Neonatal screening Flashcards
While traditional newborn screening was only concerned with a few inborn errors that led to mental retardation, programs now include disorders that can cause what four things?
premature death, infectious diseases, hearing disorders and even heart problems.
Currently the DNA research and Human Genome project are used as secondary confirmation of newborn screening conditions but one day we want them to work how?
as routine primary screening tools
WHy do you need hearing screening programs?
cuz genetic tests cannot detect his and 1 to 3 of every 1000 babies have hearing loss
What are the specimens and tests you want to do on newborns?
blood test, urine, feces
Protein analysis, DNA studies
After you do your routine blood and urine tests on the newborns, what else do you have to do?
secondary level metabolic screening
paristological test (toxoplasmosis)
diagnostic confirmation via tertiary biochemical or molecular genetic testing
What are the 2nd level tests?
urine metabolic screening (battery qualitiative test)
urine organic acid analysis (gas chromo mass spectrometetry)
plasma AAs analysis (mass spec)
DNA tests (for structure and integrity of genes)
What are tertiary level tests?
Specific “in tissue” enzyme analysis (Biopsy)
Liver Skin fibroblasts Leucocytes Erythrocytes Muscle
Molecular (DNA, Protein) diagnostics if available
How do you use mass spectrometry?
protein extraction, place on gel (use electrophoresis), gel digests protein-> liquid chromo-> electro spray-> Mass spectrometry
What are the principles of mass spectrometry?
sample-> ionization and adsorption-> fragmentation->mass analysis-> detection
(blank) are proteins which perform chemical functions
(blank) are proteins that make up the physical structure of the organism
active proteins
structural proteins
Why do you want to sequence DNA and how do you want to do this?
to find single/ multiple nucleotide mutations
Use dried blood
Do you want to use fresh blood samples for mapping mutations?
yes you do, but not very good for newborns
How do you use fresh blood to map mutations?
fresh blood-> WBC cultures-> karyotype -> apply DNA probes for DNA target-> map mutations
(blank) is a single phenotypic trait whose expression is controlled by the action of a single gene locus. It can be autosomal or “X”- or “Y”- linked, it can also be dominant or recessive.
monogenic trait
(blank) is a a single phenotypic trait whose expression is controlled/affected by the action of more than one gene locus.
polygenic trait
If a mutation is at the end of a gene then it is a (blank) mutation
neutral
What is a null mutation?
a very dangerous mutation that is in an exon or promotor and results in a non-functional enzyme
A (blank) mutation reduces but does not destroy phenotypic expression of wild type
leaky
A (blank) mutation is a change in base sequence that does not alter wild type enzyme function.
silent
If one gene is mutated, what kind of effect on the body will it have?
a cascade effect HORIZONTALLY!!!! (not vertically)
How do you manage a pathologic enzyme in metabolism?
you treat symptoms try to fix messed up enzyme (replacement, stabilization, gene transfer) limit the upstream reactants activate alternate pathways supplement the product
(blanK) results from an altered synthesis of a protein (CFTR) involved in the transport of chloride ions. The major clinical consequences abnormally thickened mucous secretions in the lungs and digestive systems.
CF
What does CFTR protein do?
a channel protein that controls flow of H20 and Cl ions.
How come you have varying severities of CF?
several different mutations can take place on CFTR causing differing defects
What are the different kinds of CFTR mutations?
Major-> protein doesnt fold properly (F508)
truncated proteins
proteins that dont utilize energy properly so degrade quickly
The most abnormal hemoglobin conditions are sickle cell anemia and (blank)
sickle beta thalassemia.
In sickle cell anemia and Beta thalassemia, how will newborns look>
look normal at birth but anemia develops w/in first few months followed by increased susceptibility to infection, slow growth rates, and life threatening splenic sequestration
SCD is dominant or recessive?
recessive
on the genetic level, why do you get sickle cell disease?
glutamine (hydrophilic and polar) is replaced by valine (hydrophobic and nonpolar) which makes hemoglobin less water soluble and can crystalilize under acidic conditions
(eventually fatal disease due to anemia and organ damage)
What kind of hemoglobin is found in individuals with SCD?
hemoglobin S (HBB gene mutation resulting in abnormal version of beta globin)
Besides HBB gene mutations creating hemoglobin s, what else can happen?
low levels of beta globin production resulting in beta thalassemia
How do you get congenital hypothyroidism?
What are the effects of this if untreated?
How can you prevent this adverse effect?
dont produce enough TH
mental retardation and stunted growth
Catch the disorder before 3 weeks of age and treat
How do you get thyroid hormone?
take an iodine off of T4
(blank) results from a deficiency in the enzyme need to metabolize galactose.
galactosemia
What is the guthrie test?
THe iit is the heal stick blood test on newborns to test for metabolic diseases
Protein function depends largely on the amino acids of which it is composed, and their precise (blank) .
order
Most phenotypic traits are produced by the interaction of what?
more than one gene and environment
What is this:
the sum of chemical processes through which food is converted into protoplasm and protoplasm is converted into smaller molecules and energy.
metabolism
What is deleted in many patients with CF?
F508 (phenylalanine)
HBB gene mutations can also result in an unusually low level of beta-globin; this abnormality is called (blank)
beta thalassemia.
Congenital hypothyroidism can occur through gene mutation in 2 ways, what are they?
1) mutation in PAX8 and TSHR gene->destroys thyroid gland BEFORE birth.
2) mutation in DUOX2, SLC5A5, TG, TPO and TSHB -> prevent or reduce production of TH even though thyroid gland is there.
Is CH a dominant or recessive disorder?
recessive
What does this do:
Critical role in the formation of tissues and organs during embryonic development
PAX 8
What does this do:
Provides instructrions for making a receptor that serves as a customized binding site for a hormone called TSH.
TSHR
What does this do:
provides instructions for making a protein called sodium idodide importer or NIS
SLC5A5
What does this do:
Combines with iodine and is modified and broken down to release small molecules known as thyroid homrone
TG
What does this do:
Assists the chemical reaction that adds iodine to a protein called thyrogloblin, a critical step in generating thryoid hormones.
TPO
What does this do:
provides instructions for making a protein subunit of a hormone called TSH
TSHB
There are three deiodinases found in the human, what are they are where are they found?
type 1-> liver and kidney
type 2 -> skeletal muscle and in the heart, fat, thyroid, and CNS
Type 3-> fetal tissue and placenta
if someone has hypothyroidism how should you give them thryoid hormone and why?
you should give them T3 and T4 because different tissues convert T4 to T3 at different rates
What is this:
Newborns typically appear normal, however, within a few days to two weeks after initiating milk feeding-> vomiting, diarrhea, lethargy, jaundice and liver damage develops.
galactasemia
If untreated, what might galactosemia result in?
Build up of galactose resulting in retardation, hepatomegaly, growth failure, cataracts, death
What enzyme is missing in galactosemia?
uridyl transferase
Is galactosemia a dominant or recessive disorder?
recessive
What is this:
enzyme deficiency that blocks the metabolism of homocysteine to cystathionine
homocystinria
What are the major clinical features of homocystinuria?
optical dislocation (80% of pnts by 15 years age)
mental retardation
osteoporosis
thromboembolism (causes death in 50% pnts by age 20, 75% by age 30)
What is the enzyme that is deficient in homocystinuria?
CBS enzyme
When you have homocystinuria, what will you have a build up of, and what will you have decreased amounts of?
build up of Met and Homocysteine
decrease amounts of cysteine
What is this:
is a disorder due to a deficiency of the branched-chain ketoacid dehydrogenase enzyme-> impaired metabolism of branched-chain amino acids (Leu, Iso-Leu, Val).
Maple syrup disease
What does maple syrup disease result in accumulation of?
iso-caproic or iso-valerianic acids
How do newborns with MSUD appear?
normal within first weeks of life but then present with lethargy, FTT
If MSUD goes untreated, what will happen?
neuro problems, acidosis, seizures, sudden apnea that can lead to coma and death
Can infants avoid having such adverse effects from MSUD?
yes if they avoid certain foods and use supplements
(blank) is the inability to breakdown the AA, phenylalanine which is found in the protein of foods.
PKU
At first, infants with PKU appear normal, but if left untreated can result in what?
mental and motor retardation, microcephaly, poor growth rate, and seizures
Where is the mutation for PKU located?
both alleles on chromosome 12 for PAH (phenylalanine hydroxylase)
What does phenylalanine hydroxylase do?
converts phenylalanine to tyrosine
What is a phenotypically mild form of PKU?
hyper-pheynyl-alanemia
What is biotinidase defiicnecy and what does it cause?
inability to liberate biotin from a bound form so that it can be used. It results in inability to breakdown fats, proteins and carbs properly.
What can biotinidase deficiency lead to?
seizures, developmental delay, eczema, and hearing loss
What are the symptoms that you might notice on infants with BTD?
hypotonia, ataxia, seizures, developmental delay, hair loss, seborhheic dermatitis, hearing loss, optic nerve atrophy. Metabolic acidosis leading to come and death
How do you treat BTD?
with biotin supplement
In BTD, Profound deficiency results when the activity < (blank percent)
Partial deficiency occurs when biotinidase activity is (blank percent)
10%
10-30%
(blank) is a rare hereditary disease that results from the lack of an enzyme required to convert fat to energy.
Medium chain acyl-coa dehydrogenase deficiency (MCAD)
When does MCAD start being a problem?
during starvation or long fasting cuz they are attempting to use their stored fats for energy
(blank) causes no apparent symptoms at birth, but low blood sugar, seizures, brain damage, cardiac arrest and serious illness can occur very quickly in infants who are not feeding well. Treatment for the disorder requires close monitoring of the infant to determine “safe” time periods between meals, and adhering to a strict feeding schedule.
MCAD
What genetically causes medium chain acyl-coa dehydrogenase deficiency?
a lysine being replaced by a glutamic acid on position 304 of the ACADM gene
What enzyme does MCAD make deficient?
succinyl-coa dehydrogenase
Explain how you end up with carnitine esters in your urine with MCAD
Since succinyl coa dehydrogenase isnt working you will get build up of organic acids which will combine with carnitine and yield carnitine esters in your urine
How do you test for MCAD?
plasma acyl-carnitines, urine organic acids and urine acyl-glycinei
What will these measurements do:
determination of FA oxidation in fibroblasts
measurement of MCAD enzyme activityin fibroblasts or other tissues
Genetic testing of ACADM gene
confirm diagnosis of MCAD
What are included in the newborn screening but should be?
marfan syndrome (only dominant disorder) intrauterine growth restriction (IUGR)
(blank) is a genetic disorder caused by the misfolding of the protein fibrillin-1 coded by the gene FBN1
marfan syndrome
What are the most serious complications of marfan syndrome?
heart valve and aorta problems
can effect lungs, eyes, dural sac around spinal cord, skeleton and hard palate
What can drigger a cardiac problem with an individual who has marfans?
pregnancy
What is known as a connective tissue disorder?
marfans
What all does fibrillin 1 protein do?
forms fibers in CT (structural support)
cell signaling via binding to growth factor (TGFB)
Since marfans syndrome results in a crazy fibrillin 1 protein that is binding all over the place to the TGFB growth factor, what will this result in?
deleterious effects on vascular smooth muscle developmet and integrity of ECM and the features of marfans syndrome
How can you treat marfans syndrome?
give Angiontensin II antagonists (ARBs)
What are the 2 major categories of IUGR?
symmetrical and asymmetrical
(blank) is the more common IUGR and resuts in restriction of weight and then length. The head grows normally and a lack of fat results in thin and small body out of proportion with the head.
asymmetrical IUGR
What can cause Asymmetrical IUGR?
extrinisic factors that affect fetus at late gestational stage:
chronic high BP, malnutrition, genetic mutaitons
What does this describe?
Other symptoms than the disproportion include dry, peeling skin and an overly-thin umbilical cord. The baby is at increased risk of hypoxia and hypoglycemia. This
Asymmetrical IUGR
WHat does this describe:
slow gestational development
normal head/body proportion
permanent neuro damage
symmetrical IUGR
What causes symmetrical IUGR?
early intrauterine infections (cytomegalovirus, rubella, toxoplasmosis, chromosomal abnormalities, anemia IUGR (3-10% of pregnancies)
Intrauterine growth restrictions trigger (blank) in the fetus that are otherwise activated in times of chronic food shortage. If offspring develops in environment rich in food, it may be more prone to metabolic disorders such as obesity and type II diabetes.
epigenetic responses
In utero, fetuses can deal with their deficiencies no problem, why is this?
because they get the normal enzyme from their mom so no problem until after birth
It was realized that if kids ate appropriate diets for their deficiencies up to a certain age, they would be able to eat whatever foods they wanted after that point because their body will have adapted. What age is this?
age 6 (before age 6 it is called the sensitive period)
What happens if mom is homo recessive for a disease?
then the baby will be subjected to toxins regardless of the babies disease state, but if mom eats appropriate diet and undergoes appropriate treatment it can be fine
