Biochemistry 7 Flashcards
Diagnosing a genetic disorder is important, but it is not
cost effective to test everyone for every type of
disorder. So, other indicators are used to determine if a genetic test is in order. These are referred to as
genetic screens.
Genetic screening
- Newborn Screening
- Heterozygote screning
Genetic screening was defined by the National Academy of Sciences (1975):
“The search in a population for persons possessing certain genotypes that (1) are already associated with
disease or predisposition to disease, or (2) may lead to disease in their descendants”.
Newborn screening
searching for a mutation that
can cause the disease in the person carrying the gene.
Heterozygote screening
searching for a mutation that
can cause the disease in the descendants of the
carrier.
Newborn screening
Presymptomatic detection and prevention of the symptoms of the genetic disease in the person carrying the mutated gene (the newborn). All states in the U.S. currently require newborn screening for at least 29 health conditions (US Department of Health and
Human Services).
The diseases tested for are those for which
early intervention is both available and critical to prevent serious health risk
In Arizona, newborn screening includes
36 genetic or congenital disorders. Initial screening done at birth, second screening done two weeks later at health care providers office. Parents may choose to refuse testing in AZ.
PKU (Phenylketonuria)
-Autosomal recessive mutation of the phenylalanine
hydroxylase (PAH) gene
-Both phenylalanine and phenylpyruvic acid
(phenylketones) accumulate in blood.
-Excess phenylalanaine also appear in the urine (phenylkeoturia)
-Symptoms: Intellectual disabilities, seizures, tremors,
hyperactivity, stunted growth
-Primary treatment: restriction of dietary phenylalanine
Amount of phenylalanine is the
danger
In PKU there is
lower levels of tyrosine, melanin, and adrenaline - messes with our brain functioning
buildup of phenylpyruvic acid can enter the brain because they cross the blood brain barrier
High levels of phenylalanine and phenylketones may be directly
toxic to the brain
The excess of phenylalanine may also saturate the
Large neutral amino acid transporter which is located at the BBB. This leads to an excess of phenylalanine in the brain and prevents other large neutral amino
acids from entering normally (tryptophan, tyrosine).
Failure to produce adequate dopamine and
adrenaline (also known as epinephrine) because of a
Lack of tyrosine. If untreated, irreversible intellectual disability can be seen by 1 month of age. By the time symptoms are detected, significant neurological damage has usually already occurred. With early detection and treatment, the damage can be avoided
PKU patients need some
phenylalanine
Phenylketonuria (PKU) primary treatment
restriction of dietary phenylalanine
If a low-phenylalanine diet is begun soon after birth (within a few weeks), virtually…
all symptoms can be prevented, this is why we screen!
Phenylalanine is an essential amino acid, and a complete lack of phenylalanine is
Fatal. It is normal to have low levels of phenylalanine in the blood. It is normal to have low levels of phenylalanine in the blood. It is harmful to have higher levels of phenylalanine, which is what the dietary restriction prevents in those with PKU.
Enzyme therapy of PKU
- Replacement of the missing enzyme
- Approved in 2018 for use in adults with poorly controlled PKU
- Palynziq
- Lots of side effects!
Maternal Phenylketonuria (PKU)
-Preparing and consuming a low phenylalanine diet is burdensome
-Most women with PKU at childbearing age do not follow the diet as closely as when they were younger
-Although the mother herself may not be as strongly affected at this age (problems can still develop), high
levels of phenylalanine in the mother’s blood will be catastrophic for the fetus.
-Phenylalanine can diffuse across the placenta, causing brain damage to the fetus, EVEN if the fetus is
heterozygous and would not normally manifest PKU.
-Women with PKU who are planning to have children need to be on a low-phenylalanine diet before
conception and throughout pregnancy.
Q: Assuming the father is homozygous normal, what is the genotype of an infant who exhibits maternal PKU?
Heterozygous (Tt) normal (silent carrier)
Detection of unaffected carriers of gene mutations (heterozygous individuals) and prevention of the genetic
disease in offspring.
Couples at risk of being carriers of a genetic disease can be screened by blood testing and informed of
options to prevent producing an affected child.
Typically, heterozygote screening is applied to recessive disorders since these disorders involve carrier
individuals.
A population at risk must be identified before applying the screening methods. (Everyone doesn’t
need to be screened for everything.)
Infantile Tay-Sachs
autosomal recessive, lysosomal storage disorder that produces neuronal damage and death by the age 5.
Preimplantation genetic diagnosis (PGD)
available for couples at significant risk (both people are carriers) have an affected child (For example, heterozygote frequency is 10X greater in Ashkenazi Jewish community compared to general
population.)
After in vitro fertilization (IVF), a single cell is
removed from the 8 cell (or sometimes 16 cell) blastomere
Polymerase Chain Reaction (PCR)
is used to amplify DNA obtained from the single cell
After testing, embryos free of mutation can be
implanted
Since the beginning of the Tay-Sachs Screening Program of North America, the number of cases has decreased by
90%
PGD has been used to prevent
Genetic disorders as well as for sex selection. The policies for
application of this technology vary by country and change frequently.
Prenatal screening =
techniques conducted before birth to screen for a genetic or chromosomal disease.
Invasive techniques
analysis of fetal tissue
Fetal tissue testing examples
-Amniocentesis
-Chorionic villus sampling
-Cordocentesis (umbilical cord sapling)
-Preimplantation genetic diagnosis (PGD)
Non-invasive techniques
blood tests (maternal) or fetal visualization
Blood tests
-Maternal serum screening
-Cell free fetal DNA testing (becoming very common)
-Ultrasonography
-MRI when more accurate imaging is needed
Chorionic Villus Sampling (CVS)
-10-12 weeks
-Sample collected is fetal trophoblastic tissue (before amniocentesis)
-Tests: Cytogenetic analysis, DNA based testing
-Condition reflected: Chromosomal abnormalities (including trisomies), and genotype status for disease
alleles
-Risk: fetal loss is 1%
-ADVANTAGE: earlier
Timing of prenatal screening
Fetal ages given for prenatal screening are “gestational age” (the number of weeks since the start of the last menstrual period: LMP)
Amniocentesis
-Optimal time: 15-20 weeks
-Sample collected: amniotic fluid _ amniocytes
-Tests: Cytogenetic analysis, DNA based testing, fetal -fetoprotein (AFP)
-Condition reflected: Chromosomal abnormalities (including trisomies), genotype status for disease alleles, and neural tube disorders
High AFP levels
indicate significant risk of neural tube disorders
Low AFP levels
indicate significant risk of trisomies (Down Syndrome)
Risk of amniocentesis
fetal loss is 0.5%
Ultrasonography (ultrasound) is based on the
Based reflection of pulsed sound waves of fetal tissue, in patterns correspond to tissue density. It allows real time visualization of the fetus. Standard (2D) ultrasounds can be performed as ell as more advanced ultrasound (3D, 4D, doppler)
Ultrasound looks for
It is a screening procedure for structural abnormalities, such as neural tube defects or congenital malformations, and structural anomalies associated with certain genetic disorders.
Ultrasound optimal time
16-18 weeks gestation (this test is routinely done during
most pregnancies)
Is there a risk with ultrasound?
no
Maternal serum screening and Nuchal translucency (NT) optimal time and sample tested
11-14 weeks gestation
Maternal serum + ultrasound
What is the test for for maternal serum screening and nuchal translucency (NT)
Increased nuchal translucency on ultrasound measures the
thickness of fluid buildup at the back of the neck: suggests a
higher risk of chromosomal anomalies (e.g., Down syndrome, trisomy 18) or congenital heart disease.
