FMS Week 3 Flashcards
congenital cytomegalovirus infection
SNHL, chorioretinitis, microcephaly, ID
inheritance characteristics of Fragile-X
most penetrant in males (only one X), female heterozygotes may have ovarian failure and ataxia, typically X-dominant
general mechanism of FMR1 silencing
mutation leads to hypermethylation, silencing by HDACS, condensation of promoter
situs ambiguous
mixed laterality or body patterning
signs/symptoms of Angelman syndrome
ID/limited speech, ataxic gait, spontaneously happy affect, seizures
thalidomide
sleep and anti-nausea med used during pregnancy
phenotypic heterogeniety
multiple distinct phenotypes arising from different mutations in the same gene
general indications for ACE inhibitors
hypertension
what is the greatest cause of genetic disease?
multifactorial disorders
inheritance of myotonic dystrophy
autosomal dominant
teratogenic effects of anticonvulsants
nail hypoplasia (phenytoin), neural tube defects (valproic acid and carbamazepine)
pathogenesis of type one DM
autoimmune destruction of the beta cells of the pancreas
HOX genes
regional selection of patterning of body from hindbrain to tail
heterotopias
apparently normal neurons in abnormal locations
what type of condition is associated with LIS1?
neuronal migration: periventricular nodular heterotopia
cause of Fragile X syndrome
CCG triplet expansion in FMR1 region of X-chromosome
general anomalies associated with 2nd and 3rd trimester?
IQ, developmental problems
best potential vector for SCIDs?
lentiviral
teratogenic effects of tobacco
poor fetal growth, behavioral teratogenicity, IQ?
what type of condition is associated with FLNA?
neuronal migration: periventricular nodular heterotopia
teratogenic effects of Isotretinoin
CNS, cardiac, ear, thymic, branchial arch anomalies
MELAS
mitochondrial disease: mitochondrial encephalopathy lactic acidosis and stroke-like episodes
cause of Angelman Syndrome
“silencing” of maternal genes at 15q
signs/symptoms of Fragile-X
15-20% have developmental delay, characteristic facial features (large forhead, long face, prominent chin/ears), joint laxity, enlarged testes in adults, associated with autism
general anomalies associated with 1st trimester?
congenital malformations
general indications for methotrexate/misoprostol
cancers, dermatomyositis
teratogenic effects of maternal PKU
microcephaly, ID, cardiac defects, pregnancy loss
Syndrome vs Sequence vs Anomaly
Syndrome: a pattern of anomalies known or thought to be related to a gene or teratogen
Sequence: one or more secondary morphologic anomalies cascading from a single malformation, disruption, or deformation
Anomaly: an anatomic phenotype substantially departing from reference population
what is the surmised mechanism of uniparental disomy?
trisomy rescue (trisomy with loss of second parent’s chromosome around fertilization)
temporal colinearity
3’ HOX genes expressed earliest
Waardenburg Type 1
mutation in PAX3, results in hypertelorism, white furlock, deafness
treatments for mitochondrial disorders
No effective treatment; cofactors like coQ10, thiamine, vitamin E, and carnitine
cause of Prader-Willi syndrome
results from “silencing” of paternal genes at 15q
number of CAG repeats associated with inormal patient (nonHD)
<26
what is organogenesis?
2-9 weeks post conception; approximately the first trimester
cause of Friedreich Ataxia
nucleotide expansion mutation in FXN gene on chromosome 9, codes for Fraxatin which removes iron in the cytoplasm around mitochondria, leads to free radical damage to mitochondrial membrane
what are the disadvantages of Lentiviral vectors?
potential for activating oncogenesis, potential for insertional mutagenesis (non selective and contains its own promoter)
spina bifida
neural tube defect, failure of fusion of vertebral arch, typically in lumbar region, varying degrees of severity
Describe Sonic hedgehog syndrome
Mutation in SHH gene, Holoprosencephaly, clefting, malformed midline structures, (cyclopia, central incisor, absent frenulum etc)
what type of slippage would lead to trinucleotide expansion?
backward slippage
Waardenburg Type IV
Hirschsprung disease (aganglionic megacolon)
Describe Tuberous sclerosis
Disease associated with TSC1, TSC2 genes. Hamartomas, cardiac thabdomyomas, ungual fibromas, facial angiofibromas, ashleaf spots, and seizures.
teratogenic effects of gestational diabetes
(“abundant fuel”) macrosomia, high insulin levels, hypoglycemia, polycythemia, hypertrophic cardiomyopathy, microcolon
CFTR gene
associated with CF, membrane bound protein associated with Cl- channels
teratogenic effects of ACE inhibitors
renal failure, skull defects
what are the 2 most common congenital anomalies?
undescended testes and heart defects
CRISPR-Cas9 gene editing involves what repair mechanism?
homologous recombination
what is the role of PAX genes?
transcription regulators, initiate and orchestrate eye development
signs/symptoms of Prader-Willi syndrome
neonatal hypotonia & cryptorchidism, hypothalamic dysfunction: lack of satiety & obesity, hypogonadotropic hypogonadism, growth hormone deficiency: short stature & hypotonia, congnitive/behavioral impairment
teratogenic effects of thalidomide
stunted growth, phocomelia (“seal limbs”)
what is “Anticipation”?
worsening of triplet repeats in subsequent generations
teratogenic effects of lithium
ebstein’s anomaly of tricuspid valve
teratogenic effects of lead
impaired CNS function
antisense RNA therapy
oligoribonucleotides that pair to mRNA, can block translation/splicing
what tissues are most affected by mitochondrial diseases?
neuro, muscular, and cardiac
teratogenic effects of 1st trimester diabetes
(insulin dependent), cardiac/sacral defects, neural tube defects, pregnancy loss
number of CAG repeats associated with juvenile HD
60+
situs inversus
mirrored laterality or body patterning
general teratogenic effects of TORCH infections
IUGR, prematurity, hypo/hypertonia, seizures, microcephaly, hydrocephalus, chorioretinitis, cataracts, glaucoma, hearing loss, pneumonia, strucural cardio defects, hepatosplenomegaly, petechiae/purpura, rash, jaundice
teratogenic effects associated with methotrexate/misoprostol
multiple organ systems/structures, most within the 1st trimester
uniparental disomy
both members of a chromosome pair are inherited from one parent
MERRF
mitochondrial disease: myclonic epilepsy and ragged red fibers
teratogenic effects of cocaine
pregnancy loss, placental abruption, intrauterine growth retardation (IUGR), microcephaly
what are the disadvantages of Adenovirus vectors?
high immune response (because they are so infectious) and not stably integrated
gene associated with CF
CFTR, large gene, associated with thousands of mutations
heteroplasmy
When a cell contains multiple mitochondrial lines (mitochondrial “mosaicism”)
teratogenic effects of methylmercury
microcephaly, ID, cerebral palsy, minamata disease
what is a gene vector?
an engineered piece of DNA derived from a naturally occurring human virus
teratogenic effects of ACE inhibitors
decreased renal blood flow, renal failure, hypotension, anuria, skull hypoplasia, morbidity
Causes of nucleotide repeat expansions
hypermethylated regions/stable hairpins, mistakes during replication/repair, unequal crossing over during meiosis (gene conversion)
qualitative traits vs quantitative traits
qualititative: traits either present or not
quantitative traits: measurable physiological/biochemical quantities
signs/symptoms of Friedreich Ataxia
muscle weakness in arms/legs, loss of coordination, vision/hearing/speech impairment, scoliosis, high plantar arches, diabetes, heart disorders
describe SCIDs
severe combined immunodeficiency; due to adenosine deaminase deficiency, leads to build up of doxyadenosine and S-adenosylhomocysteine which are toxic to immune cells
periventricular nodular heterotopia
involves clusters of neurons that never begin migration, involved in 15+ syndromes
what are the disadvantages of Adenovirus-associated vectors?
small payload, infected cells are recognized by immune system and compromised
signs/symptoms of Myotonic Dystrophy
myotonia and wasting of smooth/skeletal/cardiac muscles, cardiac conduction defects, hypersomnia, cognitive changes, dementia
teratogenic effects of Zika virus
severe microcephaly, neurological complications, eyes and ears
mechanism of defect in myotonic distrophy
regions are “decoys” for CUG RNA binding proteins for mRNA metabolism, build up of non-degraded DMPK transcripts
what tissues are most affected by HD?
brain and testes
small interference RNA
siRNA, essentially artificial microRNAs that can target mRNAs using the RISC pathway, can be sent into the cell in engineered liposomes
cause of Noonan syndrome
a syndrome that arises from mutations in various proteins/enzymes related to the RAS-MAPK pathway
types of “silencing” in Prader-Willi/Angelman syndromes
At 15q: deletion, UPD, repression from imprinting defect, UBE3 mutation in Angelman
CPEO
mitochondrial disease: chronic progressive external opthalmoplegia
signs of fetal alcohol symptom
growth deficiency, microcephaly, learning disability, mild/moderate ID, behavioral (ADHD, impulsiveness, poor memory, conduct disorder), characteristic facial features
most common mutation class in cystic fibrosis
F508del (phenylalanine deletion)
situs solitus
normal laterality or body patterning
what are the 2 types of RNA-based therapies?
antisense RNAs and RNA interference
factors affecting teratogenicity?
timing, dose, predisposition (metabolism, genetics, physiology)
congenital rubella syndrome
IUGR, microcephaly, cataracts, hearing loss, chorioretinitis, meningoencephalitis, ID
NARP
mitochondrial disease: neurogenic ataxia and retinitis pigmentosa
when is a fetus/embryo most sensitive to teratogens?
organogenesis
what is the difference between malformation, deformation, and disruption?
malformations are intrinsic abnormalities in programs driving development.
deformations are from extrinsic forces on otherwise normally developing tissues
disruptions are when normal tissues are subjected to a destructive problem causing breakdown or loss (vascular, infection, etc.)
describe WAGR
Aniridia-wilms tumor association
PAX-6 deletion leads to aniridia, WT1 gene leads to Wilms tumor
inheritance of Friedreich Ataxia
autosomal recessive (25% recurrence)
anencephaly
anterior neural tube defect, 2/3 are female, typically stillborn or death shortly after birth
Type 1 vs Type 2 myotonic dystrophy
type 1: expansion in 3’ UTR of DMPK gene on chromosome 19q
type 2: expansion in zinc finger 9 (ZNF9) gene on chromosome 3
cause of Huntington Disease
CAG repeat expansion at HTT of 4p
what type of condition is associated with DCX?
neuronal migration: periventricular nodular heterotopia
spatial colinearity
3’ HOX genes expressed more anteriorly
number of CAG repeats associated with adult onset HD
40-60
TORCH
Toxoplasmosis Other (Varicella, syphilis, Zika) Rubella Cytomegalovirus Herpes
FMRP
protein associated with FMR1 gene (fragile-X); participates in RNA transport/function in neural cells
origination of cleft lip/palate
failure of fusion of frontal process with maxillary process early on (35th day of gestation), most common in males
MHC locus
major genetic factor in type 1 diabetes
what are the potential issues with CRISPR-cas9 systems?
unintentional editing, unpredictable effects on progeny, designer medicine
most common anomaly of folic acid deficiency during pregnancy
NTD (reduced blood folate and elevated homocysteine)
characteristic trait of Van der Woude syndrome (VWS)
bilateral lower lip pits
