Autosomal Recessive Flashcards
week 5
What are the three main types of autosomal recessive disorders? What are the respective examples?
Cell metabolsim - PKU
Blood Cell function - Thalassemia, Sickle Cell, Haemochromatosis,
Membrane function- cystic fibrosis
What are compound heterozygotes?
individual with 2 different alleles (both defective)
severity depends on how much residual function is retained
Heterozygote advantage
relatively high frequency of disease-associated alleles causing reduced fitness for homozygotes = heterozygotes have a greater fitness
Features of autosomal recessive inheritance
single generation
parents and children of affeced = normally unaffected
male and female equally affected
parents = carriers
What is the recurrence risk for 2 carrier parents?
1/4
What is the chance that an unaffected sibling of affected individual is a carrier?
2/3
What is the impact of consanguineous marriage on autosomal recessive inheritance?
affected individuals seen in several generations.
What is gene therapy?
use of DNA as a pharmaceutical agent to treat lectures.
How does somatic cell gene therapy work?
replace defective genes in somatic cells so cells can produce the missing product or eliminate/ alleviate symptoms
What is germline gene therapy?
corrections are made to the germ cells such that inheritable genetic alterations are removed.
How can genes be introduced to somatic cells?
Mechanical (liposomes or microprojectiles) or Viral vectors
What are the 3 approaches to get genes to right site?
Ex vivo - target cell removed, cultured in lab, re-inserted
in situ- affected tissue directly exposed to therapy vector(not great for CF)
In Vivo- vector introduced t body, vector homes in on cells specifically designed for (best for CF)
How can an Autosomal receivve child be produced from parents with inly 1 carrier?
Germline mosaicism
de novo during embryogenesis
What is the affected gene and mutation for PKU?
Affected gene
- PAH gene
Mutation
-p.Arg408Trp
Clinical features of PKU including: early sympotims in 50% of untreated infants, nervous dysfunctions and common features of untreated individuals.
Early symptoms
-vomiting
-irritability
-eczema -like rash
-mousy urine odor
Nervous dysfunction
-increased muscle tone
-more active tendon reflexes
Untreated symptoms
-microcephaly
- widely spaced teeth
-prominent cheek and upper jaw bones
What is the screening test for PKU?
Heel prick test
Assess Phenylalanine (p) levels
Treatment of PKU?
Maintenance of blood P levels
Avoiding high-protein foods
Quality of life for PKU?
normal life and life span if following treatment
What gene is affected for a-thalassemia?
HBA1/2
What is the gene affted for b-thalassemia?
HBB
What is the phenotypic mechanism of a and b thalassemia?
incorrect or no synthesis of hemoglobin globin chains
a- a globin chain
b- b globin chain
What is the normal structure of hemoglobin and where are the genes located for a and b globin?
Normal: tetramer of 2-a-like and 2-b-like globin subunits. subunits change t fit needs of embryo, fetus and adult.
A: 4-a genes = 2 on each copy of Ch16
B: 2-b genes = 1 on each Ch11
What are the different types of a-thalassemia? Summarise each
silent
1 of 4 a mutated and asymptomatic
-minor
2 of 4 mutated = mild anaemia
-HbH
-3 of 4 mutated = mild -moderate anemia, enlarged spleen and jaundice
Hb Barts
-4 of 4 mutated = severe -excess fluid build up in developing baby = not survive after birth (usually
What are the different types of b-thalassemia? Summarise each
Minor
-1 of 2 mutated = lifelong mild anaemia
Intermediate
-2 of 2 mutated = mild/mod anameia, slow growth, symptoms early childhood or later
Major
2 of 2 = life-threatening anemia in first year, jaundice, enlarged spleen, bone changes and developmental delay.
Treatment of Major b-thalassemia.
Major B
-bone marrow transplant, cord blood transplantation and regular transfusions.
Treatment of Intermediate b-thalassemia.
splenectomy, sporadic blood transfusion and folic acid supplementation and iron chelation
Treatment of HbH (a-thalassemia)
transfusion may needed during a hemolytic or aplastic crisis
How is Thalassemia screened for?
Hematological testing of RBC
-peripheral blood smear
-supravital stain to detect RBC inclusion bodies
-electrophoresis
What is the diagnostic test for thalassemia?
molecular genetic testing of HBA1/2 and HBB
How may gene therapy be used to treat thalassemia?
haemoglobin switching (place y and a in place of defective b
Life expectancy of major-b-thalassemia.
major= delayed due to switching of y-b subunits in infancy, usually die between 3-6 months.
Affected gene and mutation of Sickle Cell anaemia.
Gene
HbA = HbS
Mutation
Non-conservative
DNA: CTC = CAC
RNA: GAG = GUG
Describe the phenotypic change in sickle cell anemia.
Changed fiber formation of RBC = distorted RBC shape
Screening for sickle cell anemia
Blood screening for deformed erythrocytes
Electrophoresis
Heel prick test of newborn
Describe the management of sickle cell anameia.
Based on crisis prevention
-drink plenty of fluids
-pain med
-blood transfusions
Affected gene and mutation of Haemochromatosis.
Gene
HFE gene
Mutation
P.Cys282Tyr or P.His63Asp
Explain the consequential phenotypic mechanism of Haemochromatosis.
Mutant HFE not bind properly to transferrin receptor which regulates Hepcidin (iron regulation)
Clinical features of Haemochromatosis.
impacts the ability to absorb all protein-associated protein from food and is instead stored in tissues
Joint pain
Fatigue
Bronze pigment
Abdominal pain
decreased libido
What is the age of onset for Haemochromatosis symptoms?
females
-symptoms present 30-50yrs old
(due to removal of iron in menstruation)
Males
-less than 50
Screening test for Haemochromatosis.
Iron content in blood or liver.
What is the treatment for haemochromatosis?
regular phlebotomy (blood enzyme tests)
Affected gene and mutation of CF.
Affected gene
-CFTR
Mutation
-p.Phe508del (misfolded protein does not migrate to cell membrane)
Clinical features of CF in terms of pancreas, lungs, Repro ducts and sweat galnds.
Pancreas
-blocked glands = cyst formation = fibrous
-decreased fat digestive enzymes = undernourishment
Lungs
-mucus thicker = persistent cough and lung infections
Reproductive ducts
-ductus deferens blocked = infertility
Sweat glands
-no-re-uptake of secreted salt = salty skin and body in salt
Is there a higher carrier or affected individual incidence of CF in Australia?
Carriers
Carriers:
1/25
Affected:
1/2500 babies (1 per 4 yrs)
Screening tests for CF.
Heel prick test – assesses pancreatic IRT
12-panel mutation screen for carriers
What is the diagnostic test for CF?
Diagnosis
Sweat chloride test
Medications and gene therpy for CF.
Medications
-antibiotics, mucous thinning drugs, bronchodilators (open airways)
Gene therapy (in Vivo is best)
Potentiators
-binds to CFTR channels and aid opening
Correctors
Helps correct processing of CFTR channel proteins
Treatment and lifestyle changes for CF
Organ transplant, chest therapy, pulmonary rehab, nebulizers every morning and night, psychological counselling and nutrition and exercise.
