L44. Genetics of Neurological Disorders Flashcards Preview

06. Neuroscience > L44. Genetics of Neurological Disorders > Flashcards

Flashcards in L44. Genetics of Neurological Disorders Deck (47):

What are the two types of neurodegenerative conditions that show motor signs changes


  1. Acquired (cerebrovascular disease, tumours, alcoholism, vitamin deficiencies, etc)
  2. Inherited: Subset are caused by a particular type of genetic mechanism: unstable repeat expansions 


A class of genetic conditions are caused by unstable repeat expansions. 

What is meant by an "unstable repeat expansion"?

It is a kind of mutation where trinucleotide (or morerepeats exceed the normal threshold of normal. 

They are characterised by the resultant expansion of a segment of DNA in this specific gene



Is it normal to have repeat regions in the gene?

There are naturally occurring repeat regions present in ‘normal’ gene. 

A specific number of repeat units make up this repeat region and each repeat is specific for each gene/condition 


What is a stable repeat segment?

When the repeat segment is below the theshold of normal range for that gene 


If there is repeat expansion in a sperm or egg cell that is below the threshold what is the implication...

  • For the individual?
  • For the offspring?

  • The individual will not have the condition
  • The offspring will most likely


What is an unstable repeat segment?

When the repeating unit is above the threshold in the sperm/egg ± spomatic cells


What is another term for an unstable repeat expansion?

Dynamic mutations 



What is meant by anticipation?

When the expansion size increases in following generations: the number of repeats increases with each generation


What is the relationship between anticipation and onset and severity of the condition?

It is usually associated with earlier onset and/or greater severity of symptoms


The more number of repeats, generally the earlier and the worse


What is the hypothesised mechanism of this repeat expansion?

Slipped mispairing is the current hypothesis:


  1. The template strand of genomic DNA undergoes normal replication (meiosis)
  2. During the replication processes the replicating strand dettaches inappropriately from the template 
  3. The replicating strand then slips from its proper alignment with the templant strand by one repeat length 
  4. This causes the process of replication to incorporate an extra repeat in the new strand


Why is there a theshold of the repeating units and what sets it?

We don't know

There is a different threshold that is unique to each gene so we don't yet understand what defines this


Complete the following statements...

  • Unstable repeat expansion disorders are primarily __________
  • _____ repeats are the most common types of repeats
  • The have _________ inheritence patterns

  • Unstable repeat expansion disorders are primarily neurological
  • Triplet repeats are the most common types of repeats
  • The have variable inheritence patterns


What the four main trinucleotide repeat disorders?

  1. Huntington Disease
  2. Fragile X syndrome
  3. Myotonic dystrophy
  4. Friedreich ataxia


What does the gene expression, protein formation and type of protein involved depend on?

Where in the gene a the unstable repeat expansion occurs


What are the classes of unstable repeat expansions?

Class 1: Non-coding repeats causing a loss of function due to impaired transcription of the affected gene

Class 2: Non-coding repeats that confer novel properties on the RNA (a toxic gain of function)

Class 3: Repeats in a codon that confer novel properties on the affected protein leading to production of modified proteins that override normal functioning



Give two examples of a class 1 (non-coding repeats leading to loss of function) unstable repeat expansion. 

  1. Fragile X syndrome
  2. Friedreich ataxia


They occur in the same gene, but the number of different repeats causes different syndromes


Give two examples of a class 2 (non-coding repeats leading to novel RNA properties) unstable repeat expansion. 

  1. Myotonic dystrophy
  2. Fragile X associated tremor ataxia (FXTAS)


Give two examples of a class 3 (coding repeats leading to impacted protein) unstable repeat expansion. 

  1. Huntington disease
  2. Some spinocerebellar ataxias (SCAs)


Characteristics of neurogenerative disorders: 

  • Characterised by a _________________
  • ________ and _______ clinical presentation
  • Mainly ______ onset disorders 
  • Symptoms are __________ over time

  • Characterised by a loss of movement control
  • Variable and overlapping clinical presentations
  • Mainly late onset disorders 
  • Symptoms are progressive (over time)


What is Huntington disease?

 A neurological condition caused by the death of brain cells in certain areas of the brain results in gradual loss of cognitive (thinking), physical and emotional function.


Describe Huntington Disease in terms of ...

  • Inheritance Pattern
  • Prevalance
  • Age of Onset
  • Main features [3]

  • Autosomal dominant
  • Around 1 in 10,000 - 20, 000
  • Late onset (35-44 year olds; 5-10% are diagnosed <20 yrs)
  • Movement/motor disorders (chorea), cognitive disorder, psychiatric/emotional disorder


If one parent has Huntington disease, what is the chance of the offspring inheriting it?

Because it is autosomal dominant, there is a 1 in 2 chance (50%) of developing Huntingon disease



What is the time from from diagnosis (clear onset of symptoms) to death for Hunginton Disease?

As a progressive disease, the time frame is roughly 10-15 years 


What are the early features of Huntington disease?

Clumsiness, agitation, irritability, apathy, anxiety, disinhibition, delusions/hallucinations, abnormal eye movements, depression 


What are the middle features of Huntington disease?

Involuntary movements, chorea, trouble with balance and walking, trouble with activities that require manual dexterity, slow voluntary movements, general weakness, weight loss, speech difficulties (dysarthria), stubbornness 


What are the late clinical signs of Huntington Disease?

Rigidity, bradykinesia (difficulty initiating and continuing movements), serious weight loss, inability to walk, inability to speak, danger of choking on food, inability to care for oneself 


Almost catatonic


Is there a way of predicting the development of Huntington's disease before onset of symptoms?

There are very subtle prodromal signs such as cognitive and motor behaviour and brain imaging but they are not large enough to be used as a screening 


What is the genetic basis of Huntington Disease?

  • CAG repeat expansion
  • In the HTT (HD) gene on chromosome 4
  • The gene spans 180kb with 67 exons
  • The repeat is in the coding region in exon 1 
  • Since CAG encodes glutamine = it is a polyclutamine problem


What protein is affected in Huntington Disease? What is the normal role of it?

Huntingtin HTT protein

  • Involved in Transcription
  • Intracellular transport of other molecules
  • Intracellular signalling and metabolism
  • Reducing apoptosis 


The expanded CAG huntingtin product (polyQ-huntingtin) is toxic to the basal ganglia. What cell type is it particularly dangerous to?

Medium spiny neurons

= progressive degeneration and loss of medium spiny neurons in the striatum of the basal ganglia


But also widespread atrophy in the brain is caused eventually


Describe the molecular pathology of Huntington Disease

  1. PolyQ-huntingtin is cleaved by caspases and other enzymes genertaing N-terminal fragments with altered conformation (these are toxic)
  2. They form aggregates and nuclear inclusions 
  3. The lost function of the normal HTT and the possible toxicity of the new mRNA might also contribute to pathogenicity



What is the effect of the extended polyglutamine tract on the huntingtin gene in the cell? (the medium spiny neuron of the basal ganglia)

  • Excitotoxicity
  • Oxidative stress
  • Impaired energy metabolism
  • Apoptosis
  • Altered interaction with proteins
  • Impaired protein clearance


What is the spectrum of CAG repeat units and the severity and penetrance of HD?

ie. the genotype/ phenotype correlation

The number of repeats determines penetrance

Normal ≤ 26 rpts

‘Normal’, mutable (intermediate size) - paternal transmission  27-35 rpts

Zone of reduced penetrance  36-39 rpts

Affected (completely penetrant) ≥ 40 rpts (100% development of HD) 





CCG interruptions are often involved in the CAG repeat segments. What is the impact of this?

 The CCG interuptions mitigate (dampen) effects of the CAG repeats (they are a good thing in this case)


Describe the classical genetic testing of HD

PCR (radioactive nucelotide ‘tagging’), gel electrophoresis and autoradiography 

Because there is a use of enzyme in PCR there is a high risk of getting errors introduced when looking for small differences in repeat numbers. The ladder pattern where no single band is seen: they took the darkest two bands as the positive


What is the current means of testing for HD?

PCR using flourescent nucleotide 'tagging' and fragment analysis on capillary electrophoresis and flourescence detection



What is spinocerebellar ataxia?

A progressive, degenerative, genetic disease with multiple types (>35 now described, 10 of which are due to unstable repeat expansions). 

Degeneration of the cerebellum is concerned with damaged coordination of movements and can bring on spasticity.




Describe spinocerebellar ataxia in terms of...

  • Inheritance pattern
  • Prevalence
  • Age of onset
  • Main features

  • Autosomal dominant
  • The frequency of the different types varies in different populations
  • Late onset (generally)
  • Progressive degeneration of cerebellum, brainstem and spinocerebellar tracts causing problems with gait, hand coordination, speech and eye movements 


What is the genetic basis of SCA?

CAG repeats occuring in a number of different genes (causing the different types) 


How is SCA 6 different to the others?

SCA6 is different because it codes a gene that encodes a subunit of a calcium channel. Abnormal repeats has a dominant negative effect and impacts on the normal channel subunits around it.

SCA6 doesn’t have anticipation compared to the others


What is Friedreich ataxia?

An nherited condition that causes progressive damage to the nervous system resulting in muscle weakness, loss of balance and coordination (ataxia), speech problems and heart disease. 


Describe Friedreich Ataxia in terms of:

  • Genetics
  • Prevalence
  • Carrier Frequency
  • Age of Onset
  • Main Features

  • Autosomal recessive
  • 2-4 in 100,000
  • 1/60 and 1/100 in Indo-europeans
  • Usually around puberty (10-15yrs)
  • Progressive limb and gait ataxia, cardiomyopathy in 65% (most common cause of death) 


Describe the genetic basis of Friedrich Ataxia

  • GAA repeat expansion
  • in the FXN gene found on chromosome 9
  • The repeat is located in an intron (non-coding) leading to an abnormal secondary structure and reduced protein production


What is the impact of the repeat GAA expansion in to the protein being coded by the affected intron?

Protein is called Frataxin

It doesn't change the protein but it swtiches off gene transcription (changed secondary structure of RNA - hairpin loops that trigger epigenetic silencing)

The defect in this protein causes mitochondrial iron accumulation leading to oxidative damage


What is the spectrum of GAA repeat units and the severity and penetrance of Friedrich Ataxia?

ie. the genotype/ phenotype correlation

Normal range: 5 to 33 repeats *

Affected range: 66 to 1700 repeats

34 - 65 (uninterrupted) repeats are regarded as premutation (mutable) range

[Can expand more than 10-fold]

* Alleles longer than 27 GAA triplet repeats are often interrupted by a (GAGGAA)n sequence – stabilises alleles? 


Because the difference between normal and affected is relatively large in the affected range, what does this mean for diagnosing tools?

We can use normal PCR very easily


What are some ethical issues in predictive/pre-symptomatic genetic testing [6]

  • Different implications in laboratory diagnosis of genetic disease
  • Implications for not only patient, but also other family members
  • Formal consent, genetic counselling and confidentiality issues, especially with predictive testing (restricted access to results)
  • Insurance (life, disability) implications (NB family history)
  • Predictive testing in children not usually encouraged (NB ‘mature minors’)
  • Prenatal testing, including pre-implantation genetic diagnosis (PGD) possible – need to know mutation/haplotype in parent