Newborn Screening Flashcards
What were the major breakthroughs in the 1960s w/ newborn screening?
PKU screening test
large scale genetic screen thru filter paper blood samples
What federal program supports newborn screening?
Maternal and Child Health Bureau of Health Resources and Services Administration
States routine screen for ____ metabolic & genetic diseases?
30
Which factors are considered when each state decides which disorders to screen for?
prevalence detectability treatment availability outcome overall cost effectiveness
Originally, screening was interested in causes of _______. But now, that scope has widened.
causes of mental retardation
What are the main screening programs in the U.S.?
US newborn screening program
US genetics program
Hearing screening
Regional Programs
Which institution creates the rules for genetic & non-genetic screening?
National Newborn Screening & Global Resource Center
What are some technological goals for the future of newborn screenings?
improving: sensitivity, specificity, scope
* *allowing genotyping as routine primary screen instead of secondary confirmation
Why is hearing screening important for newborns?
1-3/1000 babies has some degree of hearing loss
without newborn screening difficult to detect hearing loss in the first months of the baby’s life. This can detect in first few days & allow for early treatment.
With a lab evaluation of a newborn, which tests are performed? Which specimens are taken?
Specimens: blood, feces, urine
Tests: protein analysis, DNA studies
What is the Guthrie test?
it takes a sample of blood from the baby’s heel & helps doctors diagnose inborn errors of metabolism.
What is the progression of testing–from screening to diagnostic?
- Routine Blood & Urine Tests
- Parasitological Tests (toxoplasmosis)
- Second level metabolic screening
- Tertiary biochemical or molecular genetic testing for diagnostic confirmation.
What are some second level tests?
Urine metabolic screen
Urine Organic Acid Analysis
Plasma Amino Acid Analysis
DNA tests
What does the urine organic acid analysis use?
gas chromatography-mass spectrometry
What does the plasma amino acid analysis use?
mass spectrometry
What are some of the tertiary studies?
These are diagnostic.
Molecular Diagnostics or
Biopsy (w/ enzyme analysis) of the tissue in question (liver, skin, muscle etc)
How do you prepare a sample for mass spectrometry?
Blood from baby’s heel Extract the proteins from the blood. Use electrophoresis to separate the proteins based on size? Enzymatic digestions of proteins. Liquid chromatography
How does mass spectrometry work with tests?
Sample Inlet Ionization & Adsorption of excess energy Fragmentation (dissociation) Mass Analysis Detection Ex: see a lot of phenylalanine. Think: PKU.
What is the difference b/w active proteins & structural proteins?
Active: perform chemical functions
Structural: make up the physical structure of the organism.
How do you prepare a sample for sequencing & genomic analysis?
dried blood sample
DNA extraction & purification
sequencing & genomic analysis
**check for single or multiple nucleotide mutations
How do you prepare a sample for mapping mutations?
fresh blood samples
white blood cell cultures
karyotype
DNA probes for different gene targets Ex: FISH
What is a monogenic trait?
a phenotypic trait that is controlled by only one gene.
What is a polygenic trait?
a phenotypic trait that is controlled by multiple gene loci.
What does a silent mutation do to enzyme function?
this is something that does not alter the wild type enzyme function.
What is the result of a null mutation on enzyme function?
this creates a completely non-functional version of the wild type enzyme
What does a leaky mutation do to enzyme function?
it reduces, but doesn’t destroy expression of the wild type enzyme
T/F Mutation in one gene can have a cascade effect.
True. As seen in PKU.
What is an inborn error of metabolism?
inherited deficiency of a key step in a critical metabolic pathway
If A–>B–>C & the enzyme that allows B–>C is defective….what are the treatment options?
symptomatic therapy give more C limit intake of A & B activate alternative metabolic pathways help the enzymatic activity (stabilization, gene transfer etc.)
What is the inheritance pattern of cystic fibrosis?
autosomal recessive
What causes CF? What is this disease characterized by?
CF: altered synthesis of CFTR: a channel protein in the lungs.
abnormally thick mucus secretions in the lungs & digestive system.
What does the CFTR channel in the lungs do?
allow H20 & Cl- to flow freely in & out of the cells.
What is the most common mutation that causes CF?
ΔF508-CFTR
occurs in more than 90% of patients
What is the inheritance pattern of sickle cell disease?
autosomal recessive
What’s the deal with sickle cell disease?
inherited abnormalities in the function of hemoglobin
RBCs sickle as a result: become crescent-shaped, sticky, hard, can’t move smoothly through the body.
What are the 2 main types of sickle cell disease?
sickle cell anemia
sickle beta thalassemia
What is the base substitution that causes sickle cell disease frequently?
valine is placed in instead of glutamate. Hemoglobin is less hydrophilic as a result.
What is the fraction of African Americans who are carriers for sickle cell disease?
1/12
Describe the structure of hemoglobin.
4 protein subunits
2 alpha subunits
2 beta subunits (HBB gene encoded)
What is the result of mutations in the HBB gene?
one HBB gene mutation = HbS
others produce HbE & HbC
**some produce such low levels of beta hemoglobin that beta thalassemia results.
What is congenital hypothyroidism?
congenital inability to produce sufficient thyroid hormone
When do you start to see the results of congenital hypothyroidism in a child? When should you catch it? What can happen if you don’t catch it?
3 months–start to see effects
should catch w/i 3 weeks
can cause mental retardation & stunted growth
**should be put on thyroid hormone medication
What are the congenital hypothyroidism mutations that disrupt the formation of the thyroid gland?
PAX8
TSHR
What are the congenital hypothyroidism mutations that disrupt the production of thyroid hormones even if the gland is present?
DUOX2, SLC5A5, TG, TPO, and TSHB
What is the PAX8 gene responsible for?
has a role in formation of tissues during embryonic development
What is the TSHR gene responsible for?
provides instructions for making receptors of thyroid stimulating hormone.
What is the SLC5A5 gene responsible for?
provides instructions for making NIS: sodium iodide transporter
What is the TG gene responsible for?
instructions for making thyroglobulin. This combines with iodine.
releases thyroid hormones
What is the TPO gene responsible for?
instructions for thyroid peroxidase
helps add iodine to thyroglobulin
What is the TSHB gene responsible for?
provides instructions for making a subunit of TSH
Deiodination can make the less active T4 into the more active T3. Where are the 3 types of deiodinases?
Type 1: found in the liver & kidney
Type 2: skeletal muscle, cardiac muscle, fat, CNS, thyroid
Type 3: fetus, placenta
Which percentage of T3 is made in the thyroid gland, as opposed to peripheral tissues?
20%
Which is a better treatment plan: administering T3 alone or T3 & T4?
T3 & T4
What is galactosemia?
absence of enzyme to break down galactose.
seen in newborns within a few days after they start drinking mom’s milk
What symptoms are seen in patients with galactosemia after a few days?
vomiting diarrhea lethargy jaundice liver damage (after a while)
If galactosemia goes untreated, what can result?
developmental retardation hepatomegaly growth failure cataracts sometimes death
What is the management of galactosemia?
early detection
galactose-free diet
NOTE: autosomal recessive inheritance pattern
What is homocystinuria?
aut rec disease
enzyme deficiency so that can’t convert (cystathionine beta synthase)
homocysteine–>cystathionine
What are the major clinical features of homocystinuria?
optical dislocation
mental retardation
osteoporosis
thromboembolism
What causes maple syrup urine disease?
aut rec disease
caused by a deficiency of branched chain ketoacid decarboxylase
**impaired metabolism of amino acids, esp the leucine breakdown pathway
What are the less serious symptoms of maple syrup urine disease? What are the serious complications of maple syrup urine disease?
w/i 1 week newborn can show the following: feeding difficulties lethargy failure to thrive If untreated can become: neurological problems acidosis seizures sudden apnea-->coma or death
How do you treat maple syrup urine disease?
strict dietary management
supplements
What is the leucine catabolism pathway?
Leucine A-K-isocaproic acid isovaleryl CoA beta methyl crotonyl CoA MG CoA HMG CoA Acetoacetic acid or acetyl coA
What are the breakdown products of the leucine catabolic pathway?
leucine broken down to acetoacetic acid or acetyl CoA
What are the deficiencies/diseases that can result from the following step of the leucine pathway:
A-K isocaproic acid–>isovaleryl CoA
Maple syrup urine disease (branched chain dehdyrogenase deficiency)
Dihydro-lipoyl dehydrogenase deficiency
What are the deficiencies/diseases that can result from the following step of the leucine pathway:
Isovaleryl CoA–>beta methyl crotonyl CoA
isovaleric acidemia (isovaleryl CoA dehydrogenase deficiency) Glutaric acidemia Type II
What are the deficiencies/diseases that can result from the following step of the leucine pathway:
beta methyl crotonyl CoA–>MG CoA
Multiple carboxylase deficiency (beta methyl crotonyl CoA carboxylase deficiency)
What are the deficiencies/diseases that can result from the following step of the leucine pathway:
HMG CoA–>Acetoacetic acid or acetyl CoA
HMG CoA lyase deficiency
What is phenylketonuria?
PKU is an aut rec disease w/ an inability to breakdown phenylalanine in the protein of foods.
What can PKU cause in a patient if left untreated?
baby may seen normal in the first few months of life but then mental retardation, motor retardation, microcephaly, poor growth rate, seizures
What mutation causes the classical form of PKU?
a mutation on chromosome 12
phenylalanine hydroxylase
**this is the enzyme that converts phenylalanine–>tyrosine
**buildup of phenylalanine in the body–>toxic levels.
What is the phenotypically mild form of PKU?
hyper-phenyl-alanemia
What is biotinidase deficiency?
lack of enzyme biotinidase
can’t liberate the bound form of biotin
biotin necessary for function of many enzymes, including those involved in the breakdown of carbs, fats, proteins
**newborns seem normal at first, but then symptoms start w/i a few weeks or months
What level of biotinidase activity constitutes partial deficiency? What level constitutes profound deficiency?
Partial Deficiency: Biotinidase activity <10%
How do you treat biotinidase deficiency?
daily biotin supplement
What are the symptoms & complications of biotinidase deficiency?
seizures hearing loss optic nerve atrophy hypotonia ataxia developmental delay hair loss eczema seborrheic dermatitis metabolic acidosis-->coma or death
What is MCAD: medium chain acyl CoA dehydrogenase deficiency?
aut rec disease
lack of enzyme that converts fats into energy
**usu see no symptoms in newborns unless there are long periods b/w meals when they have to use their fat reserves for energy
What are the dangerous complications of MCAD?
hypoglycemia
seizures
brain damage
cardiac arrest
What is the main mutation that causes MCAD?
mutation in ACADM gene
lysine replaced by a glutamic acid
What should be included in the initial testing for MCAD?
analysis of plasma acylcarnitines, urine organic acids & urine acylglycines
How can you confirm a diagnosis of MCAD?
looking @ beta oxidation in fibroblasts
measurement of MCAD activity in fibroblasts & other tissues
molecular genetic testing of the ACADM gene
What are 2 new diseases that should be included in the newborn screening?
Marfan Syndrome
Intrauterine Growth Restriction
What is Marfan Syndrome?
aut dom disorder
caused by misfolded fibrillin protein & accumulation of TGF-beta in lungs, heart, aorta (weakens them)
considered a CT disorder
What are the normal functions of fibrillin-1?
forms fibers of CT
contributes to cell signaling by binding TGF-beta & reducing its levels
What mutation causes the misfolding of fibrillin-1?
mutation on the FBN1 gene
When fibrillin-1 isn’t folded correctly & doesn’t bind TGF-beta…what happens?
integrity of the ECM is compromised & vascular smooth muscle development is compromised
What is one of the treatment options being considered for Marfan Syndrome?
Ang II receptor antagonists given exogeneously could reduce the levels of TGF-beta
What are the symptoms/effects of Marfan syndrome?
tall long limbs long fingers defects in heart valves or aorta could affect lungs could affect eyes could affect dural sac around spinal cord could affect skeleton, hard palate
What are the 2 main categories of intrauterine growth restriction?
Symmetrical (aka global growth restriction)
Asymmetrical (more common)
What are the proportions of the baby in asymmetrical & symmetrical intrauterine growth restriction?
Asymmetrical: large head, small abdomen
Symmetrical: small head, small abdomen
Which type of IUGR begins early on in the pregnancy?
Symmetrical begins early on in the pregnancy.
Asymmetrical begins later on in gestation.
What are the causes of asymmetrical IUGR?
extrinsic factor
chronic High BP
severe malnutrition
genetic mutations
What are the causes of symmetrical IUGR?
Intrauterine infections: cytomegalovirus, rubella, toxoplasmosis
chromosomal abnormalities
anemia
Which type of IUGR has an associated epigenetic response?
symmetrical IUGR
acts like it is experiencing chronic food shortage
if survives & develops in a food-rich environment–>more likely to develop Type II Diabetes & Obesity
Describe what happens in symmetrical IUGR.
b/c of whatever cause growth restriction begins early on in pregnancy, kid is born w/ a small head & small body.
Likely to become obese later in life b/c of epigenetic response.
permanent neurological damage likely if began before the 18th week of gestation when neurons develop.
Describe what happens in asymmetrical IUGR.
happens later in pregnancy
restriction of weight followed by restriction of length
head sparing (large head)
lack of subcutaneous fat
dry, peeling skin
overly-thin umbilical cord–at risk for hypoglycemia or hypoxia
If a child has an enzyme deficiency…what is the good news for them in utero & throughout their life?
good news: mom’s sufficient enzyme will prevent damage for them in utero
can start dietary changes after birth
may outgrow issues by age 6
If the child with the enzyme deficiency (homozygous recessive) has a kid…what is the less than good news?
they will need to go back on the restricted diet during their pregnancy b/c even if their kid doesn’t have the deficiency–> can be affected by excess breakdown products from mom.
