TNR DIsorders and Imprinting Flashcards
what happens clinically because of genetic anticipation in TNR disorders
TNRs expand with subsequent generations, so the disease presents at an earlier age and becomes more severe
where in the affected gene do trinucleotide repeats occur for the following diseases:
a. Friedreich ataxia
b. myotonic dystrophy
c. Huntington’s
d. Fragile-X
5’ UTR - Fragile X —> excess repeats trigger DNA promoter methylation [DNA meXylation]
Exon - Huntington’s —> glutamine repeats (CAG) cause protein misfolding, aggregation
Intron - Friedreich ataxia —> insertion prevents intron splicing [FriedrINSERTION ataxia]
3’ UTR - myotonic dystrophy —> large hairpin loop sequesters RNA splicing factors, causing RNA toxicity [myoTOXIC dystrophy]
location of expansion impacts pathogenesis
You’re a neurologist (yay). Pt is a 32 yo M presents with dysarthria (slurred speech), dysphagia, and slow ataxic gait. SHx (social history) includes change in personality during his late 20s from extroversive to non-conversant. FHx is unremarkable. Pt is found to have dementia and be uncoordinated upon neurological exam. Cranial nerve exam reveals abnormal saccadic eye movements and increased tone in all extremities.
What will you test for, what are the characteristic features of this disease, and what is the cause and hereditary pattern?
Huntington’s - hasn’t appeared in FHx yet, but due to anticipation pt develops it sooner
characteristic features: abnormal saccadic eye movements, chorea (involuntary movements), ataxia (voluntary movements), dementia
cause: CAG (glutamine) repeats in EXON of chromosome 4 (huntingtin protein, HTT) —> protein misfolding and aggregation —> neuronal loss in caudate and putamen (striatum)
inheritance: autosomal dominant
(but expansion only happens paternally. mother can transmit if she already passes 40 repeat threshold)
what disease is this?
AD, TNR in exon of chromosome 4
Huntington’s
CAG repeats - glutamines
first exon of chromosome 4
huntingtin (HTT) protein misfolding and aggregation
name the clinical features of Huntington’s related to:
movement
cognition
mood
behavior
Huntingtons:
chorea and ataxia (movement)
dementia (cognitive)
depression (mood)
aggression (behavior)
typical onset in midlife, life expectancy 15-20 years following onset
what is the disease threshold for Huntington’s and through whom can expansion occur
40+ repeats - disease ALWAYS occurs
borderline - incomplete penetrance with 36-39 CAG, may have disease
intermediate HD gene - no diseases but tendency for expansion
repeat expansion occurs through spermatogenesis (PATERNAL transmission)
material transmission can occur if she already passes the threshold (no maternally caused expansion)
to diagnosis your patient’s Huntington’s disease, you use PCR to detect CAG expansion
the lane for the patient’s father shows bands of 20 and 37 CAG repeats
the pt’s lane shows bands of 23 and 49 CAG repeats
explain what these findings mean
father has a normal band of 20 CAG repeats and a permutation band at 37 CAG repeats
pt has a normal band of 23 CAG repeats and an abnormal (over threshold) band of 49 CAG repeats
spermatogenesis expansion must have occurred
You’re a pediatric neurologist (yay!). A mother with a mild learning disability comes brings her child into clinic because she is worried her 2yo M is not speaking. PE notes large ears and long, thin face. FHx includes uncle with intellectual disability. Neurological exam finds pt’s hearing is normal.
What disease is this, what are the characteristic features, what is the cause and inheritance pattern?
Fragile X syndrome: most common inherited cause of cognitive disability and autism spectrum disorders (X linked dominant)
cause: CGG expansion in 5’-UTR of FMR1 gene (RNA binding protein, regulates neuronal development) -> excess repeats trigger promoter methylation
characteristic features of full mutation, M: long/narrow face, prominent jaw, macro-orchidism (large testes), mitral valve prolapse
where does expansion occur in Fragile-X syndrome? describe the variation in phenotypes due to number of repeats
expansion occurs in OOGENESIS
pre-mutation: Primary Ovarian Insufficiency (early cessation of menses), Fragile X-associated ataxia syndrome
M, full mutation: cognitive disability, long/narrow face, prominent jaw, macro-orchidism (large testes, but normal function), mitral valve prolapse, joint laxity
F, full mutation: mild cognitive disability (learning and attention), autism spectrum disorder
Pt is 9yo M who presents with gradually worsening difficulty standing for periods of time and inability to run, and speech difficulties. PE is notable for broad-based gait, decreased vibratory and position sense in feet, and absent patellar and achilles reflexes. FHx is unremarkable.
What TNR disorder is this, where and what is the mutation, what is the inheritance pattern, and what are the characteristic features?
Friedreich ataxia (FRDA): autosomal recessive, GAA expansion in first INTRON of FXN gene on chromosome 9 (prevents splicing out of intron -> mRNA transcript loss)
most common cause of hereditary ataxia
clinical features: ataxic gait, progressive weakness, hypertrophic cardiomyopathy, but cognitive function preserved
[freGGGGeric’s AtaxiA]
most common cause of hereditary ataxia (and what is the mutation)
Friedreich ataxia: AR disease, TNR expansion in INTRON of chromosome 9
mutation in Frataxin mito protein (facilitates iron storage) —> mito dysfunction, energy depletion, selective cell loss (spinal cord, heart, pancreas - mito-rich tissues)
most common cause of inherited cognitive disability and autism spectrum disorders is due to what kind of mutation (and where)
Fragile X syndrome, XLD, TNR expansion in 5’-UTR of FMR1 gene (RNA binding protein, regulates neural development)
what is the clinical triad of Friedreich’s ataxia (AR TNR in INTRON of chromosome 9)
neurological dysfunction beginning in childhood - progressive ataxia (gait disturbance), sensory loss (position and vibratory)
hypertrophic cardiomyopathy (CHF, congestive heart failure) - most common cause of death
diabetes mellitus
most common cause of adult-onset muscular dystrophy
what kind of mutation is it, where is it, inheritance
myotonic dystrophy, type 1: autosomal dominant TNR expansion (CTG repeat) in 3’-UTR in DMPK gene (dystrophia myotonia protein kinase) —> surrounding genes are affected more than DMPK (RNA toxicity)
pronounced genetic anticipation (repeats into thousands)
congenital myotonic dystrophy almost always inherited MATERNALLY (worse expansion in females)
Pt is 30 yo F who presents with dysarthria (slurred speech) and grip myotonia. Neurological exam reveals weakness in many muscles. Genetic analysis finds unstable expansion of CTG repeats in the 3’-UTR region of DMPK gene. What is your diagnosis?
myotonic dystrophy, type 1
DMPK = dystrophia myotonia protein kinase gene
most common cause of adult onset muscular dystrophy
congenital MD is almost always MATERNALLY inherited (worse expansion occurs in females)
explain how number of CTG repeats in myotonic dystrophy (Type 1) can influence phenotype (what are the levels)
normal allele numbers will not expand
full mutation is either:
1. mild - mild myotonia, cataracts
2. classic DM1 - myotonia, muscle wasting, arrhythmias
3. severe/congenital - infantile hypotonia, respiratory dysfunction, cognitive impairment
what is the effect of a TNR expansion in a 3’-UTR region, such as of the DMPK gene in myotonic dystrophy (type 1)?
large hairpin loop in 3’-UTR sequesters RNA splicing factors (they are attracted to the loop) —> RNA toxicity
which of these TNR disorders are MATERNALLY transmitted (expansion occurs in females)?
a. Huntington
b Fragile X
c. Friedreich ataxia
d. myotonic dystrophy 1
MATERNAL transmission: Fragile X and Myotonic dystrophy 1
PATERNAL transmission: Huntington
Friedreich ataxia - transmission from both
what is the difference in effect between a genetically imprinted disease and a sex-limited disease?
genomic imprinting: parent of origin determines whether child has disease
sex-limited: sex of child determines the phenotype
if a gene is maternally imprinted, which allele is silenced
maternal … imprinting SILENCES the allele
paternal imprinting silences paternal allele
what happens to imprinted genes in the offsprings somatic vs germ cells
somatic cells - imprinted genes are not transcribed, regardless of the sex of the offspring (silencing depends on parent of origin… if maternal allele is imprinted, only paternal allele is expressed, even if offspring is female)
germ cells - all imprinting is erased in primordial germ cells and new imprinting occurs to correspond to sex of offspring
so… offspring somatic cells reflect parent, germ cells reflect offspring’s sex
Prader-Willi syndrome and Angelman syndrome are both due to chromosome 15q11-13 DEL
what is the key difference
Prader-Willi syndrome: PATERNAL deletion (paired with maternally imprinted allele)
[Prader = Paternal]
Angelman syndrome: MATERNAL deletion (paired with paternally imprinted allele)
[angelMan = Maternal]
explain why imprinting disorders are usually due to de novo deletions in the parent
imprinting disorders usually result in infertility, so the deletion could not be inherited
most common form of syndromic obesity
what is genetic cause
Prader-Willi syndrome: PATERNAL deletion in chromosome 15 containing maternally imprinted (silenced) genes
can also occur via maternal uniparental disomy (both genes silenced)
a child comes into your pediatric clinic presenting with hyperphagia that has led to obesity. PMH includes neonatal hypotonia, genital hypoplasia, reaching milestones late, and cognitive impairment. what are these findings consistent with, and what it’s the genetic cause?
Prader-Willi syndrome, PATERNAL deletion in chromosome 15 that includes maternally imprinted genes (or maternal uniparental disomy)
typically due to sporadic mutation in parent
what is the outcome and genetic cause of Angelman syndrome
neurodevelopmental disorder due to MATERNAL deletion of UBE3A (E3 ubiquitin ligase) gene, which is paternally imprinted
single gene defect
also could be caused by paternal uniparental disomy (because both alleles will be silenced)
a child comes into your pediatric clinic because they are non-verbal, show severe cognitive impairment, ataxia (balance issues), and microcephaly. PMH includes seizures. child is noted to have a happy demeanor.
What are these clinical findings consistent with?
Angelman syndrome: MATERNAL deletion in chromosome with paternally imprinted genes
loss of E3 ubiquitin ligase
disease phenotype will occur in offspring (be visible in pedigree) only when variant gene is inherited from female
what are the features of Beckwith-Wiedemann syndrome, an imprinting disorder involving chromosome 11
omphalocoele: abdominal wall defect
large baby and large viscera (notably large tongue)
neoplasia -> Wilm’s tumor, hepatoblastoma
