Mar29 M2-Genetic Disorders of Defense Flashcards
DiGeorge syndrome (22q11 deletion): main immune manifestation
thymus hypoplasia and immune deficiency
details of the thymic hypoplasia in DiGeorge
- 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
important cause of mortality in DiGeorge
recurrent infections that occur later in life (after neonatal period)
what kind of infections do DiGeorge patients get
infections caused by organisms related to T cell dysfunction
- fungi
- pneumocystis
- disseminated viral infections
immune disorders in DiGeorge
- autoimmune disease like autoimmune cytopenia, juvenile RA, thyroiditis, uveitis, IgA deficiency
- severe eczema and asthma
how DiGeorge is diagnosed
FISH
- metaphase spread of chromosomes
- probe with fluorescent tag anneals with 22q11 regin
- compare to control chromosome
- see if one light is missing
other genetic test for DiGeorge when you’re less suspicious of somethign specific like DiGeorge and for genetic diseases more generally
- 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
how many genes missing in the DiGeorge deletion + some important ones
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)
how the 22q11 deletion in DiGeorge occurs
- 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
most common micro-deletion syndrome (is a category of genetic diseases) and one other example
- DiGeorge* (chrom 22)
- Williams syndrome = chrom 7
inheritance pattern of DiGeorge
autosomal dominant
who should get tested for DiGeorge if someone has it in the family
future children of the mother (even though was probably a de novo mutation for the child who got it)
Familial Mediterranean Fever def
- inherited disease where get recurrent attacks of fever and pain, pleurisy, painful, swollen joints, arthralgia, occasionally arthritis
- symptoms vary a lot between pts
characteristic sign seen in FMF
characteristic ankle rash
most severe complication of FMF
amyloidosis, leading to renal failure
how symptoms evolve over time in FMF
- attacks that come and go, are periodic. abdominal, pleural or arthritic
- mimic common acquired disorders like infections, acute appendicitis, cholecystitis, arthritis
frequency of FMF
worldwide = low
in Mediterranean region = 1 in 200
cause of FMF
-mutation in MEFV gene (Mediterranean fever), on chrom 16 locus 16p13.3
what MEFV gene encodes for what prot + its fct
- pyrin protein, produced in granulocytes
- role in controlling inflam by deactivating the immune response
- prolonged inappropriate inflam response bc of the mutation
inheritance pattern of FMF
autosomal RECESSIVE (but only 1 mutation found sometimes, bc maybe didn’t find other one yet)
why FMF frequency higher in certain regions of the world
migratory wave in Mediterranean region = people going there had a higher frequency of the allele as a group
theory as to why FMF mutation persisted
- carriers (heterozygotes) may have an advantage (like sickle cell mutation carriers protect against malaria)
- no idea what FMF may protect from
dx of FMF done how
- history and symptoms
- can give cholchicine (medication that reduces episodes of pain and fever) as a test. if helps, can dx
lifelong treatment of FMF
- 1 mg cholchicine daily (prevents amyloid deposits and inflam attacks)
- less WBCs going to inflamed areas
