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
