
break at both ends of chr + fusion of damaged ends = 46XY, r(14)
Inversion
rearrangement involving 2 breaks in 1 chr + inverted intervening segments
isochromosome :
1 arm of chr is lost, remaining arm is duplicated
= chr has 2 long arms or chr has 2 short arms
Balanced reciprocal translocation
1 break in 2 chr, exchange in material + no loss in material
Roberstsonian translocation
translocation between 2 acrocentric chr (closer to centromere
=** transfer of 1 very large chr + 1 very small chr
= small one usually lost
= normal phenotype
= 1 in 1000 normal people
trisomy 21 Roberstsonian translocation
3-4%*
- q arm of chr 21 is translocated to another chr
- fetus has 46chr with 3 copies of chr 21 long arm **
SX of Trisomy 21
- epicanthal folds, slanted palpebral fissures, flat face
- brushfield spots on iris
- simian crease + clinodactyly on hands
- gap between big toe
- small hypoplastic ears
- fissured tongue
Trisomy 21 Down syndrome
47chr
- huge maternal age factor (1/1550 under 20yo, 1 in 25 in over 45yo), since extra chr is maternal origin
Trisomy 21 Down syndrome RISKS
- congenital heart D (40%), AVSD,**
- acute myeloid leukemia 500X chance, 20X chance acute B lymphoblastic leukemia
- Alzheimers (at 40yo almost all)
- serious lung or thyroid infections
chr 21 is usually coding for
mitochondria functions -ROS, apoptosis
amyloid proteins - alzheimers
IncRNAs
how to screen for congential malformations
maternal blood, which has 5-10% fetal blood
Trisomy 18
Edwards
- congenital heart problems
- horse shoe kidney
- intellectual problems
Trisomy 13
Patau
- cleft lip
- microphthalmia
- cardiac defects
- renal defects
- intellectual disability
Chr 22q11.2 Deletion Syndrome
- DiGeorge Syndrome
2. Velocardiofacial syndrome
- DiGeorges Syndrome : SX
- thymic hypoplasia = T-cell immunodeficiency *
- parathyroid hypoplasia = hypocalcemia*, cardiac malformation
- allergic rhinitis, thrombocytopenia can be seen
- Cleft palate
- Velocardiofacial syndrome : SX
- facial dysmorphism (prominent nose, retroganathia, long face, pear nose), cleft palate,
- cardiovascular anomalies
- learning disabilities
Lyonization
inactivation of all except 1 X chr
Lyon hypothesis
1 X is active
all others –> heteropyknosis, inactivate (random) = Barr body
Barr body genes
most are inactive, some escape inactivation
Klinefelter syndrome SX
47 XXY -> male
hypogonadism
dx after puberty
long legs, small testes, small penis, X secondary male characteristics, low spermatogenesis, gynecomastia
Klinefelter syndrome risk for
- T2D, metabolic syndrome
- mitral valve prolapse
- germ cell tumors, teratomas
- breast cancer
- SLE
Turner’s syndrome
45 X female Webbing of neck* + low posterior neck line* broad chest Streak fibrotic ovaries * amenorrhea most common cause* hypogonadism, short partial monosomy
Turners syndrome risks
- some have there X chr with Y-chr genes = gonadoblastoma
- Cystic hygroma : edema infant from lymph stasis in neck
- Congenital heart disease (LEFT), coarctation
- Hypothyroidism *
- glucose intolerance, obesity, insulin resistance (few)
Turners syndrome TX
estradiol given
true hermaphrodite
both ovarian and testicular tissue are present
pseudohermaphrodite
disagreement of phenotypic and gonadal sex
- female pseudohermaphrodite : ovaries + male external genitalia
- male pseudohermaphrodite : testicular tissue + female- type genitalia
trinuclear repeats usually cause
neurodegenerative disorders (usually G or C) = accumulation of aggragated mutant proteins in large intranuclear inclusions****
- loss of function trinuclear repeat
Fragile X
Toxic gain of function trinuclear repeat
HD
Toxic gain of function mediated by mRNA trinucelar repeat
Fragile X tremor-ataxia syndrome
Fragile X syndrome mutation in and reason it happens
mutated FMR1 gene trinuclear mutation with MANY CGG repeats that expand during oogenesis = loss of function
Fragile X syndrome SX
-intellectual disability, aggressive, autism, anxiety, hyperactive, long face, large mandible, large up ears, large testicles (macro-orchidism), hyperflexy, mitral valve prolapse, pectus excavatum
BIG BALLS*
Fragile X syndrome inheritance
gets worse in SX and starts earlier each generation (* esp when passed on from female) = anticipation
Fragile X syndrome who is effected
males
females can be effected (Intellectually low)
fragile X- associated primary ovarian failure
from gain of function FMR1
premature ovarian failure
fragile X-associated tremor/ataxia
in 6th decade they get this from FMR1 amplification
HD SX
AD
dementia, progressive movement disorder, striatal neurons degenerate , chorea,
- HTT (polyglutamine trinucleaotide repeat) *
= accumulated huntingtin
= during spermatogensis
= anticipation
LHON (Leber hereditary optic neuropathy)
defect in mitochondria DNA passed from mother
- progressive bilateral X central vision (age 15-35) = blindness
- cardiac conduction defects
mt diseases
- threshold effect for any disorder to happen
- heteroplasmy : both normal and mutant DNA
Prader Willi syndrome
intellectual problems, short, obese (cant stop eating, hypotonia, hypogonadism
CHR 15 deleted = paternally
Angelman syndrome
intellectual problems, ataxia happy walk, seizures, inappropriate laughter = happy puppets
CHR 15 deleted = maternally
imprinting can cause what 3 things
- Deletion of a chr : like chr 15
- Uniparental disomy : 2 chr from same parent (chr 15 both from mom - Prader willi syndrome)
- Defective imprinting : the maternal chr carries the paternal chr = X mom chr, or paternal carries the maternal chr = X dad chr
