Week 3 Flashcards
What is deamination?
Break down of amino acids to release the amino group and remove it as Ammonia NH3 for excretion in the urea cycle
What amino acid often is fed into the deamination cycle and what enzyme catalyzes the first step?
Alanine from muscle and alanine aminotransferase (ALT)
Along with B6 cofactor and alpha ketoglutarate make pyruvate and glutamate
Glutamate and NAD cofactor along with glutamate dehydrogenase makes NH3 to be fed into the Urea cycle
What is transamination?
Transfer of amino group from amino acid to alpha ketoglutarate by aminotransferases to make new non essential amino acids such most often glutamate
which is then combined with B6 cofactor and oxaloacetate and Aspartate amino transferase or AST
Which frees up alpha-ketoglutarate and makes Aspartate which feeds into the Urea cycle
Where do ALT/AST do their work?
AST- liver, muscles,kidneys, brain,RBCs
ALT- In the liver
What is one way amine groups are carried through the body?
They are attached to glutamate to make glutamine
ALT and AST can do this
Testing for ALT/AST levels tests what?
Liver function and damage
If the liver is damaged then the plasma membrane leaks proteins/AAs and ALT and AST build up…
How is ammonia fed into Urea cycle?
Aka what is the first step and what enzyme catalyzes it?
What is the product?
It is fed in as NH4 the ammonium ion.
Which reacts with Carbamoyl phosphate synthetase I enzyme to make Carbamoyl phosphate
This happens in the mitochondrial matrix of liver cells
Where does the Urea cycle happen?
Only in the liver
Hepatocyte cells
What is the 2nd step in ammonia being fed into urea cycle?
Aka what enzyme, where is cell and what product?
Carbamoyl phosphate and Ornithine reacts with the enzyme Ornithine Transcarbamoylase to make Citruline
This happens in the mitochondrial matrix of liver cells
What is the 3 step (and 3rd enzyme she wants us to remember) in the Urea cycle and where does it happen?
Citruline crosses into the cytoplasm in liver cells.
It then reacts with the Argininosuccinate Synthetase Enzyme and Aspartate and ATP to make Argininosuccinate
This goes on to make arginine the urea
What happens when the first step enzyme Carbamoyl Phosphate Synthetase enzyme is deficient and when can this happen?
This happens when Carbamoyl phosphate Synthetase leaks out of cells when liver is damaged due to cirrhosis of liver.
There is a build up of ammonia and loss of Carbamoyl phosphate
What TCA cycle intermediate is also used a lot in nitrogen metabolism?
Alpha ketoglutarate
What can amino acids be converted into?
TCA cycle intermediates
What are glucogenic AAs?
Amino acids that can be converted to glucose
What are ketogenic AAs?
Amino acids that are converted to Acetyl CoA to produce ketones
What happens if AST level is increased?
Acute hepatitis renal disease hemolytic anemia myocardial infarctions
What happens if ALT level is is increased?
Acute hepatitis
What is BUN?
Blood urea nitrogen
What does testing for BUN levels tast?
Kidney function- increased levels = kidney damage
Can also access the effectiveness of dialysis
What is often tested at the same time as BUN?
Blood creatinine (waste product filtered by kidneys)
What happens when something g goes wrong in the urea cycle?
Hyperammonenia
What is hyperammonemia?
Too much ammonia
Elevates glutamine levels
Due to urea cycle defects aka defects in detoxification or over production of ammonia
What is the most common enzyme to be defective in Urea Cycle?
Ornithine Transcarboxylase also know as OTC
What happens in OTC deficiency and what step of Urea cycle is it?
This is the second step in urea cycle.
There are increased levels of Carbamoyl Phosphate
Causes orange crystals in diaper
What part of life is OTC deficiency most common?
Early age- still in diapers
Causes orange crystals in diapers
What is CPS I?
Carbamoyl Phosphate Synthetase I
First step in urea cycle enzyme
What happens in a CPS I deficiency?
Build up of ammonia aka hyperammonemia
Inherited disorder that is often fatal
Liver damage can potentially cause the first step not to happen as well
What happens in Argininosuccinate Synthetase Deficiency?
Causes elevated levels of Citruline
Failure to thrive, vomiting lethargy mental defects
Then hyperammonemia and coma and death
Recommended that newborns be screened for it
Autosomal recessive
What Syndrome is often associated with Urea Cycle disorders?
Reyes Syndrome
Rare childhood disease
Liver failure, hyperammonemia, hypoglycemia, abnormal brain function
What is Reyes Syndrome?
Rare childhood disease associated with urea cycle disorders
Liver failure, hyperammonemia, hypoglycemia, abnormal brain function
After a viral infection in children such as chicken pox or flu it can be triggered by aspirin
Name the 6 amino acid diseases she wants us to memorize?
- Phenylketonuria
- Oculocutaneous Albinism
- Alkaptonuria
- Cystinuria
- Homocystinuria
- Maple Syrup Urine Disease (Ketoacidemia)
What amino acid is associated with PKU aka phenylketonuria?
Phenylalanine
Babies lack an enzyme responsible for breaking it down
What are the symptoms of PKU/phenylketonuria?
Intellectual disability and microcephaly since Phe is toxic to brain
Decreased skin and hair pigmentation since Phe can’t be transformed into melanin
Musty odor
Recommended routine screening of newborns for it
TX protein limited diet
True or False
It is NOT recommended to screen for PKU among newborns
False
It is recommended that all newborns be tested for Phenylketonuria
What enzyme is affected in Oculocutaneous Albinism?
Tyrosine aka Tyr
Try doesn’t get converted to melanin
What are the symptoms of Oculocutaneous Albinism?
Typical Albinos
Various enzymes affected in different types but all affect Tyrosine and melanin production
Lack pigmentation, white hair, light eyes, pale skin, light irises
Oculo is eye
Cutaneous is skin
What enzyme is affect in alkaptonuria?
Tyrosine
Also affects Phe
Alkaptonuria is an autosomal recessive disorder caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase. This enzyme deficiency results in increased levels of homogentisic acid, a product of tyrosine and phenylalanine metabolism.
What are the symptoms of alkaptonuria?
Homogenistic acid builds up causing dark discoloration
Also called black urine disease
Dark urine
Pigmented/dark sclera of eye aka ochronosis
Bluish-black discoloration of skin and cartilage
Alkaptonuria is an autosomal recessive disorder caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase. This enzyme deficiency results in increased levels of homogentisic acid, a product of tyrosine and phenylalanine metabolism.
What amino acid is affected in Cystinuria?
Cysteine
Cystinuria is an autosomal-recessive defect in reabsorptive transport of cystine and the dibasic amino acids ornithine, arginine, and lysine from the luminal fluid of the renal proximal tubule and small intestine
What are the symptoms of Cystinuria?
Excessive urinary secretion of cysteine and kidney stones
Cysteine doesn’t get reabsorbed back into blood stream and accumulates in urine and makes crystals
Can create blockages in the urinary tract causing difficulty for kidneys to eliminate waste
Increased risk of bacterial infections
TX: drink more water, change diet-less salt and medications
What amino acid is affected by homocystinuria?
Met aka methionine
Homocystinuria (HCU) is a rare but potentially serious inherited condition. It means the body can’t process the amino acid methionine. This causes a harmful build-up of substances in the blood and urine
What are the symptoms of homocystinuria?
Myopia
Marfan like skeletal changes (widening of epiphyses and metaphyses of long bones), intellectual disability, scoliosis, DVT aka deep vein thrombosis
TX- Protein restricted diet and meds
New born screening is most states
Is there screening for homocystinuria in newborns?
Yes in most states
What amino acid is affected by maple syrup urine disease aka ketoacidemia?
Ile/isoleucine
Leu/leucine
And Val/Valine
Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) proper
What are the symptoms of Maple Syrup Urine Disease (Ketoacidemia)?
Intellectual disability, Ketosis, seizures
High levels of Ile, leu, Val and other amino acids build up and are toxic to brain and other organs
TX: protein restricted diet and liver transplant
Step 1 of heme synthesis?
Reactants, enzymes and cofactors? Where?
Reactants- Glycine + Succinyl-CoA
Enzyme- ALA synthase
Cofactors- B6
Where- mitochondria
Makes- delta-Aminolevulinic Acid
What represses ALA synthase- the enzyme in the first step of heme synthesis?
Heme
2nd step of Heme synthesis?
Reactant- delta-Aminolevulinic Acid
Enzyme- ALA dehydratase (inhibited by lead)
Product- Porphobilinogen
What inhibits ALA dehydratase the enzyme responsible for the second step of heme synthesis?
Lead
What is the last step in heme synthesis?
Reactant, Enzyme, cofactor, and product?
Reactant- protoporphyrin IX
Enzyme- Ferrochelatase (inhibited by lead)
Cofactor- Fe2+
Product- Heme
What inhibits Ferrochelatase the enzyme in the last/7th step in heme synthesis?
Lead
What two enzymes in heme synthesis are inhibited by lead?
ALA dehydratase (2nd step)
Ferrochelatase (last/7th step)
Name two heme associated diseases?
Sideroblastic Anemia
Microcytic Hypochromic Anemia
What can cause Sideroblastic Anemia?
2 potentials-
B6 deficiency or lead poisoning
It is a build up of iron in cells due to heme synth not happening
What can cause Microcytic hyprochromic anemia?
Iron deficiency
Results in small and pale RBCs
What happens to heme released from hemoglobin during hemolysis of older RBCs?
It is converted to bilirubin
What can excess blood level of bilirubin lead to?
Jaundice
What happens in jaundice?
High levels of bilirubin cross blood brain barrier causing kernicterus/brain damage which
Causes cerebral palsy, hearing loss, intellectual disability and stains on enamel of primary teeth
How is jaundice treated?
Phototherapy and blood exchange transfusions
What is the Potter Sequence?
- Kidneys don’t develop correctly
- Baby doesn’t pee out enough urine to maintain amniotic fluid volume aka causes oligohydramnios
- Due to oligohydramnios the sac is smaller and the baby is compressed
- Physical symptoms like lungs not developing properly, limb contractures, hand and foot defects, altered face
What are the symptoms of the Potter Sequence?
Compression of baby leads to: Lungs not developing properly Limb contractures Hand and foot defects Altered face
What is the pathogenesis, clinical and pathological features of the Pierre Robin Sequence?
- A hypoplastic mandible at 7-11 weeks gestation cause the tongue to be not in the right place
- It is high and toward the back of the mouth which interferes with palatial formation
- U shaped cleft palate develops
- The tongue position can also cramp the airway space making it narrow
- Mandibular growth in first few weeks of life help
What is Fetal Alcohol Syndrome?
Exposure to alcohol as a fetus causes growth retardation, intellectual impairment and facial changes, heart septum defects, small birth weight
What is the number one cause of an acquired intellectual delay?
Fetal Alcohol Syndrome
True or False
Fetal alcohol syndrome babies heart septum defect close up spontaneously
True
They often heal on their own
Name 5 facial common distinguishing facial features Of Fetal Alcohol Syndrome kids?
Name 4 associated features?
Discriminating features
- Short palpebral fissures aka how wide and eye will open
- Flat midface
- Short nose
- Indistinct philtrum aka indentation above the upper lip
- Thin upper lip
Associated Features
- Epicanthal folds aka skin fold of upper lid that covers the inner corner of eye
- Low nasal bridge
- Minor ear abnormalities
- Micrognathia
What causes cleft lips and palates?
Mix of genetic and Environmental factor such as
Smoking mom, folate zinc cholesterol deficiencies, other things like maternal obesity hyperthermia, stress radiation, infections
Multi factorial threshold hypothesis
Do clefts lip, palates and bifid uvula occur alone of with other syndromes?
70% occur alone
How common are cleft lips and palates?
1.5-2.5 in 1000 births
Cleft lip is 1 in 1000
What race has the highest cleft lip rate and which is lowest?
Highest= Asian Lowest= African
What is the developmental error and when does it happen?
Failure of medial nasal and maxillary processes to close at about week 5-7 in utero
How is severity classified?
Several ways but usually unilateral or bilateral and how far up the lip it goes from edge alway up to nose or not
Veau Classification rates from I to IV
What happens in cleft palate alone? And what time of development?
Palatial shelves fail to merge at about 8-10 weeks
How common is cleft palate?
One in 2500 births
What is bifid uvula?
Mild form of cleft palate where just the uvula is affected
Not counted in to defect rate
Can cleft palate just affect the soft palate?
Yes it is super mild and often not counted into the occurrence rate
What is a submucosal cleft palate?
Where the defect in bone is covered by soft tissue
Classification of cleft palates?
Veau’s rating system
I-IV
From soft palate only to how much of palate is involved and if it is bilateral
How are cleft lips and palates treated?
Surgically
Babies can’t suckles so need prosthetic device to cover the defect, feeding tubes, a sippy cup call the NIFTY cup
Then speech therapy, cosmetic surgery, dental surgery etc
Interdisciplinary team
What is DiGeorges syndrome?
A syndrome that falls under Chromosome 22q11 Syndrome or CATCH 22 Syndrome
Velocardialfacial Syndrome falls under same umbrella group with different prominent symptoms
Caused by a deletion of band 11 on long arm of chromosome 22
What features are shared by DiGeorges Syndrome?
Spectrum of disorders sharing- Congenital heart disease Palatal Abnormalities Facial Dismorphology Developmental Delay Thymic hypoplasia- impaired T-cells Parathyroid hypoplasia- hypocalcemia
What are the most prominent symptoms of DiGeorges Syndrome?
Both thymic and parathyroid hypoplasia resulting In immunodeficiency and hypocalcemia
What is the cause of DiGeorges Syndrome and how often does it occur?
A defect in the 3rd and 4 branchial pouches
Occurs in 1 in 3000 births
What is does CATCH 22 stand for?
C cardiac- aortic arch anomalies
A abnormal face- short down slanting eyes, high broad (wide spaced eyes) nasal bridge, long face, micrognathy, short philtrum, ear anomalies with recurrent ear infections, velopharyngeal incompetence 20%, sucking and swallowing problems
T thymic hypoplasia- cellular immune deficiency aka abnormal function and number of T-cells aka Bcells don’t work with out TCells
C Cleft Palate
H Hypoparathyroid cause hypocalcemia, parathyroid make PTH which controls calcium, this can cause muscle tetany/spasms
22 deletion on 22q11 chromosome
Diagnosed by FISH
What is Cri du Chat Syndrome?
A rate syndrome where chromosome 5 is missing part of small arm
Named after the high pitched mewing sound the babies make like a cats cry
What determines severity of Cri du Chat?
Amount of genetic material missing
What are the symptoms of Cri du Chat?
Intellectual delay and language difficulty, microcephaly/small head, low birthweight, hypotonia/poor muscle tone, hypertelorism/widely spaced eyes
What is Marfans Syndrome?
An autosomal dominant disorder of connective tissue cause by defective gene for Fibrillin (FBN1)
How often does Marfans Syndrome occur?
Once in every 10-20 K
What’s parts of the body does Marfans affect?
Connective tissue found all over body so it effects many parts all over including skeleton, lungs, eye, heart, and blood vessels
Symptoms of Marfans Syndrome?
Long fingers and bones, tall and thin, arm span can exceed height, week vessel walls and heart with increases potential for aneurysms- need to control blood pressure, can have dissecting aneurysms in aortic arch, mitral valve prolapse, near-sighted and can have dislocated lenses
What is Elhers Danlos Syndrome or EDS?
A group of 10+ connective tissue disorders caused by faulty collagen synthesis or structure.
How common is Elhers Danlos Syndrome?
1 in 5 to 10K
Symptoms of Elhers Danlos Syndrome?
Not all types have same symptoms but they include:
Joint hypermobility, stretchy skin, fragile skin, periodontal disease due to weak perio ligaments, weak arteries, weak uterus, blue sclera,
What is Osteogenesis Imperfecta?
A disease that involve faulty collagen that impacts bone formation- also called brittle bone disease
There are at least 4 subtypes and they all can vary in severity
What are symptoms of Osteogenesis Imperfecta aka OI?
Fragile bones that fracture easy. Long and bowed bones
Blue Sclera
Lax ligaments
Hearing loss
Defective dentin aka dentinogenesis Imperfecta
Does dentiogenesis Imperfecta always occur with OI?
No DI can occur on its own or as a part of OI and not every one with OI has DI
What is Treacher Collins Syndrome?
A condition caused by an AD mutation on chromosome 5 resulting in defective Treacle proteins that cause malformations of 1st and 2 branchial arches.
Mostly affects the face
What defects does Treacher Collins cause?
Mainly cosmetic defects- melting face
Ears- absent, undeveloped or malformed (microtia), cumductiv hearing loss of varying degrees to deafness. Can use bone conduction hearing aids if born with out external ears
Face- hypoplastic sinuses, zygomatic bones can be absent, malformed or hyperplastic
Eyes- downward slanting due to no zygomating arch support, no eyelashes on lower inner 1/3 of eyelid notched iris and or choroid, notched lower lid
Jaws- mandible under developed aka micrognathia, can be misaligned, generally short with steep gonial angle, chin may be underdeveloped
Mouth- Large oral opening aka macrostomia, sometime fissures extend from corner of mouth to ears, high palate or 30% cleft palate, parotid glands can be absent
Surgical interventions
