Genetics 4: autosoma recessive disease Flashcards
Urine darkens upon standing, arthritis, darkening of the ear, dark spots on sclera, cornea. Enzyme deficiency?
Homogentisic acid oxidase, alkaptonuria
Gene HGD
When deficient in Homogentisic acid oxidase, because of mutation in —— gene, the body cannot break down ——+ and ——-.
Gene HGD
Cannot break Tyrosine and Phenylalanine
Alkaptonuria
Inheritance for Alkaptonuria
Autosoma recessive
Accumulation of Homogentisic acid in the skin and tissues is called
Ochronosis
To Dx Alkaptonuria, add ——— to the urine sample
Ferric chloride - this darkens the urine
White crystals in diaper?
Orotic aciduria
Yellow crystals in diaper?
Leysh nehan Syndrome
Dark urine in diaper ?
Alkaptonuria
Ataxia before 5 years old. Myoclonus and chorea. Chronic sinopulmonary infections (weak immune system). Increased risk of cancer (lack of dna repair), oculomotor apraxia (absence or defect in voluntary eye movement). Gene?
Mutation in gene ATM - codes for cell growth and division
Telangiectasias in the eyes and skin, higher risk for developing leukemia’s and lymphomas, decreased IgG production. Dx?
Ataxia telangiectasia
Gene ATM
Inheritance autosoma recessive
Defect in dna repair (stress induced dsDNA breaks), affects nervous system (ataxia), immune system (decreased IgG) and other body systems. Gene? Dx?
Ataxia telangiectasia
Gene ATM
Child with spider vessels in the sclera, chronic sinopulmonary infections, labs reveal decreased IgG. Inheritance? Gene? Dx?
Autosomal recessive
Gene ATM
Ataxia telangiectasia
Albinism inheritance?
Autosoma recessive
child susceptible to sunburn, need Uv protection for the eyes so they don’t develop melanoma of the eye. Tyrosine deficiency. Dx?
Albinism
Melanin is made from —— which comes from —- via —— enzyme.
Tyrosine——> Dopa (vía tyrosine)———> Melanin
Tyrosine deficiency causing oculocutaneous disorder or ocular disorder
Albinism
Causes panacinar emphysema in a young, non smoker patient, liver cirrhosis,
Alpha 1 antitrypsin deficiency
Loss of protection for the liver and the lungs from tissue destroying proteasas (neutrophil elastase)
Alpha 1 antitrypsin deficiency
Enzyme made by the liver to protect it from elastase breaking elastin. Patient more prone to aneurysm
Alpha anti trypsin A1AT
Pulmonary sx: short of breath, chronic lung infections, young patient, non smoker, hepatic findings
Alpha 1 antitrypsin deficiency.
Baby neonatal hepatitis and asthma
Alpha 1 antyitrypsin deficiency A1AT
Alpha 1 antitrypsin deficiency inheritance mode?
Autosoma recessive
Thalassemia mode of inheritance?
Autosoma recessive
Common in Mediterranean individuals. Involve alpha and beta globin chains.
Thalassemia
Normal hemoglobin
2 alpha 2 beta
Adult hemoglobin, found in small amounts, hold soxygen with high affinity so doesn’t let it go well into tissues
2 alpha 2 delta, found in small amounts in adults normally
hemoglobin found during the first six months of life
Fetal hemoglobin, 2 alpha, 2 gamma chains
Beta thalassemia, gene? Chromosome?
Gene HBB
Chromosome 11
Mutation in the kozac sequence of the beta globin gene associated with hypochromic, mycrocytic anemia
Thalassemia intermedia
Two beta globin genes missing, patient can only make HbA2 and HbF, after six months f life severe anemia ensues and patient needs continuous transfusions.
Beta thalassemia major
Consequence of beta thalassemia major?
Continuous transfusions so iron overload.
How to treat the consequence of beta thalassemia major?
Iron overload from continuous transfusions of blood is treated with a chelator for iron such as Deferoxamin.
ATP binding transmembrane ion transporter that pumps chloride ions out of the epithelial cells
CFTR
Cystic fibrosis. Gene mutated?
Chromosome?
Gene CFTR delta F508
Chromosome 7
Deletion in 3 nucleotides that code for PHE results in loss of phenylalanine.
Cystic fibrosis
Gene CFTR delta F508
Chromosome 7
In cystic fibrosis, there is a deletion in three genes that code for |———- which results in a loss of ———-.
PHE
Phenylalanine
CFTR is a ——+ transmembrane ion transporter that pumps ——- out of the ——- cells
ATP dependent transmembrane ion transporter
Chloride
Epithelial cells
What is one reason why patients with CF develop so many sinopulmonary infections?
The mucus that has accumulated acts as a culture nidus.
Explain how a sweat gland works normally versus in CF
Normally the NaCl is reabsorbed to ? and what comes out to the surface of the skin is a substance that is hypotonic (not much solute in it).
In CF, the NaCl is not reabsorbed and so the substance that gets put into the surface of the skin is hypertonic (contains a lot of solutes, salt). So that substance, that sweat, is “salty.”
90% of these patients have pancreatic insufficiency so lack of enzymes for absorption. Malabsorption then leads to decreased caloric absorption, and failure to grow.
CF
Gene CFTR
Chromosome 7
Newborn with meconium Ileus. What’s could be a likely Dx?
CF
5-10% newborns with Cf will get this. It I should very specific for CF.
Vitamins deficient in CF
ADEK
A group of rings emerging from the rectum. Seen in 10% patients with CF
Rectal prolapse - due to pushing too hard
In men with CF there is likely infertility because their ——— isn’t working well
vas deference not working well
Bacteria that thrive in the lungs of CF patients
Staph aureus (g +) hemophilous influenza (g -)
Later on: pseudomonas aeuroginosa (g-)
By 18 years old, almost every CF patient is colonized with pseudomonas aeruginosa (g-)
CF
Gene CFTR, delta508 mutation
Chromosome 7
Management for CF
Clear airway of mucus everyday in a child
Ensure growth,caloric, nutrients
Any hint of infection, give antibiotics
How do you loosen the mucus in a CF patient?
Dornase alpha
MOA of N acetylcysteine
Breaks the S-S bonds in mucus, but this is not effective in CF
MOA of dornase alpha
Breaks the dna in the mucus, effective in CF.
What is N acetylcysteine used for? What is it effective for?
Tx of Overdose of acetaminophen
What is the problem in 21-hydroxylase deficiency?
There is congenital adrenal hyperplasia, the adrenals then, are not making enough aldosterone and cortisol. Everything will go to the androgen path. So you’ll see hypotension and virilization in a patient with this deficiency.
Can’t make aldosterone and cortisol, but buildup of progesterone, whcih shunts to pathway of testosterone. Deficiency? Consequence?
Deficiency of 21 hydroxylase. Women will have ambiguous genitalia. Males will have precocious puberty.
What will you see in a patient with 11 - hydroxylase deficiency?
Hypertension and virilization. everything shunts to the testosterone pathway. So virilization, precocious puberty. But there are aldosterone like effects, so hypertension instead of hypotension because there is an accumulation of 11-depxy ortisone whcoh is what has the aldosterone-like effected causing hypertension.
Deficiency in 17- alpha hydroxylase
You can only make aldosterone, so you’ll have hypertension. XX lacks secondary development. XY has ambiguous genitalia,
All congenital adrenal enzyme deficiencies are characterized by —-+++++ because there is elevated ——- production coproduced and secreted with ———-. They will also all show bilateral ——+++++ due to elevated ——— stimulation.
Skin hyperpigmentation Elevated MSH production ACTH Also: bilateral adrenal enlargement Due to elevated ACTH stimulation.
Cheddar higashi.
Gene?
Gene LYST
A LYST mutation means
Lysosomal trafficking problem. Seen in
Chediak-higashi
This gene has a role in transporting enzymes to lysosome. If they can’t get to lysosome, then lysosomes cannot work well and so the become ——, have ———- size, cause ——— hypopigmentation (photophobia),
LYST gene
Lysosomes become enlarged
Increased in size (bloated neutrophil).
Ocular hypO pigmentation.
Bloated neutrophils in histology. Dx?
C
This histology corresponds to Chediak higashi Syndrome.
LYST gene mutation
Neutrophils phagosize lots of stuff but can’t destroy any of it.
Problem in LYST gene. Chediak higashi.
Causes albinism, recurrent pyogenic infections MCC by staph aureus and strep species, nystagmus, peripheral neuropathie, oculovcutaneous albinism
Chediak Higashi sx.
Gene LYST
What does C.O.L.A. Stand for and what is this related to?
Cysteine Ornitine Lysine Arginine These are aa that buildup in urine of person with Cystinuria .they float in the lumen of the nephron because they cannot be absorbed.
Problem in the SLC 3A1 and
SLC 7A9 genes.
Cannot absorb COLA aa. Cysteine, ornitine, arginine, lysine.
Cystinuria.
Code for a transporter protein in the kidney that transports COLA aa. Build up cysteine in urine, form stones. Severe flank pain radiating to the groin. Hematuria. Painful.
SLC 3A1
SLC7A9
How do you manage Cystinuria?
Must diagnose stones first with ultrasound or x Ray.
Give fluids to dilute the urine,
Lithotrypsy for big stones
Alkalinization of stones
Cysteine stones precipitate in ——- environments.
These stones precipitate in acidic environment. You must alkalinize the urine.
Drug to alkalinize the urine to manage cystine stones.
Azithazolemide or
Citrate
Patient with Pale stools. Jaundice seen first in the frenulum of the tongue.
Dubinsky Johnson Syndrome.
Liver turns black because of epinephrine metabolites
Dublin Johnson syndrome
Why does the liver then black in Dubln Johnson syndrome
Accumulation of epinephrine metabolites
How to distinguish between Dubin Johnson syndrome and Rotor syndrome?
Liver composed of epinephrine metabolites causing liver to turn black in Dubin but not in Rotor.
Benign. Seen in adolescence and early adulthood. Presence of jaundice. Mutated ABCC2 gene coding for protein MRP2
Dubin Johnson Syndrome
Mutated ABCC2 gene, coding for protein MRP2
Dubin johnson
Gene ABCC2 codes for protein ——which produces a pump that transports bilirubin into the bile
Gene ABCC2
Protein is MRP2
Pump transports bilirubin into bile
Problem transporting bilirubin into cannaliculi to the bile. Bilirubin accumulated in tissues of body. Causing ————
Hyper bilirubinemia. Dubin Johnson. Or rotor.
