Term
| genetic basis of disease: traditional mechanisms |
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Definition
1. chromosomal disorders
2. single-gene disorders
3. polygenic/multifactorial disorders |
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Term
| genetic basis of disease: novel mechanism |
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Definition
1. mosaicism
2. imprinting: uniparental disomy, parent of origin effects
3. unstable DNA: trinucleotide repeat disorders
4. maternal (cytoplasmic) inheritance |
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Term
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Definition
responsible mutation for genetic disorder is stable from across generations, all affected members share identical inherited mutation
- different from trinucleotide repeat disorders |
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Term
| unstable dynamic mutations in a gene |
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Definition
new class of genetic disorders
most common is trinucleotide repeat disorders |
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Term
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Definition
a mutation which changes upon transmission
ex. trinucleotide repeat disorders |
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Term
| trinucleotide repeat disorders |
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Definition
- characterized by expansion in "increasing number of 3 nucleotide repeats"
ex: CAG CAG CAG CAG ... etc.
- disease occurs when expansion of repeat is beyond a certain threshold
1. below threshold: length of repeat is stable in both mitosis and meiosis
2. beyond threshold: length of repeat unstable at meosis and maybe mitosis |
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Term
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Definition
progressively earlier onset and increased severity in successive generations
- mild symptoms in 1st generation to severe in successive generations
- general mechanism: stepwise expansion of unstable triplet repeats over generations
- hallmark of several trinucleotide repeat expansion disorders |
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Term
| important features of trinucleotide repeat expansion disorders |
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Definition
1. repeats change size from parent to offspring
2. sex of transmitting parent = parental gender bias (some more unstable from mom, some from dad) |
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Term
| molecular mechanism of trinucleotide repeat expansion disorders |
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Definition
slippage mispairing mechanism:
1. replicating strand detaches inappropriately from template during replication
2. replicating strand slips from proper position w/ template strand by 1 repeat length
3. mismatch repeat loops out
4. newly synthesized strand contains an extra repeat |
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Term
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Definition
- most common heritable neuromuscular disorder
- triplet expansion of CTG in noncoding region (3' end of gene) of myotonic dystrophy gene at 19q13.3
- characterized by extreme variability, anticipation, differential expansion in maternal and paternal alleles
- maternal allele bias: greater expansion
- clinical features: neuromuscular, progressive disease, multi-organ-system disorder of skeletal and smooth mm, heart, eyes, endocrine system and CNS |
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Term
| myotonic dystrophy: molecular features |
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Definition
3 types:
1. mild: cataract and mild myopia = 50-150 CTG repeats
2. classic: muscle weakness and wasting, myotonia cataract, arrythmia, grip myotonia = 100-1000 CTG repeats
3. congenital: hypotonia and severe general weakness at birth, respiratory insufficiency, early death, mental retardation is common = >2000 CTG repeats
- clinical tests: EMG, serum creatine kinase (CK), eye exam |
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Term
| myotonic dystrophy: inheritance |
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Definition
autosomal dominant
incidence 1/8000 |
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Term
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Definition
19q13.3
dystrophy myotonic protein kinase (DMPK)
RNAs from expanded allele create gain-of-function mutation by inappropriate binding of proteins to CUG repeats (RNA binding proteins) |
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Term
| myotonic dystrophy: molecular genetics |
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Definition
5-30 repeats: normal allele, no clinical feature
38-54: premutation, usually asymptomatic w/ increased risk of passing on fully expanded repeats
50-100: mildly affected, severity increases and age of onset decreases as expansion increases in lenght |
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Term
| myotonic dystrophy: congenital form |
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Definition
always maternally inherited
- facial weakness
- heart defect
- developmental delay |
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Term
| myotonic dystrophy: in males |
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Definition
distal weakness
frontal baldness
myotonic grip
cardiac arrythmia
infertility |
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Term
| fragile X syndrome: major phenotypic featurese |
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Definition
- x-linked mental retardation disorder (leading cause)
- moderate mental retardation in males, mild in females
- behavioral abnormalities: hyperactivity, hand flapping, biting, temper tantrums, poor eye contact, autistic features
- before puberty in males: large head
- after: long face, large ears, prominent jaw, large testis
- age of onset: childhood |
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Term
| fragile X syndrome: molecular genetic features |
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Definition
- prevalence 1/4000 males, 1/8000 females
- FRM1 gene encodes for RNA-binding protein called FRMP, expressed in cells including neurons = loss of function mutation
- 99% of FRM1 mutations are expansion of CGG repeat at 5' end of gene |
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Term
| fragile X syndrome: different types of mutated alleles |
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Definition
- normal alleles of FMR1: 6-50 CGG repeats (no risk)
- premutation alleles 59-200 CGG repeats - normal intellect
- full mutation >200 CGG repeats leading to hypermethylation of promoter region of FMR1 gene (at 5' end)
- full mutation occurs from premutation alleles w/ maternal transmission = loss of function
- risk of expansion increases w/ length of premutation |
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Term
| fragile X syndrome: somatic mosaicism |
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Definition
| - full mutation is mitotically unstable leading to somatic mosaicism where some pts have mixture of cells from premutations to full mutations |
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Term
| fragile X syndrome: female carriers |
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Definition
| female premutation carriers are at risk (20%) risk of premature ovarian failure (POF) |
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Term
| fragile X syndrome: male carriers |
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Definition
male premutation carriers are at risk of fragile x-associated tremor/ataxia syndrome (FXTAXS)
- manifest progressive cerebellar ataxia and tremor
- loss of short term memory and parkinsonism
- penetrance is age dependent (17% at 60 yrs of age) |
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Term
| fragile X syndrome: analysis |
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Definition
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Term
| fragile X syndrome: risk determined by? |
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Definition
1. size of premutation
2. sex of fetus
3. family history |
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Term
| huntington disease: incidence |
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Definition
panethic autosomal dominant
3-7/10,000 in western europeans |
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Term
| huntington disease: phenotype |
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Definition
voluntary and involuntary muscle movement
cognitive abnormalities being early, affect language
behavioral disturbances: aggression, outbursts, apathy sexual deviation, incr appetite
psychiatric manifestations
at end stage - severe motor impairment, fully dependent
mean age of presentation: 35-44 yrs |
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Term
| huntington disease: pathogenesis |
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Definition
huntingtin gene on chr 4p
gene product toxic to cells: gain of function mutation
expansion of CAG repeat in exon 1 encoding polyglutamine
normal allele <26
mutant normal allele 27-35
HD allele w/ reduced penetrance 36-39
HD allele >40 - 99% penetrance
age of onset is inversely proportional to # of CAG repeats |
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Term
| huntington disease: pedigree |
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Definition
| can miss generations even tho its autosomal dominant |
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Term
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Definition
alleles >36 repeats expands in lenght from paternal transmission
expansion from maternal expansion is less frequent |
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Term
| huntington disease: molecular diagnostics |
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Definition
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Term
| huntington disease: management, inheritance risk |
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Definition
no curative tx available
therapy focuses on supportive care
each child of parent has 50% risk of inheriting mutant HD allele
except for alleles of incomplete penetrance (36-39) all children inherting HD allele will develop HD |
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