Genetics

Question 1

Inheritance of duchenne muscular dystrophy?

Answer 1

X-linked recessive - Boys only
Delay in motor development
Onset of weakness around 3-4 years
Die from resp depression in 20s

Question 2

How do you diagnose Duchenne muscular dystrophy?

Answer 2

• Developmental delay in boys
• Muscle weakness (Gower’s sign, toe walking)
• Raised CK
• EMG

DDx for duchennes is autosomal recessive limb girdle muscular dystrophies (some caused by sarcoglycan deficiencies)

Question 3

Inheritance pattern of Huntington’s disease?

Answer 3

Autosomal dominant,

• involuntary movements
• dementia
• progression to severe disability and dependence within 15-20years
• age dependent penetrance

CAUDATE atrophy

Question 4

Late clinical signs of Huntington’s disease?

Answer 4

Bradykinesia (difficulty initiating and continuing movements)
Rigidity
Severe chorea (less common)

Question 5

What is the molecular genetic defect in Huntington’s disease?

Answer 5

It is in the Huntingtin gene, CAG codes for glutamine and it is the CAG42 that is mutated.

Question 6

What is the pathology seen in Alzheimers disease?

Answer 6

• Loss of cortical neurones
• Neurofibrillary tangles (intracellular)
• Senile plaques (extracellular)

Senile plaques are extracellular protein deposits containing amyloid beta protein.

Question 7

Genetic aetiology of Alzheimers disease?

Answer 7

Autosomal dominant in 10%
Down syndrome (onset in 3rd or 4th decade)

Question 8

Name a primary cause of demyelination?

Answer 8

Multiple Sclerosis

Question 9

Name a few secondary causes of demyelination?

Answer 9

Central pontine myelinosis.

Progressive multifocal leucoencephalopathy.

Question 10

Common clinical manifestations of multiple sclerosis?

Answer 10

• Visual disturbance
• Parasthesia
• Spasticity of one or more of the extremities.
• Gait abnormalities.

Question 11

Multiple sclerosis morphology?

Answer 11

External appearance of the brain and spinal cord is usually normal.
Cut surface - multiple areas of demyelination termed “plaques”

MS is a white matter disease and it is grey matter that covers most of the surface of the hemispheres.

Question 12

How do acute multiple scelerosis appear?

Answer 12

Demyelinated plaques that are yellow/brown with an ill defined edge that blends into the surrounding white matter.

Question 13

How do chronic multiple sclerosis plaques appear?

Answer 13

Well demarcated grey / brown lesions in the white matter that are classically situated around the lateral ventricles.

Question 14

Main histological features of MS? (3)

Answer 14

• Inflammation
• Demyelination
• Gliosis

Question 15

Dementia is a neurodegenerative disorder of which there are two groups:

Answer 15

Primary dementias (organic dementias) - Alzheimer’s disease, diffuse Lewy body disease, Huntington’s disease, Pick’s disease

Secondary dementias – other disorders resulting in secondary changes in the CNS resulting in dementia such as; vascular, metabolic, infection and trauma

Question 16

Describe Alzheimer’s disease

Answer 16

Insidious impairment of of higher intellectual function, with alterations in mood and behaviour

Later – progressive disorientation, memory loss and aphasia indicate severe cortical dysfunction

Question 17

What genes are involved in Alzheimers disease?

Answer 17

It is usually a sporadic disease however certain genes can play a role:

Amyloid precursor protein (APP) - Chromosome 21
Presenelin 1 - Chromosome 14
Presenelin 2 - Chromosome 1

Apolipoprotein E - Allele E4

Question 18

What macroscopic pathology can be seen in Alzheimers disease?

Answer 18

• Decreased size and weight of brain (cortical atrophy), particularly in the frontal and temporal lobes. Parietal lobe can also be affected.
• Widening of sulci
• Narrowing of gyri
• Compensatory dilatation of ventricles, 2* hydrocephalus
• Brainstem and cerebellum normal

Question 19

Microscopic / Histological features of Alzheimers disease?

Answer 19

• intracytoplasmic neurofibrillary tangles (TAU Protein)
• Aß amyloid plaques (extracellular senile or neuritic plaques)
• amyloid angiopathy
• extensive neuronal loss with astrocytosis

Question 20

Pathological features of dementia with levy bodies?

Answer 20

• Degeneration of the substantia nigra (as seen in Parkinson’s disease)
• Remaining nerve cells contain abnormal structures called lewy bodies.

Question 21

Lewy bodies can be detected how?

Answer 21

By immunochemical staining for the protein ubiquitin.

Question 22

What is the inheritance pattern of Huntington’s disease?

Answer 22

Autosomal dominant (huntingtin gene on chromosome 4p)

Question 23

List some of the symptoms of Huntington’s disease?

Answer 23

Chorea (dance like movements), myoclonus, clumsiness, slurred speech, depression, apathy (lack of interest or enthusiasm)

Question 24

Microscopic / Histological appearance of Huntington’s disease?

Answer 24

Loss of neurones in the caudate nucleus and cerebral cortex accompanied by a reactive fibrillary gliosis.

Question 25

What is Pick’s disease?

Answer 25

A progressive dementia commencing in middle life (usually between 50 and 60 years) characterised by slowly progressing changes in character and social deterioration leading to impairment of intellect, memory and language

Question 26

What are picks cells?

What are pick bodies?

Answer 26

Pick cells = swollen neurones

pick bodies = intracytoplasmic filamentous inclusions

Question 27

What are the main symptoms of Pick’s disease?

Answer 27

- Progressive changes related to frontal and temporal lobes.
Personality and behavioural change
Speech and communication problems
Changes in eating habits
Reduced attention span

Rapidly progressive, mean length of illness = 7 years.

Question 28

How many repeats need to be present for Huntington’s to present?

Answer 28

Disease definitely seen in > 40 repeats and not seen if <35 repeats.

CAG42 on Chromosome 4p results in production of a neurotoxin.

Question 29

What is Sydenham’s chorea?

Answer 29

Self limiting chorea that occurs in children after a strep throat infection.

Question 30

What is the average lifespan after diagnosis of Huntington’s?

Answer 30

15years.