Mar29 M2-Genetic Disorders of Defense

Question 1

DiGeorge syndrome (22q11 deletion): main immune manifestation

Answer 1

thymus hypoplasia and immune deficiency

Question 2

details of the thymic hypoplasia in DiGeorge

Answer 2

• failure of dev of 3rd and 4th pharyngeal pouches (DGCR6 is missing, gene for NCC migration for thymus)
• variable loss of T cell mediated immunity

Question 3

important cause of mortality in DiGeorge

Answer 3

recurrent infections that occur later in life (after neonatal period)

Question 4

what kind of infections do DiGeorge patients get

Answer 4

infections caused by organisms related to T cell dysfunction

• fungi
• pneumocystis
• disseminated viral infections

Question 5

immune disorders in DiGeorge

Answer 5

• autoimmune disease like autoimmune cytopenia, juvenile RA, thyroiditis, uveitis, IgA deficiency
• severe eczema and asthma

Question 6

how DiGeorge is diagnosed

Answer 6

FISH

• metaphase spread of chromosomes
• probe with fluorescent tag anneals with 22q11 regin
• compare to control chromosome
• see if one light is missing

Question 7

other genetic test for DiGeorge when you’re less suspicious of somethign specific like DiGeorge and for genetic diseases more generally

Answer 7

• Array CGH (comparative genomic hybridization)
• reference genome chopped up in pieces and placed on a plate
• pt genome mixed with control genome and all that added on the reference plate check where not enough hybridization or excess DNA

Question 8

how many genes missing in the DiGeorge deletion + some important ones

Answer 8

30-40 genes

• DGCR6 responsible for NCC migration in pharyngeal pouches causing thymic hypoplasia
• TBX1 = TF for dev of face, neck, heart, etc.
• COMT (catechol. transferase. important for ntr regulation, explains psychiatric problems)

Question 9

how the 22q11 deletion in DiGeorge occurs

Answer 9

• region is flanked by 2 low copy repeat sequences
• meiosis mistake in parent germ cells: chromosomes align and cross over
• one strand with duplicated region and one strand with deleted region

Question 10

most common micro-deletion syndrome (is a category of genetic diseases) and one other example

Answer 10

• DiGeorge* (chrom 22)

- Williams syndrome = chrom 7

Question 11

inheritance pattern of DiGeorge

Answer 11

autosomal dominant

Question 12

who should get tested for DiGeorge if someone has it in the family

Answer 12

future children of the mother (even though was probably a de novo mutation for the child who got it)

Question 13

Familial Mediterranean Fever def

Answer 13

• inherited disease where get recurrent attacks of fever and pain, pleurisy, painful, swollen joints, arthralgia, occasionally arthritis
• symptoms vary a lot between pts

Question 14

characteristic sign seen in FMF

Answer 14

characteristic ankle rash

Question 15

most severe complication of FMF

Answer 15

amyloidosis, leading to renal failure

Question 16

how symptoms evolve over time in FMF

Answer 16

• attacks that come and go, are periodic. abdominal, pleural or arthritic
• mimic common acquired disorders like infections, acute appendicitis, cholecystitis, arthritis

Question 17

frequency of FMF

Answer 17

worldwide = low

in Mediterranean region = 1 in 200

Question 18

cause of FMF

Answer 18

-mutation in MEFV gene (Mediterranean fever), on chrom 16 locus 16p13.3

Question 19

what MEFV gene encodes for what prot + its fct

Answer 19

• pyrin protein, produced in granulocytes
• role in controlling inflam by deactivating the immune response
• prolonged inappropriate inflam response bc of the mutation

Question 20

inheritance pattern of FMF

Answer 20

autosomal RECESSIVE (but only 1 mutation found sometimes, bc maybe didn’t find other one yet)

Question 21

why FMF frequency higher in certain regions of the world

Answer 21

migratory wave in Mediterranean region = people going there had a higher frequency of the allele as a group

Question 22

theory as to why FMF mutation persisted

Answer 22

• carriers (heterozygotes) may have an advantage (like sickle cell mutation carriers protect against malaria)
• no idea what FMF may protect from

Question 23

dx of FMF done how

Answer 23

• history and symptoms

- can give cholchicine (medication that reduces episodes of pain and fever) as a test. if helps, can dx

Question 24

lifelong treatment of FMF

Answer 24

• 1 mg cholchicine daily (prevents amyloid deposits and inflam attacks)
• less WBCs going to inflamed areas

Question 25

other treatments in FMF

Answer 25

• acute attacks = IV NS for hydration + NSAIDs, paracetamol, dipyrone for pain relief
• treatment of ESRD + renal transplant

Question 26

how colchicine acts in FMF

Answer 26

• drug known to interfere with tubulin and destabilize mtbs

- pyrin interacts with tubulin and colocalizes with mtbs

Question 27

long-term monitoring in FMF

Answer 27

monitor for amyloidosis (careful about kidney disease)