Clinical Coorelates of Genetic Anticipation

what specific gene and chromosome is impacted by Myotonic Dystrophy (MD)

Dystrophia Myotonica Protein Kinase (DMPK) gene on chromosome 19q

what gene causes fragile X syndrome

FMR1

in Friedreich's Ataxia (FRDA), what portion of what gene is impacted? how is it impacted?

GAA triplet expansion in an intron of the frataxin gene

the Sherman Paradox observed what 2 things?

1- The effects of Fragile X cognitive impairment seemed to worsen with each successive generation 2- The risk of expressing cognitive impairment could also be dependent on the position of an individual in the pedigree

what are the two subclasses of trinucleotide repeat disorders

1- Trinucleotide repeat in the non-coding regions 2- Trinucleotide repeat in coding regions --- those in which the trinucleotide repeat expansion are exonic

describe the link of autism and fragile X

2-6% of individuals with autism are because of fragile X - autism can be caused by things other than fragile X but it is important to know the reasons behind why an individual has autism because if it is due to a genetic condition there is usually other medical manifestations that need to be addressed

what specific non-coding region is impacted in Myotonic Dystonia (MD)

3' UTR

premutation repeat size 3' UTR MPK gene

38-49 repeats

In unaffected individuals (of fragile X) , the CGG triplet number is stable and usually less than ____

40

normal repeat size 3' UTR DMPK gene

5-37 repeats

what does genetic anticipation mean

Phenotype appears to get progressively worse in subsequent generations

what does FMR1 protein do

an RNA-binding protein. Normally, it functions to regulate/repress mRNA translation

The greater the number of repeats the greater the chance that ______________________

an individual will be affected = mechanism for Genetic Anticipation

symptoms of mild myotonic dystrophy

cataracts, mild myotonia, premature balding starting around age 60

what part of the brain is impacted by Friedreich's Ataxia (FRDA)

cerebellum

CTG repeat size of 100 to1000 or 1500 results in

classical myotonic dystrophy

CTG repeat size of 1000 to >2000 results in

congenital myotonic dystrophy (most extreme form)

in fragile X- where on the pedigree was the risk of expressing cognitive impairment most likely to be affected

daughter of an unaffected male carrier was more likely to have an affected offspring than the mother of the unaffected male carrier

what is the underlying etiology of the genetic anticipation phenomenon

due to the expansion of the number of repeats of a trinucleotide sequence in the causative gene

how does increased expansion impact age of onset in huntington disease

earlier age of onset of typical Huntington neurodegenerative symptoms

Larger GAA expansions in FRDA do correlate with ____________________________________ clinical features

earlier onset and/or more severe

what is a premutation

expansion of repeat, but not significant enough tocause phenotype

what is the most common form of inherited genetic impairment

fragile X

what are the results of the mRNA in individuals with >200 repeats in the frataxin gene

gene silencing or lack of transcription of the frataxin mRNA

what is an example of a disorder that is caused by a trinucleotide repeat in coding regions

huntington disease

sx of congenital myotonic dystrophy

infantile hypotonia, respiratory insufficiency/failure, cognitive impairment (typically lethal)

Low expression of Frataxin results in mitochondrial dysfunction due to __________ accumulation

iron

what does the frataxin gene do

localizes to the mitochondrial membrane

As the length increases in Fragile X, the probability of additional CGG repeats (insertions) also increases during ______________________

meiosis and gamete production

Expansion > 200 repeats of a trinucleotide results in

methylation of the promoter and decreased ability to express the FMR1 mRNA/protein

CTG repeat size of 50 to 150 results in

mild myotonic dystrophy

When child is affected with congenital myotonic dystrophy, mother is expected to exhibit

mild/classical form for example, in this case, the child congenital, mother is classical, grandmother is mild

Huntington disease is a progressive disorder of ______________________ disturbances

motor, cognitive, and psychiatric

DMPK gene codes for

myotonin protein kinase

Friedreich's Ataxia (FRDA) causes what type of deterioration? when would this manifest?

neurological deterioration, beginning durig puberty

what type of disorders are caused by the protein aggregation in trinucleotide repeats of coding regions. when in life does this present?

neuronal dysfunction that begins in mid-life

are children able to be tested for huntington disease- why or why not

no because they would not manifest sx until beyond age of consent. they can choose to test for themselves when they are old enough

because Females with premutations of the FMR1 gene are at an increased risk for premature ovarian cancer, are females with full mutations guaranteed to get it?

no they are not associated with any premature ovarian failure

why might there be a larger GAA expansion in the FRDA gene

occur as gene is passed from generation to generation but these expansions themselves are unstable and can also contract, especially upon inheritance via sperm transmission

who is most likely to show clinical symptoms of FXTAS: Fragile X-associated Tremor/Ataxia syndrome

older individuals carrying premutation expansions of the CGG repeat

what is an unstable premutation

one that may expand or contract during replication

Fragile X syndrome: trinucleotide expansion more likely wheninherited via

oocyte

CTG premutation repeat associated with Myotonic Dystrophy (MD) can expand when inheritance is via an __________ and contract when inheritance is via a __________

oocyte, sperm

Females with premutations of the FMR1 gene are at an increased risk for premature

ovarian failure

CAG repeats results in a tract of _________________________ in protein coded by gene

polyglutamine residues

Sherman suggested that a "_____________" doesn't cause severe symptoms but, as the gene is passed from generation to generation, the likelihood that this would convert to a "full" mutation, resulting in the classical signs of Fragile X syndrome, increased especially when passed through _______________-

premutation, a female

describe the mechanism of FXTAS: Fragile X-associated Tremor/Ataxia syndrome

premutation- create extra amounts of mRNA and abnormal amounts of FMR protein full mutation- promotor completely shut off and no protein created = full effects of fragile X

what are the signs of FXTAS: Fragile X-associated Tremor/Ataxia syndrome

progressive neurologic disorder with worseningtremor and ataxia (balance disorder)

We now know that the etiology of the sherman paradox is due to the expansion of the number of repeats of a trinucleotide sequence (CGG) normally present in the________________ of the FMR1 gene

promoter (5' end)

Polyglutamine causes_________________________, especially in the nucleus. These are "____________________" mutations

protein aggregation; gain of function

what clinical manifestations are there when there is unregulated proteins translation in Fragile X

seizures, hypersensitivity to sensory stimuli, and loss of normal learning

Overall phenotype corresponds with length of the ____________ of the two frataxin alleles

shorter

Expansion of Huntington gene primarily occurs after __________ mediated inheritance

sperm

why are females with premutations of the FMR1 gene are at an increased risk for premature ovarian failure while females with FULL FMR1 mutations are not affected?

the LENGTH of the trinucleotide expansion determines this risk, with those females having ~80 CGG trinucleotide repeats being at the highest risk for POF, relative to females with lesser, or greater expansions

with the increased repeat size of the DMPK gene, how does this impact DMPK protein

they are unaffected

How are fragile X syndrome and Down syndrome similar?

they both have cognitive impairment 1- down is the most common form of genetic impairment but it is not always INHERETED 2- fragile X is the most common form of inherited genetic impairment

Myotonic Dystrophy (MD) is due to trinucleotide repeat generally in what region of the genome

trinucleotide CTG repeat in the non-coding region, this time an autosomal gene

Symptomatic forms of Myotonic Dystrophy depend on

trinucleotide expansion size

loss of FMR1 protein in Fragile X leads to __________________ which impacts __________________

unregulated protein translation, neuronal development that needs to happening in a timed fashion

sx of classical myotonic dystrophy

weakness, myotonia, cardiac arrhythmias, pulmonary weakness with respiratory insufficiency

symptoms that manifest due to the cerebellar involvement in Friedreich's Ataxia (FRDA)

- Ataxia (gait disturbance) - Dysarthria (speech problem and subsequent dysphagia) - Titubation (excessive bobbing back and forth of head or trunk to maintain position in space) - scoliosis - pes cavus (high arched feet) - hearing loss other system involvement: - Cardiac (arrhythmia, hypertrophy) - Endocrine (diabetes)

what are examples of trinucleotide repeats in the non-coding regions

- Fragile X syndrome (FRAXA) - Myotonic dystrophy (MD) - Friedreich ataxia (FRDA)

what is an examples of trinucleotide repeats in the coding regions

- Huntington's disease

what are the clinical features of fragile X syndrome

- Macrocephaly - Large ears - Macro-orchidism (measured with orchidometer) - Echolalia- repetition of speech - Perseverative speech- can't get off a thought - Gaze avoidance

Why or how are carrier females of Fragile X carrying full mutation affected or not affected? (3)

- Maybe they are affected (soft signs of cognitive delay, poor school performance) - X-inactivation of mutant X chromosome - They haven't manifested yet -- need time

if testing for huntington disease, what is required first

- psychiatric evaluation of pt because carrier and non-carrier status have equally distressing associations - two physicians to sign off

clinical presentation of a person with huntington disease

- spasticity - chorea (form of movements; chorea is from the Greek = dance) - bradykinesia- move slower - hyperreflexia - personality changes - psychosis

explain why BRCA1 and BRCA2 genes show genetic anticipation

As the BRCA1 and BRCA2 mutations are passed on in families, the telomeres of BRCA1 or 2 carriers are SHORTER than in the general population, and correlate with an increased risk of getting breast cancer at an earlier age

what is the inheritance pattern of Huntington disease

Autosomal dominant

Friedreich's Ataxia (FRDA) inheritance pattern

Autosomal recessive

age of onset and death for classical myotonic dystrophy

Average age of onset: 10-30 years Average age of death: 48-55 years

what is another diseases showing genetic anticipation that is not based on trinucleotide repeats

BRCA1/2 genes

Trinucleotide repeat in coding regions are often repeats of what nucleotides?

CAG codon - codes for glutamine

_______________ repeats in the___________ region ► abnormal _________________ in Huntingtin protein, which eventuates in neuronal dysfunction

CAG; coding; polyglutamine tract