Week 3 - B - Neurogenetics - Huntington's, DMD, Alzheimer's disease

Question 1

X-linked recessive genetic condition only occurs in males Involves dystrophin gene What is this?

Answer 1

This is duchenne muscular dystrophy

Question 2

Why might females show symptoms of duchennes musular dystophy if they inherit one abnormal x gene?

Answer 2

• Females are XX thus can be carriers and show symptoms of muscle weakness due to X inactivation Normal X-inactivation happens in females so they can sometimes express some phenotype

Question 3

At what age should a child be able to walk by and at what age should you start worrying about a cause likes DMD?

Answer 3

Should be able to walk by 12months If unable by 18months then worry

Question 4

What does death in DMD usually occur due to?

Answer 4

Death from involvement of respiratory and cardiac muscles in 20s

Question 5

What muslces are typically enlarged in DMD? (it is known as a false enlargement) What is this type of hypertrophy known as?

Answer 5

These are the calf muscles Pseudohypertrophy as the muscle is often replaced with fat or scar tissue

Question 6

Mutation in a gene that codes for which protein is the main cause of DMD? What is the sign known as seen when a boy tries to stand and has to use his hands to help aid him? How do boys with Duchennes muscular dystophy tend to walk? What can be said about the boys posture?

Answer 6

The protein is dystrophin It is known as Gower’s sign - weakness in the proximal musces makes it difficult for the boys to stand They tend to walk on their toes - toe walking Also have an excessive lumbar lordosis

Question 7

What investigations carried out in DMD?

Answer 7

Raised serum creatine kinase Carry out electromyography Muscle biopsy - stain for dystrophin gene

Question 8

When identifying the cause of the proximal girdle weakness in suspected duchenne or beckers muscular dystrophy, it is important to rule out other causes of dystophies that can occur Name an autosomal recessive type of limb dystophy?

Answer 8

This would be autosomal recessive limb girdle muscular dystrophy (ARLGMD) LGMD usually manifests in the proximal muscles around the hips and shoulders.

Question 9

• Children present with characteristic posture of exaggerated lumbar lordosis What percentage of boys with DMD present with a de novo mutation causing the disease?

Answer 9

This is seen in 1/3rd of cases where the mother is not actually a carrier of the disease

Question 10

Huntingson’s disease occurs due to progressive degeneration of which parts of the brain?

Answer 10

Progressive degeneration of the basal ganglia and cerebral cortex

Question 11

At what age does Huntington’s disease typically present?

Answer 11

Usually presents between the ages of 30-50 years of age

Question 12

Huntingtons occurs due to an inherited mutation in the HTT gene which codes for huntingtin protein This mutation increases the number of trinucleotide CAG repeats. WHat is normally the number of these repeats in the HTT gene? How many are ther ein Huntington disease? People with juvenile huntingtons tend to have how many CAG repeats?

Answer 12

This is a trinucleotide repeat expansion in the CAG segement of the HTT gene which codes for huntingtin protein Normally there is up to 35 CAG repeats but in Huntington’s 36 and above is where people usually have the disease. Pe ople with the juvenile form of the disorder tend to have more than 60 CAG repeats.

Question 13

What chromosome codes for the huntingtin protein? Which amino acid does the CAG codon code for?

Answer 13

Chromosome 4 CAG codes for glutamine

Question 14

What are the two main symptoms of Huntington’s disease?

Answer 14

Chorea and progressive dementia Behavioural changes such as irritability are very common and depression

Question 15

Clumsiness, chorea and progressive dementia are all signs of Huntington’s disease What is a common late sign in the present

Answer 15

Slurred speech is a late presenting sign in Huntington’s disease, swallowing difficulties also arise

Question 16

Which parts of the basal ganglia usually have atrophy? How many CAG repeats are nromal again and how many in Huntington’s?

Answer 16

Caudate nucleus and putamen atrophy Up to 35 CAG repeats in the HTT gene (Huntingtin gene) and above 40 in Huntingtons disease

Question 17

What is the commonest form of dementia? Usually results in atrophy of which parts of the brain and widening of which parts?

Answer 17

Alzheimer’s disease is the commonest form of dementia Macroscopic – decreased size and weight of brain , there is widening of sulci and narrowing of gyri

Question 18

Pathology of Alzheimer disease- Loss of cortical neurones Neurofibrillary tangles (intracellular) Senile plaques (extra cellular depositis) What are the neufribillary tangles?

Answer 18

These are aggregates of a protein called Tau proteins

Question 19

What are the senile (neuritic) plaques in alzhiemers disease formed from?

Answer 19

The plaques are extra cellular protein depositis containing amyloid beta-protein

Question 20

• The central element of the neuritic plaques in dementia is the amyloid AB produced by cleavage of amyloid precursor protein. How does this cause further brain damage in alzheimers disease?

Answer 20

They recruit inflammatory cells and markers which further damage the brain

Question 21

Why is there a connection between Down syndrome and Alzhiemer’s disease? When does alzheimers disease tend to present in patients with downs syndrome?

Answer 21

This is because the amyloid precursor protein is found on chromosome 21 and therefore if there are trisomy 21, more likely to have more amyloid beta protein Patients with Downs syndrome typically acquire alzhimers disease far earlier ie age 30-40

Question 22

What are the three patholgoical traits of Alzheimer’s disease?

Answer 22

Cortical neuronal loss Neurofibrillary tangles - Tau protein aggregates Senile (neuritic) plaques due to amyloid beta protein

Question 23

In 5-10% of cases, what mode of inheritance is Alzhimer’s disease?

Answer 23

Autosomal dominant

Question 24

What three mutations are linked to autosomal dominant alzheimers disease? State the gene mutation and the chromosome?

Answer 24

• Usually associated with mutation in Presenilin 1 (chromosome 14) and Presenilin 2 genes (chromosome 1) or With mutation in amyloid precursor protiein on chromosome 21

Question 25

Apolipoproteins are also associated with an increased risk of developing alzheimers disease What is the main apoliopoprotein which has an increased risk of developing late onset alzheimers disease?

Answer 25

• E4 allele predisposes to Alzheimer disease with clustering in families • E4 genotype = 55% patients develop Alzheimer’s by 80 years old

Question 26

What medications can be given for DMD? What medications can be given for Huntington’s?

Answer 26

DMD - physiotherapy is important for the muscles, steroid usage has been shown to help reduce speed of muscle weakening also Huntington’s disease - anti-depressants and regular exercise

Question 27

AChE inhibitors can be given in the treatment of alzheimer’s disease Name one AchE inhibitor?

Answer 27

Donepezil Rivastigmine Galantamine

Question 28

which drug can be given for severe Alzheimers disease?

Answer 28

anti-glutamergic memantine this is an NMDA receptor antagonist which is where gluatamte can bind to therefore decreases the excitation caused by glutamate and no overproduction of calcium which can be damaging

Question 29

what herbal remedy is sometimes bought by patients with Alzheimer’s disease? what drug can it interact with?

Answer 29

ginkgo biloba - this is a herbal remedy and can interact with warfarin therefore important to ask about if patients have dementia and or on the warfarin anticoagulant

Question 30

There are different clinical screening tests for cognitive impairment

What screening assessments would be used in a patient with dementia?

Answer 30

• MOCA - montreal cogntivie assessment
• Could then do an Addenbrooke’s - big 100 marker

Likely ones done in Tayside