Genetic Neuro Disorders

Question 1

Define chorea

Answer 1

excessive, irregular movements flitting from one body part to another

Question 2

Define tremor

Answer 2

rhythmic sinusoidal oscillation of a body part

Question 3

What is Huntingtons disease?

Answer 3

A progressive neurodegenerative disorder characterised by involuntary movements, dementia and progression to severe dependency and death over 15-20 years from onset of first symptoms.

Question 4

What is the pattern of inheritance with Huntingtons disease?

Answer 4

Autosomal dominant trait with age dependent penetrance

Question 5

Describe the pathogenesis of Huntingtons disease?

Answer 5

Pathological expansion of a trinucleotide repeat in the Huntingtin gene.
In a normal gene there is around 20 CAG repeats at one position in the gene coding for around 20 glutamine residues.
In Huntingtons disease the number of CAG repeats is expanded so increased glutamines on the protein.
This new protein is actually neurotoxic so causes progressive damage to the nervous system.

Question 6

Describe what happens to the brain in Huntingtons?

Answer 6

There is loss of cells from the basal ganglia causing flattening of the normal convex curve of the ventricles. The caudate nucleus is usually severely atrophic. There is also loss of cells in the cerebral cortex.

Question 7

Why does age of onset become earlier as you move down generations of families carrying the Huntingtons gene?

Answer 7

The CAG repeat is highly unstable during meiosis particularly spermatogenesis which often means there are bigger expansions that are passed down. Bigger expansions mean earlier onset of disease.

Question 8

Describe some early signs of Huntingtons?

Answer 8

subtle fidgetiness, difficulty concentrating, memory lapses, mood swings, clumsiness

Question 9

Describe some later signs of Huntingtons?

Answer 9

development of chorea (abnormal involuntary movements), inability to walk, speak, swallow, bradykinesia, dementia, ultimately death

Question 10

Define bradykinesia?

Answer 10

difficulty in initiating and continuing movements

Question 11

Prognosis of Huntingtons?

Answer 11

Patients usually die 10-20 years after 1st symptoms (1st onset is usually in the 30s or 40s)

Question 12

2 investigations for Huntingtons disease?

Answer 12

Genetic testing

MRI will show loss of caudate heads

Question 13

Describe management of Huntingtons disease?

Answer 13

There are no disease modifying drugs

Chorea can improve with treatment such as risperidone or sulpiride

Question 14

What is Duchenne Muscular Dystrophy?

Answer 14

A genetic disorder that causes loss of muscle cells and therefore muscle wasting and weakness.

Question 15

What is the pattern of inheritance with Duchenne muscular dystrophy?

Answer 15

X linked recessive disorder (although 1/3 can be spontaneous mutations)

Question 16

Describe the pathogenesis of Duchenne muscular dystrophy?

Answer 16

Mutation in the dystrophin gene that codes for dystrophin proteins that connect actin filaments to the cell membrane and ECM. The mutation results in progressive loss of muscle cells causing muscle wasting and weakness.

Usually the mutation is a large scale deletion or duplication although about 30% are point mutations.

Question 17

Describe presentation of Duchenne muscular dystrophy?

Answer 17

Developmental delay in boys (usually a specific motor delay)
Gowers sign (the boy puts hands down to push themselves up)
Toe walking
Exaggerated lumbar lordosis
Calf hypertrophy

Question 18

Describe some investigations for Duchenne muscular dystrophy?

Answer 18

Initial screening (not v specific but v sensitive): look for raised CK 
Definitive testing is genetic testing from a blood or saliva sample

Question 19

Why is it important to distinguish Duchenne Muscular dystrophy from other types of muscular dystrophy?

Answer 19

There are different patterns of inheritance so need to confirm for genetic counselling ie some girls could get, some are x linked

Question 20

Describe management and prognosis of Duchenne muscular dystrophy?

Answer 20

There is no curative treatment, severely disabled by 10 and usually die in 20s
Sometimes steroids delay progression
Physio can help prevent contractures in later stages

Question 21

What is spinal muscular atrophy?

Answer 21

A genetic disorder that causes loss of anterior horn cells in the spinal cord

Question 22

What is the pattern of inheritance with spinal muscular atrophy?

Answer 22

autosomal recessive disorder

Question 23

Describe the pathogenesis of spinal muscular atrophy?

Answer 23

Most common forms are due to deficiency in SMN1 gene

SMN1 has an essential exon (exon 7) that stops motor neuron loss

Question 24

Describe presentation of spinal muscular atrophy?

Answer 24

Usually occurs in babies- precise age of onset depends on the type
Hypotonia and muscle weakness (floppy and weak)
Can cause respiratory failure if it affects the muscles of breathing

Question 25

Describe management of spinal muscular atrophy?

Answer 25

Treatments have been developed that get the similar gene SMN2 to keep this essential exon 7 in its mature mRNA (SMN2 usually splices it out)
This prevents progression of the disease but doesn’t reverse what has happened
Ideally it would be tested for at brith so the baby could be instantly treated