Patterns of inheritance and mutations associated with the common muscular dystrophies and ataxias Flashcards
Define rare disease?
Disease that affects less than 1 in 2000 of the general population
Why is it important to perform genetic testing when a patient is suspected of having a rare disease?
80% rare diseases arise from a genetic cause
What is meant by an X-linked gene variant?
Gene variant is present on X-chromosome only, so phenotype is always expressed in males and in homozygous females
What is the chance of a male offspring having an X-linked recessive disease and why?
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
If female offspring receive the X-linked recessive gene variant from their mother, what is the chance that they will have the disease?
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
If male offspring inherit the X-linked recessive gene variant from their mother, can they become carriers?
No, they only have this copy of the gene so they will have disease
Give 2 examples of X-linked recessive diseases that are caused by mutation of the DMD gene on the X chromosome?
Duchenne and Becker muscular dystrophy
Define frameshift mutation?
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
Do patients with Duchenne and Becker muscular dystrophy usually have previous family history?
No, as it is usually caused by a new (de novo) mutation
1 in how many males are affected by Duchenne muscular dystrophy, and what is the typical onset age range?
1 in 3500 males with typical onset between ages 3-5
How does Duchenne muscular dystrophy affect walking ability, and give 2 examples of affected actions?
Progressive walking difficulties
eg. Going up and down stairs
eg. Rising from floor
How does Duchenne muscular dystrophy affect the spine?
Can cause scoliosis
Also contractures
How does Duchenne muscular dystrophy affect visible muscle bulk?
Causes Muscle pseudohypertrophy (muscle appears to have increased in size due to muscle replacement with fat and collagen)
Which 3 places in the body commonly have muscular pseudohypertrophy, in patients with Duchenne muscular dystrophy?
Calves
Buttocks
Shoulders
How does Duchenne muscular dystrophy affect learning abilities, and why?
Learning difficulties due to low IQ
What 3 conditions arise from cardiac myopathy caused by Duchenne muscular dystrophy?
cardiac fibrosis, arrhythmias, heart failure
Does Duchenne muscular dystrophy affect the respiratory system?
Yes, it can cause respiratory failure
What is the characteristic gait caused by Duchenne muscular dystrophy?
Waddling gait
What is the Gower’s test, and describe a positive and negative Gower’s sign?
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
Is a negative or positive Gower’s sign seen in Duchenne muscular dystrophy, and why does a positive test occur?
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
In patients with Duchenne muscular dystrophy, what is the characteristic finding of their muscle biopsy?
Absence of dystrophin surrounding muscle fibres
What is the difference between Duchenne and Becker muscular dystrophy in terms of their genetic mutations, effect on dystrophin and progression rate?
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
1 in how many males are affected by Becker muscular dystrophy, and what is the typical onset age range?
1 in 30,000 males with typical onset age from 7 years old (11 yrs is mean age)
What is the characteristic gait of Becker muscular dystrophy?
Toe walking
Does muscle pseudohypertrophy occur in Becker muscular dystrophy?
Yes, commonly in calves
What is the Gower’s sign in Becker muscular dystrophy, and why?
Positive Gower’s sign
Proximal weakness in pelvic girdle and quadriceps
Does Becker muscular dystrophy cause heart involvement?
Yes, cardiomyopathy and abnormal heart function
What 2 muscles are first weakened due to muscle loss in Becker muscular dystrophy, and which 2 muscles does it spread to?
Muscle loss starts in pelvis and quadriceps (proximal) then moves to shoulders and respiratory muscle involvement
How does Becker muscular dystrophy affect spine?
Causes scoliosis
Also contractures
Does Becker muscular dystrophy affect learning abilities?
Yes, causes mild learning disabilities
In patients with Becker muscular dystrophy, what is the characteristic finding of their muscle biopsy?
Reduced dystrophin surrounding muscle fibres
Define trinucleotide repeat expansion?
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
What is meant by trinucleotide repeat expansion being able to cause genetic anticipation?
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
Which trinucleotide undergoes trinucleotide repeat expansion to cause Autosomal Dominant Cerebellar Ataxias (ADCAs)?
CAG repeat
What protein is elongated due to trinucleotide repeat expansion of CAG repeats, causing Autosomal Dominant Cerebellar Ataxias (ADCAs), and can this cause anticipation?
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)
What trinucleotide repeat undergoes trinucleotide repeat expansion to cause Friedreich Ataxia, and which gene contains this trinucleotide?
Friedreich Ataxia caused by trinucleotide repeat expansion of GAA trinucleotide repeat in X25 gene coding for frataxin, chromosome 9
Does Friedreich Ataxia cause genetic anticipation?
No
How many identified subtypes of Autosomal Dominant Cerebellar Ataxias (ADCAs) are there, and what 2 classes are these subtypes split into?
27 identified subtypes that are generally classified into Spino-Cerebellar Ataxias (SCA) and Dentatorubral pallidoluysian atrophy (DRPLA)
Does Autosomal Dominant Cerebellar Ataxias (ADCAs) typically affect children or adults?
Typically adult onset
What do all of the various phenotypes of Autosomal Dominant Cerebellar Ataxias (ADCAs) have in common?
They all express ataxia
What is meant by ataxia?
Disturbance of coordination/speech/gait
Describe the 2 types of ataxia?
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
What is the name of Autosomal Recessive Cerebellar Ataxia?
Friedreich ataxia
1 in how many people have Friedreich ataxia, and 1 in how many people are carriers?
1 in 50,000 people affected with carrier frequency being 1 in 100
What is the typical and mean onset age of Friedreich ataxia?
Typical onset age is before 25 yrs old (10yrs is mean age)
At what age do people with Friedreich ataxia usually die?
In mid 30s
What condition is the commonest familial ataxia?
Friedreich ataxia
What are the 3 characteristic clinical features of Friedreich ataxia?
Gait ataxia eg. Stumbling, unbalanced
Limb ataxia
Pes cavus (foot with an abnormally high plantar longitudinal arch)
How does Friedreich ataxia affect neurological reflexes?
Lower limb areflexia: Absence of neurologic reflexes eg. knee-jerk reaction, positive babinski sign
What is meant by pyramidal weakness, and which type of ataxia causes this?
eg. weakness of upper limb extensors, lower limb flexors
Caused by Friedreich ataxia
Why does Friedreich ataxia eventually lead to wheelchair dependence?
Impaired joint position sense
What percentage of Friedreich ataxia cases cause hypertrophic cardiomyopathy, and give 2 examples?
50% cases have hypertrophic cardiomyopathy
which is characterised by heart failure and arrhythmia
How does Friedreich ataxia affect the spine?
Scoliosis
What percentage of Friedreich ataxia cases cause diabetes?
10%
