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AUTOSOMAL RECESSIVE DISORDERS Flashcards

1
Q
  • Phenylketonuria (PKU)
    • Mechanism
      • What gene?
      • What kind of genetic change?
      • Protein result of that change?
      • How it affects the human body - clinical features?
    • Screening and diagnosis
      • Is it screened for at birth?
      • Or does it require specialist testing?
    • Management
      • Medication?
      • Lifestyle changes?
      • Exclusion diets?
      • Is there no treatment?
    • Quality of life and outlook
      • Are they able to function?
      • Impairment adjustments?
      • Life span?
      • Cures/treatments being trailed?
A
  • Overview
    • PKU is a metabolic disorder that causes a loss of phenylalanine hydroxylase (PAH) which breaks down phenylalanine
    • PKU is an autosomal recessive trait with no obvious phenotype in heterozygotes despite a 50% reduction in PAH enzyme activity
    • In PKU individuals and carriers, the amount of enzyme is the same as for normal individuals, but the quality (Or activity) of the enzyme is reduced, and thus the activity is too
  • Mechanism - chromosome affected and mutation
    • Mutation in the PAH gene
    • Most common
      • p.Arg480Trp
    • Without this enzyme, phenylalanine accumulates in tissues
  • Clinical features of PKU phenotype
    • About 50% of untreated infants have early symptoms
      • Vomiting, irritability, eczema-like rash, a mousy odour to urine
    • Some may also show subtle signs of nervous system function problems
      • Increased muscle tone
      • More active muscle tendon reflexes
    • Other commonly noted features include
      • Microcephaly
        • Small head
      • Prominent cheek and upper jaw bones with widely spaced teeth
      • Poor development of tooth enamel
      • Decreased body growth
    • Later, severe brain problems occur
      • Cognitive impairment
      • Seizures
  • Screening and diagnosis
    • Australia
      • Screen all newborns for PKU for early identification and management
    • Newborns are screened for levels of phenylalanine at about 3 days of age
      • A few drops of blood are obtained by a small prick on the heel, placed on a Guthrie card, and then sent for measurement
      • This is one of several newborn screening tests performed before or soon after discharge from the hospital
  • Treatment
    • Management of PKU is to maintain a blood level of phenylalanine within 2-10mg/dL
      • We need some for growth so it cannot be entirely eliminated, just reduced
    • Reduction in diet - high protein foods such as meat, fish, poultry, eggs, cheese, milk, dried beans and peas are avoided
      • Measured amounts of cereals, starches, fruits, vegetables and milk substitutes are recommended
    • If affected person is vigilant about their diet, normal quality of life and lifespan
    • Homozygous women with PKU have difficulty producing healthy children
    • Babies born to mothers with PKU are exposed to uncontrolled phenylalanine levels (women who cannot follow a low-phenylalanine diet during pregnancy) have a significant risk of intellectual disability because they are exposed to very high levels of phenylalanine before birth
    • This is known as the maternal effect
      • Where the mother’s genetic disorder affects the child regardless of inheritance
    • Heterogeneity is due to differing enzyme activities in different mutant alleles
    • Most PKU affected are compound heterozygotes
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2
Q
  • Thalassemia
    • Mechanism
      • What gene?
      • What kind of genetic change?
      • Protein result of that change?
      • How it affects the human body - clinical features?
    • Screening and diagnosis
      • Is it screened for at birth?
      • Or does it require specialist testing?
    • Management
      • Medication?
      • Lifestyle changes?
      • Exclusion diets?
      • Is there no treatment?
    • Quality of life and outlook
      • Are they able to function?
      • Impairment adjustments?
      • Life span?
      • Cures/treatments being trailed?
A
  • Overview
    • A group of heterogenous blood disorders where one of the globin chains of hemoglobin has not been synthesised correctly
      • If it involves the α-globin chain - α-thalassemia
        • Main regions affected - China, South East Asia, Eastern Mediterranean, Africa, the Pacific Islands and New Zealand (Maori)
      • If it involves the β-globin chain - β-thalassemia
        • Main regions affected - Middle East, Mediterranean, Africa, Indian Subcontinent, Central and South East Asia and the Caribbean
  • Mechanism - chromosome affected and mutation
    • Thalassemia’s are usually deletions that block globin protein production (Either α or β thalassemia)
    • HBA1 or HBA2 genes are affected in α-thalassemia
    • HBB gene affected in β-thalassemia with over 400 documented mutations
  • Oxygen requirements are regulated by changes in globin gene expression
    • Hemoglobin is a tetramer of two alpha-like and two beta-like globin subunits
    • Subunits change to suit the gas carrying needs of embryo, fetus and adult
      • Researchers are trying to understand globin gene switching in detail as it seems likely that tricking cells into producing embryonic or foetal globin proteins could be used to treat people with Thalassemia
    • Four different compounds - will not show any symptoms in utero, but after being born, they will display the symptoms as they begin to switch from gamma to beta genes
  • Clinical features
    • Hemoglobin H - mild
      • Enlarged spleen
      • Jaundice of eyes and skin
      • 3/4 faulty α-globin’s
    • Hemoglobin Bart’s hydrops fetalis (Hb Bart’s) syndrome - severe
      • Excess fluid builds up in baby
      • Does not survive long after birth
      • 4/4 faulty α-globin’s
    • Beta-thalassemia intermedia - milder
      • Symptoms early childhood or later in life
      • Slow growth and bone changes
      • 2/2 faulty β-globin’s (with some function still preserved)
    • Beta-thalassemia major - severe
      • Life threatening anemia within first year of life
      • Failure to thrive
      • Jaundice of eyes and skin
      • Enlarged spleen
      • Bone changes
      • Developmental delay
      • 2/2 faulty β-globin’s
  • Screening and diagnosis
    • Screening (indication of risk of having disorder)
      • Hematologic testing of RBS indices, peripheral blood smear, supravital stain to detect RBC inclusion bodies and qualitative and quantitative hemoglobin analysis (electrophoresis)
    • Diagnosis
      • Molecular genetic testing of HBA1 and HBA2 defects deletions in about 90% and point mutations in about 10% of affected individuals
      • Molecular testing of HBB routinely identifies all variant types, including silent mutations
  • Treatment
    • Blood transfusion, regular or intermittently
    • Alpha-thalassemia
      • No treatment for Hb Bart’s
      • For HbH, occasional red blood cell transfusions may be needed during hemolytic or aplastic crises
    • Beta-thalassemia
      • Intermedia
        • Symptomatic therapy based on splenectomy in most affected individuals, sporadic RBC transfusions in some, folic acid supplements and iron chelation
      • Major
        • Regular transfusions correct anemia, suppress erythropoiesis and inhibit increased GI absorption of iron
        • In some cases, bone marrow transplant from matched donor or cord blood transplantation from a related donor
    • New treatment approaches - switching on fetal globin genes to treat adults
      • Relevant to β-thalassemia as γ-globin can partner with α-globin in place of the defective β-globin
      • Need to switch on various transcription factors in order to do this which may affect other systems
        • There is a need to ensure this only affects the blood
      • Currently 54 clinical trials underway using drugs, dietary, stem cells and genetic interventions as methods of cure or treatment
  • Most thalassemia heterozygotes have mild symptoms and are undiagnosed due to incomplete dominance
  • Thalassemia major affected babies are normal at birth but become anaemic between 3-18 months
  • If untreated, most will die
  • Mild forms of thalassemia do not shorten life span
  • β-thalassemia is the most common form in Australia because of the high number of people who have migrated from Mediterranean countries
  • More migration of people from Asia means that the number of people with α-thalassemia has increased in Australia
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3
Q
  • Sickle cell anemia
    • Mechanism
      • What gene?
      • What kind of genetic change?
      • Protein result of that change?
      • How it affects the human body - clinical features?
    • Screening and diagnosis
      • Is it screened for at birth?
      • Or does it require specialist testing?
    • Management
      • Medication?
      • Lifestyle changes?
      • Exclusion diets?
      • Is there no treatment?
    • Quality of life and outlook
      • Are they able to function?
      • Impairment adjustments?
      • Life span?
      • Cures/treatments being trailed?
A
  • Overview
    • Misshaped RBC due to mutant allele of hemoglobin subunit (HBB gene; same as Thalassemia, but with a different outcome)
    • A blood disease most often affecting people with ancestors from Africa; Mediterranean countries such as Greece, Turkey, and Italy; the Arabian Peninsula; India; and Spanish-speaking regions in South America, Central America, and parts of the Caribbean
  • Mechanism - chromosome affected and mutation
    • β-chain of the human hemoglobin has a single amino acid substitution (HbS allele), causing fiber formation compared to the wild type heterotetramer (HbA)
      • S = Sickle cell
  • Clinical features
    • Early signs and symptoms of sickle cell disease include swelling of the hands and feet; symptoms of anemia, including fatigue, or extreme tiredness; and jaundice
    • Over time, sickle cell disease can lead to complications such as infections, delayed growth, and episodes of pain, called pain crises
  • Screening and diagnosis
    • One particular HBB gene mutation produces an abnormal version of beta-globin known as hemoglobin S (HbS) resulting from a single amino acid change
    • Diagnosis is done by blood screening for deformed erythrocytes using a microscope
    • Included in newborn screening
  • Treatment
    • Management is based on the prevention of crisis
    • Outlook is good if routinely checked up
  • Beta-globin point mutation associated with sickle cell anemia
    • Hb Thalassemia (Nonsense)
      • Stops chain too early
    • Hb Thalassemia (Frameshift)
      • Loss of amino acid changes the chain
    • HbC (Missense) hemolytic anemia
      • Change on the 6th codon
    • HbS sickle cell (Missense)
      • Change in the 6th codon
  • Malaria and HbS
    • Theory of beginning is due to the presence of Malaria
    • Parasites grow poorly in RBC’s of homozygous recessive and heterozygous genotypes
    • Provides a protective advantage
    • As a direct consequence, the frequency of HbS alleles in populations that are exposed to Malaria is maintained at high levels through natural selection
  • Heterozygote advantage
    • The relatively high frequency of disease-associated alleles causing reduced “fitness” on homozygotes (E.g. Sickle-cell anaemia in Africans) has been explained by assuming that the heterozygotes (Aa) have a greater fitness than either of the homozygotes (AA or aa)
    • This is called heterozygote advantage
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4
Q
  • Haemochromatosis
    • Mechanism
      • What gene?
      • What kind of genetic change?
      • Protein result of that change?
      • How it affects the human body - clinical features?
    • Screening and diagnosis
      • Is it screened for at birth?
      • Or does it require specialist testing?
    • Management
      • Medication?
      • Lifestyle changes?
      • Exclusion diets?
      • Is there no treatment?
    • Quality of life and outlook
      • Are they able to function?
      • Impairment adjustments?
      • Life span?
      • Cures/treatments being trailed?
A
  • ​Overview
    • Most common form of iron overload disease
      • Is an inherited disorder that causes the body to absorb too much iron
    • Incidence is between 1:200 and 1:500 for populations of Northern European, caucasian descent
    • The genetic defect likely arose in a Celtic population in the early middle ages and may have provided a selective advantage to persons living under conditions in which iron deficiency was common and for whom the life expectancy was in the 40s
      • The allele frequency is as high as 1 in 9, or 11% of persons with this ancestry
  • Mechanism - chromosome affected and mutation
    • Mutations in the HFE gene (High iron)
    • Two most common mutations found in Europeans are missense mutations
      • Designated Cys282Tyr (Cysteine to Tyrosine) and His63Asp (Histidine to Aspartic acid)
    • The Cys282Tyr mutation, a single point mutation (Missense) that substitutes tyrosine for cysteine at position 282, accounts for most cases of hereditary haemochromatosis (HHC)
      • 85% of caucasians with clinically diagnosed hemochromatosis are homozygous for Cys282Tyr
      • Exact mechanism for development of hemochromatosis is unknown, but mutant HFE does not bind properly to transferrin receptor
      • Important for transcriptional regulation of Hepcidin - master iron regulator hormone in the body
  • Clinical Features
    • Excess iron builds up in organs and damages them
      • Without treatment, the disease can cause these organs to fail
    • Once in the body, iron becomes part of hemoglobin, the molecule in the blood that transports oxygen from the lungs to all body tissues
    • Healthy people will absorb only a proportion of the protein-associated iron contained in the food they eat
      • People with haemochromatosis absorb nearly all protein associated iron contained in the food they eat
      • The body has no natural way to remove excess iron
      • The extra iron is stored in body tissues, especially the liver, heart and pancreas
    • Joint pain is the most common complaint of people with haemochromatosis
    • Common symptoms include fatigue, arthritis, cirrhosis of liver, cardiomyopathy, diabetes, weakness, weight loss, loss of libido, abdominal pain, muscle tenderness, cramps in arms and legs, lack of energy, and heart problems
    • Symptoms tend to occur in men between the ages of 30 and 50 and in women over age of 50
      • Later onset in women due to monthly blood loss through menstruation
    • Many show few symptoms before irreversible organ damage commences
  • Screening and diagnosis
    • Iron content in blood (serum transferrin saturation)
    • Iron content in liver (serum ferritin)
  • Treatment
    • Regular phlebotomy (removing blood from a vein) to reduce the high levels of iron in the blood
    • Often results in an early death
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5
Q
  • Cystic fibrosis
    • Mechanism
      • What gene?
      • What kind of genetic change?
      • Protein result of that change?
      • How it affects the human body à Clinical features?
    • Screening and diagnosis
      • Is it screened for at birth?
      • Or does it require specialist testing?
    • Management
      • Medication?
      • Lifestyle changes?
      • Exclusion diets?
      • Is there no treatment?
    • Quality of life and outlook
      • Are they able to function?
      • Impairment adjustments?
      • Life span?
      • Cures/treatments being trailed?
A
  • Overview
    • Most common life threatening, recessive genetic condition affecting Australian children
    • Cystic fibrosis is caused by mutations in a transmembrane transporter gene, disrupting the function of chloride channels systemically
    • The CFTR (Cystic fibrosis transmembrane regulator) gene transplants into an ATP-binding cassette (ABC) transmembrane transporter (Cytogenic location - 7q31.2) that functions as a low conductance Cl- selective channel gated by ATP binding and hydrolysis
    • In Australia
      • 1 in 25 people are unknown carriers of a cystic fibrosis allele
      • 1 in 2,500 babies are born with cystic fibrosis
        • 1 every 4 days
    • Characterized by the build-up of thick, sticky mucus that can damage many of the body’s organs with most common signs and symptoms include progressive damage to the respiratory system and chronic digestive system problems
    • 80-95% of patients with cystic fibrosis will die of respiratory failure brought on by chronic bacterial infection and associated air inflammation
      • Main causative bacteria is pseudomonas aeruginosa
      • 50% of patients with cystic fibrosis live past the age of 41
  • Mechanism - chromosome affected and mutation
    • Mutation in the CFTR gene on chromosome 7 salt transporter channel
    • More than 2,000 mutations in the CFTR gene have been identified in people with cystic fibrosis
    • The most common mutation, called delta F508 (ΔF508; p.Phe508del), is a deletion of one amino acid at position 508 in the CFTR protein
    • Followed by W1282X (Trp1282*), G542X (Gly542*), G551D (Gly551Asp) and N1303K (Asn1303Lys)
    • ΔF508 is a 3 base pair deletion - p.Phe508del
      • About 60-70% of cystic fibrosis patients have the delta F508 mutation
      • ΔF508 is the single deletion of the amino acid phenylalanine present in the nucleotide binding domain of CFTR
      • Misshapen protein for Cl- selective channel gated by ATP binding and hydrolysis
  • Clinical features
    • Lungs
      • Mucus in the lungs is secreted to trap particles, bacteria, etc; ciliated cells move the mucus up towards the mouth
      • In cystic fibrosis the mucus is much thicker and not moved by the ciliated cells, but stays in the lungs
      • Results in persistent cough and recurrent lung infections
    • Pancreas
      • The pancreas secretes digestive enzymes into the intestine through a gland
      • In cystic fibrosis the gland becomes clogged which causes the formation of a cysts and eventually becomes fibrous - thus the name cystic fibrosis of the pancreas
    • Intestine
      • In cystic fibrosis the intestine does not receive enough digestive enzymes for fats resulting in undernourishment and excess fats in the stool (steatorrhea)
    • Reproductive ducts
      • In cystic fibrosis the vas deferens in males becomes blocked leading to sterility
    • Sweat glands
      • Sweat glands secrete salt in order to induce the flow of water to the surface of the skin for the purpose of cooling; much of the salt is taken back up by the body
      • In cystic fibrosis, salt is not taken back up, leaving a salt residue on the skin and a salt deficit in the body
    • Molecular consequences of CFTR mutations
      • 1,480 amino acid long CFTR protein
  • Screening and diagnosis
    • Screening tests are generally used for a general population
      • Guthrie card/assign a risk of a particular diagnosis
      • Ultrasound
    • Diagnostic tests are confirmatory and are done at the individual level
      • CVS, amniocentesis, buccal swab for sequencing
    • Screen newborns via blood sample, which is checked for higher than normal levels or an immunoreactive trypsinogen (IRT) released by the pancreas
    • If the child is negative then continues to show symptoms of cystic fibrosis, secondary confirmatory tests will be carried out
    • Each state has different protocols for cystic fibrosis diagnosis
  • Treatment
    • Medications
      • Antibiotics to treat and prevent lung infections
      • Mucus-thinning drugs to help the patient cough up the mucus, which improves lung function
      • Bronchodilators to help keep the airway open by relaxing the muscles around the bronchial tubes
      • Oral pancreatic enzyme to help the digestive tract to absorb nutrients
    • Daily physiotherapy to reduce load of mucus in lungs
    • Pulmonary rehabilitation
    • Organ transplant
    • Daily routine can include one or two nebulisers every morning and every night with physiotherapy sessions in between, up to 40 tablets a day
      • Nutrition is very important due to the mucus which can interfere with nutrient absorption
    • Psychological counselling is recommended in most countries
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GH (4 decks)

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