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24 Cards in this Set
- Front
- Back
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Fragile X incidence
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1/4000 males, 1/8000 females
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Fragile X inheritance
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X-linked with anticipation due to trinucleotide repeat expansion of CGG in the first exon of FMR1 gene
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Fragile X mutation status
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– normal (~5 to ~44) - intermediate (~45 to ~58) - premutation (~59 to ~200) - full mutation (over 200 and highly methylated)
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Fragile X labs
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– Southern blot detects presence of full and pre-mutations, approximation of repeat number, and methylation status
- PCR yields accurate estimates of normal and small pre-mutation alleles |
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What can premutation carries of fragile X develop
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- Premutation females may develop premature ovarian failure
- premutation males may develop an ataxia/tremor syndrome |
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Huntington’s Incidence
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- 3-7/100,000 in those of Western European descent
– less in Asia and Africa |
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Huntington’s genetics
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- Expansion of a CAG triplet repeat within the HD gene on chromosome 4p
- normal (< 26) - intermediate-sized alleles (27-35, ok but can pass to kids) - reduced penetrance alleles (36-39, sx in some) - adult onset (40-59) - juvenile onset (above 60) |
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Huntington’s labs
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PCR detects repeat number
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How is CAG different from CGG
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- smaller expansions
– Methylation is not involved in expression of the genes – expansions larger when expanded allele inherited from father |
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2C9
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– 5% of Rx (Warfarin, Phenytoin, Glipizide)
– poor metabolizers are 2C9*2 and 2C9*3 |
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2D6
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– 25% of Rx (TCAs, SSRIs, beta blockers, antipsychotics)
– poor metabolizers are 2D6*3, *4, *5del, *10, *17 – ultra rapid metabolizers are *2XN |
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2C19
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– 15% of Rx (Antiarrhythmics, SSRIs, Diazepam)
– poor metabolizers are *2, *3 |
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Poor metabolizers
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– from 2 inactive gene copies (alleles)
– drug rxns are Adverse events/ toxicity – Poor response to prodrug |
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Intermediate metabolizers
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– from 2 alleles with reduced activity/ 1 inactive allele
– drug rxns are some adverse events – Reduced response to prodrug |
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Extensive metabolizers
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– from 2 normal alleles
– drug rxns are expected response – Expected response to prodrug |
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Ultrarapid metabolizers
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– from more than 2 copies of gene (duplication)
– Poor response to drugs – Adverse effects in response to prodrug |
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Psychiatric drugs CYPs
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2D6 and 2C19
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2C9 and warfarin
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– Metabolizes >90% of S-Warfarin
– 2C9*3 in 15% W and <5% A, B and reduces enzyme activity by 50% – 2C9*2 in 10% Cauc and <5% A, B and reduces enzyme activity by 15% – Variant alleles need lower doses, more time to stabilize INR, higher risk of bleeding |
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R98W VKORC1
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– enzyme activity is way down w/ spontaneous bleeding (VKCFD2)
– introns means decreased warfarin binding and warfarin resistance – SNP’s can increase or decrease enzyme activity |
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DMD incidence
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- Most common childhood muscular dystrophy
- 1/3500 male births - female carriers estimated to be 1/1500 |
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DMD inheritance
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- X-linked recessive, gene on Xp21
- 2/3 of mothers are carriers, 1/3 are new mutations - a genetic lethal as affected males rarely, if ever, reproduce |
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DMD mutations
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- Allelic heterogeneity
– dystrophin gene large (2300 kb) - 70% of w/ DMD and 85% w/ BMD have a deletion or duplication - detectable by PCR or Southern blotting – 30% w/ DMD have small insertion, deletion, point mutation, or splice site mutation - detectable by mutation scanning and/or sequencing |
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What are DMD carriers at greater risk for?
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LV dilation and cardiomyopathy
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for MCAD deficiency, what do you look for on MS/MS
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look for C8 and C10
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