Genetics Diseases Flashcards
Hypophosphatemic Rickets
“Vitamin D-resistant rickets”
Inherited X-link dominant.
-> Increased phosphate wasting at proximal tubule with rickets-like presentation (kidneys cant reabsorb phosphate)
Rickets symptoms:
- delayed growth
- pain in spine
- muscle weakness
- bowed legs
- increased thickness wrists/ankles
- breastbone projection
Mitochondrial myopathies
Rare disease, Often present with myopathy and CNS disease.
Muscle Biopsy shows “ragged red fibers”
Myopathy
Disease associated with muscle fibers resulting in muscle weakness. As opposed to neuropathy…
Charcot-Marie-Tooth CMT 1A1
AUTOSOMAL DOMINANT
Gain of function NAHR occurrence -> duplication of gene chr.17
Gene codes peripheral myelin protein-22 (PMP-22).
PMP22 protein is an integral membrane glycoprotein in nerves
Increased expression PMP-22 ->Onset in first 2 decades -> weakness of foot/lower leg muscles-> (middle stage) -> foot deformity (hammertoes: permanent distal IP flexion) -> (late stage) weakness/atrophy of hands.
Hereditary neuropathy with liability to pressure palsies (HNPP)
AUTOSOMAL DOMINANT
Loss of Function
deletion of the gene encoding peripheral myelin protein-22 (PMP22 gene), 17p11.2
NAHR occurrence (opposite of CMT)
patients have temporary (usually reversible)
neuropathy when pressure is applied to various nerves. Just as your arm may go to sleep if
left in a certain position, these patients are more sensitive to pressure on nerves and their
limbs can ‘go to sleep’ for longer periods of time (hours, days, to months)
PMP22 protein is an integral membrane glycoprotein in nerves
DiGeorge syndrome
and
Velocardiofacial Syndrome
Autosomal Dominant (but usually a result of mutation in gametogenesis) CATCH-22
(del 22q11) (Contiguous gene syndrome –> DiGeorge slightly diff. microdeletion than velocardiofacial synd) (bc of NAHR -> aberrant recombination)
Cardiac defects: tetralogy of Fallot, VSD, many others
Abnormal facial features
Thymic aplasia → T-cell dysfunction/deficiency
Cleft palate
Hypocalcemia: due to hypoparathyroidism
ALSO
Involves developmental defect in third and fourth pharyngeal pouches.
50% of spontaneous abortions due to chromosomal abnormality, what kind of abnormality most common?
Abnormal # of chromosomes. (Numerical abnormality)
contiguous gene syndrome
a syndrome caused by abnormalities of 2 or more genes that are located next to each other on a chromosome.
Prader-Willi Syndrome
contiguous gene
del(15q11-q13) -> deletion/nonexistance of paternal side imprinting.
Only maternal imprinting present
- defects in SNORD116 snoRNA genes -> defect in guiding RNA modification
- > excessive eating, short stature, hypogonadism, some degree of intellectual disability
HYPOTONIA at birth bigtime, later not as much
Angelman Syndrome
contiguous gene with PW
maternal deletion : del(15q11-q13)
only paternal imprinting present
-defects in the expression of UBE3A (maternal usually expresses) -> encodes a ubiquitin ligase involved in early brain development
- > severe intellectual disabilities, spasticity/ataxia, seizures.
- Inappropriate laughter
Uniparental Disomy
Result in 2 chromosomes of maternal or paternal inheritance
- > Prader-Willi or Angelman Syndrome
- This is more rare than simple deletion of 15q11-q13
Acute Myeloid Leukemia
AML
A cancer of the blood and bone marrow. Has different types:
t(15;17) -> PML (Acute Promyelocytic Leukemia)
Auer rods present present in PML
Different fusion protein RAWR-alpha PML protein = retinoic alpha receptor alpha
=> bind DNA such that maturation factors are blocked (blasts are arresteD)
tx with retinoic acid (vitamin A) -> binds retinoic acid receptor, allows activators to get to DNA instead of repressors -> DNA matures
t(8;21) -> AML M1/M2
(normal AML)
Blasts Increased in both.
“Myeloid” leukemia because it affects a group of white blood cells called the myeloid cells, which normally develop into the various types of mature blood cells, such as red blood cells, white blood cells and platelets.
“acute” denotes rapid disease progression.
Acute lymphocytic leukemia (ALL)
t(12,21)
polyploidy = better, reduced numbers of chromosmes is worse.
A type of cancer of the blood and bone marrow
Most common type of cancer in children, and treatments result in a good chance for a cure.
Can occur in adults with worse prognosis
“acute” refers to rapid disease progression
tx; 6-mercaptopurine and 6-thioguanine
(metabolized by TPMT)
drugs cause myelosuppression (death if TPMT is defective)
Chronic myelogenous leukemia (CML), or chronic granulocytic leukemia (CGL).
t(9;22)(q34;q11) -> fusion protein
The truncated chromosome 22 = the Philadelphia chromosome.
BCR able - hyperactive tyrosine kinase
Symptoms: Night sweats, fatigue, weight loss,
anemia
Lab: Peripheral blood smear shows lobulated
large cells
Tx; Imantinib mesylate (Gleevec)
A cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood.
adults and children (more frequent in adults)
AML vs CML
The blood-forming (hematopoietic) cells of acute leukemia remain in an immature state, so they reproduce and accumulate very rapidly. Therefore, acute leukemia needs to be treated immediately, otherwise the disease may be fatal within a few months. Fortunately, some subtypes of acute leukemia respond very well to available therapies and they are curable. Children often develop acute forms of leukemia, which are managed differently from leukemia in adults.
In chronic leukemia, the blood-forming cells eventually mature, or differentiate, but they are not “normal.” They remain in the bloodstream much longer than normal white blood cells, and they are unable to combat infection well.
Acute Promyelocytic Leukemia (APL) also called (PML) are a subtype of _______
AML
t(15;17)
tx of APL/PML
Tx; Vit A/Retinoic acid
In disease PML bound with RAR represses some genes -> differentiation block
Retinoic acid activates complex to allow differentiation.
Imantinib mesylate
Gleevec
Targeted, biological therapy specific for CML cells
Molecular antagonist: binds at ATP binding site in abl tyrosine kinase and bcr/abl tyrosine kinase
Inhibits cell proliferation and apoptosis
Down Syndrome (DS)
Trisomy 21
• Short Stature
• Intellectual disabilities
-Autism:~10%
• Hypotonia (often at birth)
• Dysmorphic features
– characteristic facies
-epicanthal folds, broad flat bridge nose, relatively large tongue
– short fingers, transverse
palmar crease
– clinodactyly: medical term describing a bend or curvature of the fifth fingers
– wide “sandle gap” (1st and 2nd toe)
• Congenital heart disease
• Gastrointestinal abnormalities 10-15%: such as Hirschsprung's disease (HD),celiac, duodenal atresia/stenosis.
• Early onset Alzheimer disease (40y/o)
- Thyroid Disease 25% by adulthood
-DS infants and children have 20-100 fold
Elevated risk for developing ALL or AML
500 x more likely to get AMKL
del 16p11.2
Glycogen storage disease
Gaucher’s disease
Most common lysosomal storage disease
Defective/deficient enzyme glucocerebrosidase -> Accumulation of glucosylceramide (a sphingolipid??)
Build up of Gaucher cell’s (Hypertrophy of splenic and Liver cells due to stress on cells)
Characteristics
- Anemia
- low blood platelets
- bruising
- fatigue
- enlargement of the liver and spleen
Tx;
Enzyme Replacement Therapy (ERT) -> intracellular
Neurofibromatosis Type 1
AUTOSOMAL DOMINANT loss of function highly penetrant pleiotropic 50% new mutation rate
Mutation of NF1 on chr17 -> usually makes neurofibromin (a tumor supressor gene)
Clinical = 2+ mutations for diagnosis showing….
6 or more café au lait spots
2 or more neurofibromas
1 plexifom neurofibroma
Freckling in the axillary or inguinal area
Optic glioma (glial tumor optic nerve)
2 or more Lisch Nodules (iris spots of overgrowth)
Distinctive osseous lesions
Affected first degree relative
neurofibroma = "benign nerve sheath tumor" plexiform = nerve bundle (more severe)
Turner Syndrome
Monosomy of sex chromosome (partial or full loss of second sex chromosome)
- pleiotropic
- variable expressivity
Characteristics
-phenotypically female
-short stature (only one “shocks gene”)
-gonadal/ovarian dysgenesis (loss of germ cells -> hypoplastic and dysfunctional gonads)
-> streak gonads: fibrous nonfunctional gonads
-cystic hygroma -> (resolves to webbed neck) -> heighten suspicion for congenital heart defects
-Lymphadema of hands and feet
-Coarctation of the aorta and bicuspid aortic valve
-Fused (horseshoe) kidneys
-Small mandible, narrow maxilla and high arched palate, epicanthal folds, impaired hearing,
-wide nipples and shield chest
Normal Intelligence: delay in motor skill development
Amenorrhoea
The absence of a menstrual period in a woman of reproductive age.
primary amenorrhoea = Menstruation cycle never starts
secondary amenorrhoea = Menstruation cycle ceased
Cystic fibrosis
Autosomal Recessive
Complete penetrance
allelic heterogeneity with locus homogeneity
DIsease affects most notably the lungs, but also pancreas/liver/intestine
DM II
Risk factors: increasing age obesity, physical inactivity family history prior gestational diabetes impaired glucose tolerance (IGT)
Associated with:
Increased LDL cholesterol, triglycerides, blood pressure
Control often attained with diet, exercise
facies
are distinctive facial expressions or appearances associated with specific medical condition (like Trisomy 21)
Hirschsprung’s disease (HD)
a disorder of the abdomen that occurs when part or all of the large intestine or antecedent parts of the gastrointestinal tract have no nerves and therefore cannot function. -> the affected segment of the colon cannot relax and pass stool through the colon, creating an obstruction
Dosage Sensitive Sex Reversal (DSS)
In humans duplication of a gene DAX1 leads to development of ovaries even in the presence of expressed SRY, a disorder called Dosage Sensitive Sex Reversal (DSS).
Androgen Insensitivity
Genotype: 46,XY
Insensitivity of Androgen receptor that is X-linked
“Testicular feminization”
Person develops testes and MIF -> doesn’t develop a uterus. But because of insensitivity to testosterone has external female characteristics.
5 alpha reductase: if malformed, does not convert Dihydroxytestosterone to testosterone
Osteogenesis imperfecta type I:
AUTOSOMAL DOMINANT
Loss of function
Nonsense (stop) mutations / frameshift mutations in COL1A1 -> premature termination.
Reduced amount (1 instead of 2) of normal COL1A1 (collagen) protein causing a ‘milder’ form of osteogenesis imperfect. (few - 100 fx in lifetime) - THIS is compared to other types of osteogenesis imperfecta.
Collagen is normal but there is reduced amount. (have to go though a “2nd” cycle to complete triple helix for collagen.
Clinically
- increased fractures
- brittle bones
- blue sclera (thinner connective tissue “seeing through eye!”.
- In adults: progressive hearing loss
Hemoglobin Kempsey
gain of function mutation
(Beta hemoglobin gene, Asp99Asn missense mutation): leads to a hemoglobin molecule which has higher than normal oxygen affinity, and is less able to unload oxygen in the tissues.
Body ‘thinks’ it needs more oxygen -> makes more red blood cells -> polycythemia
Achondroplasia
AUTOSOMAL DOMINANT
GAIN OF FUNCTION mutation
80% new mutation rate predominantly from fathers germline.
PATERNAL AGING EFFECT
(FGFR3) gene chr.4 -> produces Fibroblast Growth Factor Receptor 3 which is a Tyrosine kinase receptor. (2x gene mutations most common)
G->A (98%)
G->C (2%)
MUTATION -> Amino acid substitution Gly380Arg -> Inhibits chondrocyte proliferation and differentiation (receptor is turned “on” all the time) -> inhibits bony growth (growth plates close prematurely).
**homozygous achondroplasia = lethal
Characteristics
Small stature Males 4’ 3” Females 4’
Rhizomelic limb shortening (proximal bones shorter than distal ones)
Short fingers
Genu varum (bow legs)
Trident hands
Large head/frontal bossing (prominant forhead)
Midfacial retrusion (nose and philtrum “in”)
Small Foramen Magnum/Craniocervical instability
spinal cord compression
brainstem compression
->3% and 7% of patients die unexpectedly during their first year of life because of brainstem compression (central apnea) or obstructive apnea = MOST FEARED COMPLICATION
Charcot-Marie Tooth vs. Hereditary neuropathy with liability to pressure palsies (HNPP)
CMT due to duplication of PNP22 protein (has 3 total copies) whereas HNPP has a deletion of PMP22 (1 total copy)
Alzheimer disease in Trisomy 21
Gain of Function
Patients with an extra copy of
chromosome 21 have 3 total copies of the APP (21q21) leading to increased production of
APP protein which contributes to early-onset Alzheimer disease in this patient population.
Sickle cell anemia
NOVEL PROPERTY MUTATION AUTOSOMAL RECESSIVE(ish) -They are clinically normal except when under severe low pO2 stress.
Glu6Val mutation of the beta globin
gene results in a hemoglobin molecule which transports oxygen essentially normally.
However under low oxygen states the Val residue leads to polymerization of hemoglobin into
long protein-fibers which deform and restrict the normally flexible red blood cells
Huntington disease
NOVEL PROPERTY MUTATION
AUTOSOMAL DOMINANT
PATERNAL TRANSMISSION bias (gametogenesis)
HTT gene chr4 -> encodes HUNTINGTON protein
A triplet repeat disorder -> CAG repeat ‘triplets’ in the gene increase the number of glutamine residues. Increased polyglutamine residues above a certain threshold leads to a novel toxic effect on the huntingtin protein
Huntington disease →Expansion of codons in exons -Novel property on expressed protein -Mutant RNA is made protein is made and is toxic
> 35 CAG repeats (variable penetrance)
39/40 CAG = 100% penetrance
60 = juvenile onset
S/Sx: Progressive dementia, chorea (dance-like motions of involuntary movement), caudate atrophy.
Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances
Age of onset 35-44
Death approximately 15 years after onset
heterochronic vs. ectopic expression mutations
wrong time = heterochronic
wrong place = ectopic
ie: cancer: Oncogenes turned on in differentiated cells.
or
Hereditary persistence of fetal hemoglobin
Hereditary persistence of fetal hemoglobin
the normal switch from fetal to adult
hemoglobin does not occur and fetal hemoglobin, which has a higher affinity for oxygen,
remains expressed beyond infancy.
Duchenne’s Muscular Dystrophy
and Becker’s) … and (DMD-associated DCM
X-linked Recessive:
DMD gene chr Xp21-21.1 -> encodes Dystrophin
-Largest human gene
Dystrophin links the actin cytoskeleton of smooth, cardiac and skeletal muscle cells to the extracellular matrix.
->Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue
Deletion/frameshift/stop codon = no dystrophin-> Duchenne’s = death 30’s
No frameshift (some AA missing) = less or abnormal quality dystrophin -> Becker’s (less severe) = death 40’s
Clinically (Duchenne) Boys with abnormal gait at 3-5 years Progressive muscular weakness proximal (greater)>(lesser) distal Calf pseudohypertrophy CK (creatinine kinase) levels 10x Gowers maneuver Progressive involvement of respiratory muscles Median age of death 18 years Dilated cardiomyopathy
Clinically (Becker’s) later onset
Progressive muscular weakness proximal > distal
Dilated cardiomyopathy
CK levels 5x
Death in their 40’s (more often bc cardiomyopathy)
Abnormal quantity or quality of Dystrophin
Clinically (DMD-associated DCM) ONLY WOMEN
Dilated cardiomyopathy presenting between 20-40 years of age
Early death
No skeletal muscle involvement
No Dystrophin in the myocardium
Osteogenesis Imperfecta type II, III, IV
Novel Property Mutation in COL1A2 collagen coding gene -> abnormal collagen protein -> VERY BRITTLE BONES MUCH WORSE THAN type I.
Hemoglobin Kempsey vs Hereditary persistence of fetal hemoglobin vs Hemoglobin Kansas vs thalassemia’s
Kempsey is gain of function (stronger oxygen binding) = polycythemia (body thinks it needs more blood bc of low oxygen in tissue)
(HPFH) is altered expression/failure of switch (remains expressed after infancy) . This is a timing problem (due to deletions of mature hemoglobin genes Delta and Beta). -> clinically benign
Kansas is loss of function (weaker oxygen binding, qualitative difference) = cyanosis
Thallassemia’s - Loss of expression (quantitative Hb difference)
Phenylketonuria (PKU)
AUTOSOMAL RECESSIVE
early onset
Phenotype
Highly allelically heterogenic
High phenylalanine and low tyrosine levels in the plasma because the conversion from Phe to Tyr is impaired. High levels of phenylalanine metabolites in urine and sweat gives a characteristic “mousy” odor.
High Phenylalanine Levels Microcephaly Cognitive Disability (profound if untreated, mild to none if treated) Epilepsy (seizure/tremor/gate disorders) Fair pigmentation
PKU = defect of phenylalanine metabolism.
- Usually defect in PAH gene encoding phenylalanine hydroxylase.
- Usually Loss of Function PAH gene on chromosome 12
- sometimes defect is in cofactor BH4 -> Also leads to neurotransmitter loss of dopamine and serotonin.
Tx; low phenylalanine diet
+
if BH4 cofactor defect ->
medicine for neurotransmitter balance
Timing Test
1st right when born within 1-2 days
2nd after 10 days
(bc of residual mother’s protein…?)
Maternal Effect: PKU (keep low phe diet for baby)
Test Guthrie:
if phenylalanine is elevated the bacteria will grow
α1-Antitrypsin Deficiency (ATD)
α1-Antitrypsin also called SERPINA1 (serine protease inhibitor)
AUTOSOMAL RECESSIVE
late onset
ATD patients have a 20-fold increased risk of developing emphysema.
Many patients also develop liver cirrhosis and have increased risk of liver carcinoma due to the accumulation of a misfolded α1-AT mutant protein in the ER of liver. (Z allele is at risk of this)
SERPINA1 -> released into plasma -l elastase ( but when there is deficeincy)
-> elastase is released by neutrophils in lungs -> if not mediated it destroys connective tissue (mostly elastin in lungs) -> alveolar wall damage and emphysema
tx; in R&D
recombinant protein replacement therapy can mitigate the effects of the disease (not that effective) -> it is extracellular
• Most effective therapy remains avoidance of smoking
** Of note, smoking results in neutrophil accumulation -> release of elastase -> greater elastin destuction -> earlier and more severe emphysema.
Z allele: more severe mutation (more zerious)
Z/Z genotype -> 15% normal SERPINA1
Z is misfolded protein that gets sequestered in ER of liver cause they can’t get out->Hepatomegaly
S allele
S/S genotype -> 50-60% normal lvl SERPINA1
M allele is “Mormal”
SERPIN is a class of protease inhibitor
Tay-Sachs Disease
AUTOSOMAL RECESSIVE
many different onsets, here we talk about infant onset
allelic heterogeneity
Lysosomal Storage Disease:
- Inability to degrade GM2 ganglioside (a sphingolipid) within lysosomes of neurons in CNS because of defective hexosaminidase A enzyme
- > progressively destroys neurons of brain and spinal cord.
Hexosaminidase A has an alpha and beta subunit
Characteristics
-“cherry red spot” of eye
At 3-4 months
- decreased attentiveness
- increased startle reflex
- muscle weakness
Neurodegenerative Progression
- seizures
- hearing and vision loss
- paralysis
- Death at 3-4yrs age
- 100x increased risk for Ashkenazi Jewish population
- *and cajuns
screen with enzyme test of HEXA
No Tx
Tay-Sachs disease type 1 vs Sandhoff disease type 2 vs AB variant of Tay-Sachs disease
HexA gene chr 15 -> Alpha protein (defective type 1)
HexB gene chr 5-> Beta protein (defective type 2)
GM2AP gene chr 5 -> activator for HexA enzyme because it brings it the sphingolipid (defective in AB variant T-S)
HexA enzyme (alpha/beta + activator subunits) -> degrade GM2 gangliosides
HexB enzyme (Beta/Beta subunit) -> degrade GM2 gangliosides and globosides
Hemoglobin C disease (HbCC)
Autosomal RECESSIVE(ish) -They are clinically normal except when under severe low pO2 stress.
A milder form of hemolytic anemia than sickle cell anemia. Caused by a single base
mutation at codon#6 of the β-globin gene, changing glutamate to lysine. HbC is less
soluble than HbA and tends to form crystals, reducing the deformability of RBC.
Hemoglobin SC disease
Compound heterozygotes (βS/βC) have a milder anemia than sickle cell disease.
HbS Diagnosis Using RFLP
A recognition site (CCTNAGG) of the restriction enzyme MstII is destroyed in exon 1 by
the A-to-T change in the βS mutant allele. The normal allele βA gives 1.15 kb + 0.20 kb
fragments, whereas the βS mutant allele give one1.35 kb fragment.
MUTANT ALLELE IS LARGER (cut by MstII)
alpha thalassemia 1 trait vs alpha-thalassemia 2 trait
Both result in mild anemia (still have 2 copies of alpha globin gene, bc 2 have been deleted) = 50% reduction
trait 1 = 2 deletions on 1 chromosome (more problem (in asia) bc during chromosome seperation -> can end up with 0 genes.
trait 2 - 1 deletion on each of 2 chromosomes
only 1 of 4 alpha thalassemia genes =
severe anemia = 25% alpha globin expression
Lots of HbH (B4) tetramers
“hemoglobin H disease)
** if no alpha genes = fetal death “hydrops fetalis”
Beta thalassemia
Low lvl Beta
- shows up after birth (bc have gamma lvl)
- B+ = some protein is there so HbA is present
- Hb0 = no protein present so no HbA is made
- Major vs minor thalassemia’s are clinical descriptions (treatment vs not)
- so… Beta-zero heterozygote = 50% beta globin = minor thalassemia.
- Major basically refers to Beta-0 homozygous, or Beta-0 with a very poor Beta+ –>
simple vs complex Beta thal
- simple = mutation in single gene
- complex = deviation in > 1 gene: such as delete locus control region (LCR) or delete multiple genes.
Tx; (for major thalassemia)
- RBC transfusion and iron chelation therapy (to reduce iron store accumulation)
- Vitamin C
- Splenectomy/cholecystectomy
- Bone marrow transplant (problem in marrow stem cells)
Hereteditary Persistance of Fetal Hb (HbF)
(HPFH) occurs due to deletions of mature hemoglobin genes Delta and Beta -> clinically benign
mechanism: large deletions AND promoter mutations -> Alpha2Gamma2 hemoglobin persists
clinical trials -> to turn on hemoglobin F expression and help other diseases like HgS (sickle cell) as well as Beta-thal
Qualitative hemoglobinopathies
Hb S (15% Africans)
Hb C
Hb E - (7% SE asians)
** SE Asia: α, β thalassemia and E Africa – S, C, α and β thalassemia West Pacific – α and β thalassemia and E East Mediterranean – β thalassemia and S
**Don’t have to remember, just historical (defense of malaria reasons predicted)
Thalassemia definition
Thalassemia is a disorder in which a reduced rate of one or more of the globin chain synthesis leads to imbalanced globin chain production, defective hemoglobin production and damage to the red cells and their precursors.
Alpha thalassemia types
α thalassemia types:
α thalassemia major
α thalassemia 3 gene deletion (Hgb H disease)
α thalassemia 2 gene deletion (α thalassemia trait)
α thalassemia 1 gene deletion – clinically insignificant
α thalassemia + Hgb Constant Spring = BAD PHENOTYPE
β Thalassemia types
β Thalassemias:
β+ means there is a disfunction in the Beta globin gene but is still funcitonal.
B0 is nonfunctional/deleted
β thalassemia major “Cooley’s anemia”
βo/βo or βo/β+(severemut)
β thalassemia intermediate
β+/β+ (mild/modmut) or βo/β+ (mildmut)
β thalassemia trait
B° /B or B/B+
Marfan Syndrome
AUTOSOMAL DOMINANT
25% new mutation rate
FBN1gene chr15 -> produces Fibrillin, an extracellular matrix protein.
Dominant negative activity mutation (Loss in function splicing defect)
Severe reduction in the number of microfibrils
Clinically generally tall (for family) Systemic disorder of connective tissue protruding sternum Occular Skeletal Cardiovascular mitral valve prolapse
If no family hx
Aortic root enlargement -> aneurisms -> rupture = death
+
Ectopia Lentis (displacement of lense from eye)
FBN1 mutation
systemic score > 7 (connective tissue scoring)
If family hx
aortic root enlargement
systemic score >7
ectopia lentis
Autosomal Dominant Polycystic Kidney Disease
AUTOSOMAL DOMINANT Mutations demonstrate LOCUS HETEROGENEITY Can be either PKD1 or 2 PKD1 chromosome 16p13.3 (85% of cases) PKD2 chromosome 4q22.1 Polycystin 1 and 2 produced respectively Produces a truncated protien
Clinically Bilateral renal cysts Cysts in other organs Vascular abnormalities End stage renal disease in 50% by 60 years old
Familial Hypercholesterolemia
AUTOSOMAL DOMINANT
Loss of Function
ALU family insertion/deletion/translocation in LDLR area
LDLR gene chr19 -> Encodes for the LDL receptor
Clinically
High cholesterol and LDL levels
Xanthomas (cholesterol deposition in skin)
Premature coronary artery disease and death
atherosclerosis
Tx; For homozygous
-plasmapheresis
Lots of ppl at risk
Safrican
ashkanazi jew
Hemophilia A
X-linked Recessive
10% carrier females affected (less severe for females)
Mutation F8 chrXq28 -> encodes Factor VIII = Deficiency of Factor VIII
22A inversion causes 50%
Clinically
Spontaneous bleeds into joints, muscles or intracranial
Excessive bruising
Prolonged bleeding after injury or incision
Delayed wound healing
Tx; replace Factor VIII (extracellular admin)
Fragile X Syndrome
X-linked Recessive with Maternal anticipation
Trinucleotide repeat Disorder-CGG > 200
MATERNAL TRANSMISSION BIAS (chance of expansion)
Sex-specific anticipation
Most common cause of mental retardation in males
1/3 of females affected
Mutation FMR1 gene chrXq27.3 -> Encodes FMRP
=Failure to express protein
Clinically childhood onset Intellectual disabilities Dysmorphic features: large ears, long face, macroorchidism Autistic behavior Social anxiety Hand flapping/biting Aggression
also some aortic root enlargement
Mitochondrial DNA
Encodes 37 genes, most of which are responsible for respiratory chain
Mutation -> disorders of respiratory chain-> affects tissues that need ATP (heart, brain, retina, skeletal muscle)
17000bp
ONly mothers mitochondrial DNA inherited
Klinefelter’s Syndrome
SEX CHROMOSOME Aneuploidy (pg.106 T&T)
XXY
Testicular atrophy, azoospermia
- Eunuchoid appearance (wide hips and gynecomastia)
- Female distribution of body hair
- Tall stature (fusion of epiphyses is delayed)
- Associated with normal -> mild intellectual disability: severity correlates with ↑ number of X chromosomes
Acute Lymphoblastic Leukemia tx with 6-mercaptopurine
Cures ALL but with myelosuppression
Pt. with low/absent TPMT gene -> myelosuppression will KILL child. -> 6-mercaptopurine dosage can be decreased and work effectively
List microdeletion syndromes… ugh, I dunno, maybe delete this card
Cri-du-chat, Smith-Magenis, DiGeorge (22qdel),
Williams syndrome, Wolf-Hirschhorn, Prader-Willi syndrome, Angelman syndrome.
WAGR
Del 11p13 Wilms Tumor Aniridia (loss of iris) Genitourinary... ? Retardation
Fabry Disease
X-linked condition (not totally recessive)
Lysosomal storage disease
Deficiency alpha-galactosidase -> usually degrades glycosphingolipids -> widespread microvascular changes
Neuron damage: neurologic pain crises in childhood… neuropathy ( in particular, burning extremity pain)
Sweat gland damage: reduced sweating, risk of heat stroke
Renal damage/nephropathies: progressive renal failure (cause of death prior to renal
transplanation)
Vascular damage: risk of heart attacks
and stroke
Cardiovascular: hypertrophy of cardiac
tissue also seen
Tx
Recombinant enzyme replacement
therapy appears to mitigate some
aspects of the disease
Intravenous infusion with galactose -> improvement in alpha-gal A to 10% activity
Nonsyndromic Deafness
Genetic and allelic heterogeneity
Congenital deafness predominates in the recessive form
- 1/2 congenital deafness = genetic
- 1/4 infectious
- 1/4 idiopathic
FOR congenital deafness from Genetic causes
- 3/4 non-syndromic -> GJB2 mutations most common cause (recessive)
- 1/4 syndromic = other stuff going on
Progressive childhood deafness in the dominant form
Pompe (what kind of disease?)
Lysosomal Storage Disease
Autosomal Recessive
- cannot store glyogergen
- > Progressive muscular failure
- > heart problems
Friedreich’s Ataxia
Autosomal recessive
> 100 GAA repeats within intron of the FXN gene on chromosome 9
Expansion of noncoding repeats and loss of function -> no transcription = no protein
FXN codes- > frataxin (mitochondrial protein involved in iron metabolism)
clinically
-progressive damage to the nervous system, resulting in symptoms ranging from gait disturbance to speech problems
+ sometimes
- heart disease
- diabetes.
Syndromic Deafness
-Deafness
+ retinitis pigmentosa = Usher (AR)syndrome
+ thyroid goiter = Pendred (#2 AR) syndrome
+ arrhythmia or sudden death = Jervell and Lange-Nielson (AR) syndrome
+ white forelock = Waardenburg (#1 AD)syndrome
+ 8th nerve schwannomas (vestibulocochlear nerve tumors)= Neurofibromatosis type II
AD: autosomal dominant // AR: autosomal recessive
fragile X-associated tremor/ataxia syndrome (FXTAS)
X-Linked Premutation Triplet repeat expansion Age at onset: Adulthood Ataxia, tremor Memory loss, parkinsonism, peripheral neuropathy Men >> women
Premutations: 59-200 CGG repeats
Not hypermethylated -> Increased FMRP protein
maternally unstable
Larger premutations have higher risk of maternal expansion
Expansion risk influenced by haplotype (AGGs reduce risk)
Premature Ovarian Failure
X-linked
Premutation Triplet repeat expansion
Women (not men)
Fragile X Syndrome
X-Linked PRINCIPLES Full Triplet repeat expansion Somatic mosaicism Sex-specific anticipation DNA methylation Haplotype effect MAJOR PHENOTYPIC FEATURES Age at onset: childhood Mental deficiency Dysmorphic facies Male postpubertal macroorchidism
Myotonic Dystrophy 1
Autosomal Dominant
gene DMPK (protein kinase) chr 19
-MATERNAL gametogenesis expansion of repeats
-variable penetrance
-pleiotropic
-variable expressivity (age and severity)
-evidence of anticipation
- CTG repeats 3’ untranslated region, penetrance usually begins >50 repeats.
- Expanded repeats in RNA (noncoding) confer novel properties to RNA → Expanded CUG repeats bind increased amount of RNA-Binding Protein which leads to impaired RNA splicing of key proteins → a mutant protein is NOT made.
Clinically
-characterized by wasting of the muscles (muscular dystrophy), cataracts, heart conduction defects, endocrine changes, and myotonia (prolonged contraction/delayed relaxation).
Inclusion-cell (I-cell) disease
Lysosomal Storage Disease
Autosomal Recessive
Deficiency of GlcNAc phosphotransferase -> normally phosphorylates mannose to glycoproteins that targets them to lysosomes -> Without the mannose phosphorylation the lysosomal enzyme proteins are not targeted to the lysosomes and end up outside the cell. As a result, other materials that need to be degraded are not, they are “included” within the cell, building up, hence the name of the disease.
-> leads to developmental delays and other problems…
Most Metabolic Diseases are Autosomal _____
Recessive
don’t need to treat parents
5 alpha reductase
if malformed, does not convert Dihydroxytestosterone to testosterone
progeria
Defect in LaminAC -> mutant progerin -> increased aging
sequesters in nuclear membrance
Farnesyl transports progerin and sequesters progerin in nuclear membrance
tx; inhibit farnesyl (with farnesyl transferase inhibitor)
