Patterns of inheritance and mutations associated with the common muscular dystrophies and ataxias

Question 1

Define rare disease?

Answer 1

Disease that affects less than 1 in 2000 of the general population

Question 2

Why is it important to perform genetic testing when a patient is suspected of having a rare disease?

Answer 2

80% rare diseases arise from a genetic cause

Question 3

What is meant by an X-linked gene variant?

Answer 3

Gene variant is present on X-chromosome only, so phenotype is always expressed in males and in homozygous females

Question 4

What is the chance of a male offspring having an X-linked recessive disease and why?

Answer 4

Males have 50% chance of having X-linked recessive disease

If the male offspring receives the X-linked recessive gene variant from the mother, they will have the disease as they have no other copy of this gene

If the male offspring inherits the normal X-linked gene from the mother, they will not have the disease

Question 5

If female offspring receive the X-linked recessive gene variant from their mother, what is the chance that they will have the disease?

Answer 5

50% chance of a female offspring having a X-linked recessive disease if they inherit the X-linked recessive gene variant

This is because they can inherit the normal gene from the X chromosome from the father, so instead the female offspring will be a carrier

Question 6

If male offspring inherit the X-linked recessive gene variant from their mother, can they become carriers?

Answer 6

No, they only have this copy of the gene so they will have disease

Question 7

Give 2 examples of X-linked recessive diseases that are caused by mutation of the DMD gene on the X chromosome?

Answer 7

Duchenne and Becker muscular dystrophy

Question 8

Define frameshift mutation?

Answer 8

Insertion/deletion of single/multiple bases alters reading frame of the gene, therefore altering codons which translate into an abnormal protein due to mutation’s phenotypic effects

Question 9

Do patients with Duchenne and Becker muscular dystrophy usually have previous family history?

Answer 9

No, as it is usually caused by a new (de novo) mutation

Question 10

1 in how many males are affected by Duchenne muscular dystrophy, and what is the typical onset age range?

Answer 10

1 in 3500 males with typical onset between ages 3-5

Question 11

How does Duchenne muscular dystrophy affect walking ability, and give 2 examples of affected actions?

Answer 11

Progressive walking difficulties

eg. Going up and down stairs
eg. Rising from floor

Question 12

How does Duchenne muscular dystrophy affect the spine?

Answer 12

Can cause scoliosis

Also contractures

Question 13

How does Duchenne muscular dystrophy affect visible muscle bulk?

Answer 13

Causes Muscle pseudohypertrophy (muscle appears to have increased in size due to muscle replacement with fat and collagen)

Question 14

Which 3 places in the body commonly have muscular pseudohypertrophy, in patients with Duchenne muscular dystrophy?

Answer 14

Calves

Buttocks

Shoulders

Question 15

How does Duchenne muscular dystrophy affect learning abilities, and why?

Answer 15

Learning difficulties due to low IQ

Question 16

What 3 conditions arise from cardiac myopathy caused by Duchenne muscular dystrophy?

Answer 16

cardiac fibrosis, arrhythmias, heart failure

Question 17

Does Duchenne muscular dystrophy affect the respiratory system?

Answer 17

Yes, it can cause respiratory failure

Question 18

What is the characteristic gait caused by Duchenne muscular dystrophy?

Answer 18

Waddling gait

Question 19

What is the Gower’s test, and describe a positive and negative Gower’s sign?

Answer 19

Patient starts in hands-on-knees/sitting/supine position and has to move to standing position

Positive Gower’s sign: Patient climbs to a stand by “walking” his hands progressively up his shins, knees, and thighs

Negative Gower’s sign: Patient can stand without walking hands up legs

Question 20

Is a negative or positive Gower’s sign seen in Duchenne muscular dystrophy, and why does a positive test occur?

Answer 20

Positive Gower’s sign: Patient climbs to a stand by “walking” his hands progressively up his shins, knees, and thighs

Positive sign seen in any condition that is associated with weakness of the pelvic girdle or proximal muscles of lower extremities, but is mostly seen in Duchenne muscular dystrophy

Question 21

In patients with Duchenne muscular dystrophy, what is the characteristic finding of their muscle biopsy?

Answer 21

Absence of dystrophin surrounding muscle fibres

Question 22

What is the difference between Duchenne and Becker muscular dystrophy in terms of their genetic mutations, effect on dystrophin and progression rate?

Answer 22

Duchenne Muscular Dystrophy: Mutated DMD gene by frameshift mutation which usually prevents production of functional dystrophin, characterised by rapidly progressing muscle weakness

Becker Muscular Dystrophy: Mutated DMD gene by ‘in frame’ mutation usually leads to an abnormal version of dystrophin that retains some function, characterised by slowly-progressing muscle weakness

Question 23

1 in how many males are affected by Becker muscular dystrophy, and what is the typical onset age range?

Answer 23

1 in 30,000 males with typical onset age from 7 years old (11 yrs is mean age)

Question 24

What is the characteristic gait of Becker muscular dystrophy?

Answer 24

Toe walking

Question 25

Does muscle pseudohypertrophy occur in Becker muscular dystrophy?

Answer 25

Yes, commonly in calves

Question 26

What is the Gower’s sign in Becker muscular dystrophy, and why?

Answer 26

Positive Gower’s sign

Proximal weakness in pelvic girdle and quadriceps

Question 27

Does Becker muscular dystrophy cause heart involvement?

Answer 27

Yes, cardiomyopathy and abnormal heart function

Question 28

What 2 muscles are first weakened due to muscle loss in Becker muscular dystrophy, and which 2 muscles does it spread to?

Answer 28

Muscle loss starts in pelvis and quadriceps (proximal) then moves to shoulders and respiratory muscle involvement

Question 29

How does Becker muscular dystrophy affect spine?

Answer 29

Causes scoliosis

Also contractures

Question 30

Does Becker muscular dystrophy affect learning abilities?

Answer 30

Yes, causes mild learning disabilities

Question 31

In patients with Becker muscular dystrophy, what is the characteristic finding of their muscle biopsy?

Answer 31

Reduced dystrophin surrounding muscle fibres

Question 32

Define trinucleotide repeat expansion?

Answer 32

Mutation that occurs when the number of triplets present in a mutated gene is greater than the number found in a normal gene and eventually overtakes threshold number of repeats, which results in expression of the disease phenotype

Question 33

What is meant by trinucleotide repeat expansion being able to cause genetic anticipation?

Answer 33

Anticipation: Signs and symptoms of a genetic condition tend to become more severe and/or appear at an earlier age as the condition is inherited

Question 34

Which trinucleotide undergoes trinucleotide repeat expansion to cause Autosomal Dominant Cerebellar Ataxias (ADCAs)?

Answer 34

CAG repeat

Question 35

What protein is elongated due to trinucleotide repeat expansion of CAG repeats, causing Autosomal Dominant Cerebellar Ataxias (ADCAs), and can this cause anticipation?

Answer 35

Expansion of the CAG repeats produces an elongated polyglutamine tract in the corresponding protein

The expanded repeats are variable in size and unstable, usually increasing in size when transmitted to successive generations (anticipation)

Question 36

What trinucleotide repeat undergoes trinucleotide repeat expansion to cause Friedreich Ataxia, and which gene contains this trinucleotide?

Answer 36

Friedreich Ataxia caused by trinucleotide repeat expansion of GAA trinucleotide repeat in X25 gene coding for frataxin, chromosome 9

Question 37

Does Friedreich Ataxia cause genetic anticipation?

Answer 37

No

Question 38

How many identified subtypes of Autosomal Dominant Cerebellar Ataxias (ADCAs) are there, and what 2 classes are these subtypes split into?

Answer 38

27 identified subtypes that are generally classified into Spino-Cerebellar Ataxias (SCA) and Dentatorubral pallidoluysian atrophy (DRPLA)

Question 39

Does Autosomal Dominant Cerebellar Ataxias (ADCAs) typically affect children or adults?

Answer 39

Typically adult onset

Question 40

What do all of the various phenotypes of Autosomal Dominant Cerebellar Ataxias (ADCAs) have in common?

Answer 40

They all express ataxia

Question 41

What is meant by ataxia?

Answer 41

Disturbance of coordination/speech/gait

Question 42

Describe the 2 types of ataxia?

Answer 42

Cerebellar ataxia: Wide-based gait, intention tremor due to limb ataxia, slurred and slow speech,
Can be acquired or hereditary (autosomal dominant, autosomal recessive, mitochondrial eg.)

Sensory ataxia: unsteady high-stepping gait that is worse in dark

Question 43

What is the name of Autosomal Recessive Cerebellar Ataxia?

Answer 43

Friedreich ataxia

Question 44

1 in how many people have Friedreich ataxia, and 1 in how many people are carriers?

Answer 44

1 in 50,000 people affected with carrier frequency being 1 in 100

Question 45

What is the typical and mean onset age of Friedreich ataxia?

Answer 45

Typical onset age is before 25 yrs old (10yrs is mean age)

Question 46

At what age do people with Friedreich ataxia usually die?

Answer 46

In mid 30s

Question 47

What condition is the commonest familial ataxia?

Answer 47

Friedreich ataxia

Question 48

What are the 3 characteristic clinical features of Friedreich ataxia?

Answer 48

Gait ataxia eg. Stumbling, unbalanced

Limb ataxia

Pes cavus (foot with an abnormally high plantar longitudinal arch)

Question 49

How does Friedreich ataxia affect neurological reflexes?

Answer 49

Lower limb areflexia: Absence of neurologic reflexes eg. knee-jerk reaction, positive babinski sign

Question 50

What is meant by pyramidal weakness, and which type of ataxia causes this?

Answer 50

eg. weakness of upper limb extensors, lower limb flexors

Caused by Friedreich ataxia

Question 51

Why does Friedreich ataxia eventually lead to wheelchair dependence?

Answer 51

Impaired joint position sense

Question 52

What percentage of Friedreich ataxia cases cause hypertrophic cardiomyopathy, and give 2 examples?

Answer 52

50% cases have hypertrophic cardiomyopathy

which is characterised by heart failure and arrhythmia

Question 53

How does Friedreich ataxia affect the spine?

Answer 53

Scoliosis

Question 54

What percentage of Friedreich ataxia cases cause diabetes?

Answer 54

10%