Autosomal Recessive Disorders Flashcards
What are the common characteristics of autosomal recessive disorders?
Phenotype expressed only in people who have two mutant alleles of the same gene.Both parents of an affected child are obligated carriers of the disease-causing allele(s).Men and women are usually equally affected.Horizontal pedigree (affected individuals are usually siblings).Carriers are usually undetected, thus the birth of the first affected child is usually unexpected. The recurrence risk is 1 in 4 (25%) for each unborn child of the same couple.The probability of an unaffected sibling being a carrier is 2/3. The majority of mutant allele(s) are present in carriers instead of patients.Often a predisposition for certain ethnic group (high-risk group).Increased incidence of parental consanguinity for a child affected by a rare AR disorder.
Do you know how to use Hardy Weinberg yet?
Please do!
What does allelic heterogeneity mean?Compound heterozygote?Parental consanguinity?High risk group?
Allelic heterogeneity - the existence of multiple alleles of a single gene.Compound heterozygote - one who carries different mutant alleles at the same genetic locus.Parental consanguinity - parents sharing one or more common ancestors.High-risk group - the ethnic group in which an AR disease occurs with higher frequency.
What are the biochemical deficiencies in PKU patients and the appropriate treatments?
PKU is an inborn defect of phenylalanine metabolism. Most PKU cases are caused by defects in the PAH gene encoding phenylalanine hydroxylase (98% of the time), a liver enzyme that catalyzes the conversion of Phe to Tyr using molecular oxygen and a cofactor tetrahydrobiopterin (BH4). 1-2% of times, the enzyme is normal but BH4 is missing.When treated early with low-phenylalanine diet, the mental retardation can be prevented. Phenylalanine is an essential amino acid and thus cannot be eliminated from the diet. Low- phenylalanine diet should be maintained throughout childhood and school years, and preferably the patient’s whole life. BH4-deficient PKU patients are to be treated with oral BH4, low-phenylalanine diet, and supplements (L-dopa and 5-hydroxytryptophan etc) to balance neurotransmitter levels.
What is maternal PKU? What is its treatment?
It is important to maintain PKU women on a low-phenylalanine diet throughout their child- bearing years. PKU mothers who are not on a low-phenylalanine diet have a markedly increased risk of miscarriage and giving birth to children with congenital malformations, mental retardation, and growth impairment, irrespective of the genotypes of the children.These defects are caused by elevated phenylalaine levels in the maternal circulation during fetal development and thus termed maternal PKU.
What are the 2 newborn screening processes for PKU?
Guthrie test: This test is based on the findings that thienylalanine inhibits the growth of the bacterium Bacillus subtilis and that such inhibition can be overcome by a high level of phenylalanine in the blood sample of a PKU baby (old)Mass Spectrometry is the current method of choice for many newborn screenings including PKU. A mass spectrometer simultaneously sorts many molecules in a blood specimen by weight (mass) and size, and also measures the quantity of each molecule.
What are the clinical features of α1-antitrypsin deficiency and the influence of environmental factors on the expression and severity of the disease (ecogenetics)?
ATD patients have a 20-fold increased risk of developing emphysema, with more severe symptoms among smokers. This disorder is late-onset, especially in non-smokers, but 80- 90% of deficient individuals will eventually develop disease symptoms. Many patients also develop liver cirrhosis and have increased risk of liver carcinoma due to the accumulation of a misfolded !1-AT mutant protein in the liver.Smoking accelerates the onset of emphysema in ATD patients. Tobacco smoke damages the lung, prompting the body to send more neutrophils to the lung for protection. More neutrophils release more elastase, causing more severe lung damage.
Which enzyme is the primary target of α1-antitrypsin?
Elastase, which is released by neutrophils in the lung. When left unchecked, elastase can destroy the connective tissue proteins (particularly elastin) of the lung, causing alveolar wall damage and emphysema.
What are the two most common mutant alleles that cause ATD and the severity of different allelic combinations?Why do some ATD patients have liver failure?
Individuals with Z/Z genotype have only 10-15% of normal alpha1-AT activity and account for most cases of the disease. Individuals with S/S genotype have 50-60% of normal alpha1-AT activity and usually do not express disease symptoms. Z/S compound heterozygotes have 30-35 % of normal alpha1-AT activity and may develop emphysema.The Alpha1-AT gene is on chromosome 14. There are ~20 different mutant alleles, although the Z & S alleles account for most of the disease cases. The Z allele (Glu342Lys) expresses a misfolded protein that aggregates in the endoplasmic reticulum (ER) of liver cells, causing damage to the liver in addition to the lung. The S allele (Glu264Val) expresses an unstable protein that is less effective.
Why is the timing of the PKU test important?
Timing of Test The sensitivity of PKU screening is influenced by the age of the newborn when the blood sample is obtained. Phenylalanine level is typically normal in PKU babies at birth because of normal PAH in maternal supply and increases progressively with the initiation of protein feedings during the first days of life.Early detection and treatment is crucial to prevent irreversible damage to the developing brain. However, if tested too early (within 1-2 days of birth), some affected children can be missed.Newborns are tested first after birth and then again at their first pediatrician’s visit days later.
What are biochemical defects in Tay-Sachs disease and why is the brain the major target?
T-S is a lysosomal storage disease. Inability to degrade GM2 ganglioside results in up to 300-fold accumulation of this sphingolipid inside swollen lysosomes in neurons of the central nervous system.A defective hexosaminidase A (HexA) needed for in metabolizing GM2 is responsible for T-S.HexA is a heterodimer of AlphaBeta, which are encoded by the HEXA and HEXB genes, respectively. Although HexA is a ubiquitous enzyme, the impact of T-S is primarily in the brain where most of GM2 ganglioside is synthesized.
What is the highest risk group for Tay-Sachs disease?
The Ashkenazic Jewish population is at 100-fold higher risk for T-S (~1/3,600) than the general population (~1/360,000).Other high-risk groups for T-S are certain French- Canadian communities of Quebec, the Old Order Amish community in Pennsylvania, and the Cajun population of Louisiana.
What are the different screening methods for Tay-Sachs disease (4)?
Enzymatic activity assay: both HexA and HexB enzymes are present in the serum. Their activities can be distinguished in such assays because only HexA is inactivated by heat.Carrier Screening: primarily among Ashkenazi Jewish population, the enzyme test has 97% accuracy because carriers have lower HexA enzyme levels in the blood.Prenatal screening: the enzyme test can also be performed on cultured amniotic fluid cells to detect T-S fetus when both parents are known to be carriers. Notably, this screening has reduced the number of T-S cases by about 95% over the past 30 years.DNA testing: The tests currently available can detect about 95% of carriers in the Ashkenazi Jewish population and about 60% of carriers among non-Jewish individuals. Therefore, some carriers will be missed by DNA test alone.
Describe the layout of the alpha and beta-globin gene clusters on hemoglobin.
All the alpha like genes are located in the same cluster on the same chromosome (16). Same situation for Beta on a different chromosome (11).The hemoglobin composition changes throughout development.Alpha is expressed on two chromosomes. Alpha must always equal beta + gamma.
Describe the switch between different forms of hemoglobin (Hb) during development.
Adults make the change from HbA2 to HbA as development occurs (beta subunit replaces gamma in most cases). There are many early embryonic forms of hemoglobin made in the yolk sac. Switching occurs because the lung has a higher oxygen environment so the high binding affinity of HbF is no longer necessary.
