Neonatal screening Flashcards by Danielle Hayes

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.

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

WHy do you need hearing screening programs?

cuz genetic tests cannot detect his and 1 to 3 of every 1000 babies have hearing loss

How well did you know this?

Not at all

Perfectly

What are the specimens and tests you want to do on newborns?

blood test, urine, feces

Protein analysis, DNA studies

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

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)

How well did you know this?

Not at all

Perfectly

What are tertiary level tests?

Specific “in tissue” enzyme analysis (Biopsy)

Liver
Skin fibroblasts
Leucocytes
Erythrocytes
Muscle

Molecular (DNA, Protein) diagnostics if available

How well did you know this?

Not at all

Perfectly

How do you use mass spectrometry?

protein extraction, place on gel (use electrophoresis), gel digests protein-> liquid chromo-> electro spray-> Mass spectrometry

How well did you know this?

Not at all

Perfectly

What are the principles of mass spectrometry?

sample-> ionization and adsorption-> fragmentation->mass analysis-> detection

How well did you know this?

Not at all

Perfectly

(blank) are proteins which perform chemical functions

(blank) are proteins that make up the physical structure of the organism

active proteins

structural proteins

How well did you know this?

Not at all

Perfectly

Why do you want to sequence DNA and how do you want to do this?

to find single/ multiple nucleotide mutations

Use dried blood

How well did you know this?

Not at all

Perfectly

Do you want to use fresh blood samples for mapping mutations?

yes you do, but not very good for newborns

How well did you know this?

Not at all

Perfectly

How do you use fresh blood to map mutations?

fresh blood-> WBC cultures-> karyotype -> apply DNA probes for DNA target-> map mutations

How well did you know this?

Not at all

Perfectly

(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

How well did you know this?

Not at all

Perfectly

(blank) is a a single phenotypic trait whose expression is controlled/affected by the action of more than one gene locus.

polygenic trait

How well did you know this?

Not at all

Perfectly

If a mutation is at the end of a gene then it is a (blank) mutation

neutral

How well did you know this?

Not at all

Perfectly

What is a null mutation?

a very dangerous mutation that is in an exon or promotor and results in a non-functional enzyme

How well did you know this?

Not at all

Perfectly

A (blank) mutation reduces but does not destroy phenotypic expression of wild type

leaky

How well did you know this?

Not at all

Perfectly

A (blank) mutation is a change in base sequence that does not alter wild type enzyme function.

silent

How well did you know this?

Not at all

Perfectly

If one gene is mutated, what kind of effect on the body will it have?

a cascade effect HORIZONTALLY!!!! (not vertically)

How well did you know this?

Not at all

Perfectly

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

How well did you know this?

Not at all

Perfectly

(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.

How well did you know this?

Not at all

Perfectly

What does CFTR protein do?

a channel protein that controls flow of H20 and Cl ions.

How well did you know this?

Not at all

Perfectly

How come you have varying severities of CF?

several different mutations can take place on CFTR causing differing defects

How well did you know this?

Not at all

Perfectly

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

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