20.03.03 X-linked recessive Flashcards
1
Q
Features of X-linked recessive inheritance
A
- Vertical transmission, where carrier females pass disorder on to affected sons
- All daughters of affected males will inherit mutation (obligate carriers)
- Women who are carriers have 50% chance of passing mutation on to children
- Absence of male to male transmission
2
Q
What can affect variable expressivity of X-linked disorders (e.g. affected females)
A
- Skewed X chromosome inactivation
- Somatic mosaicism
3
Q
Other times when females could be affected
A
- XCI
- Deletion on X chromosome
- Aneuploidy (Turner syndrome)
- 2 variants (compound het)
- UPD
4
Q
Review of dystrophinopathies
A
- Muscular dystrophy is a group of inherited conditions where muscles progressively weaken.
- DMD affects 1 in 4,000 males. Progressive muscle weakness, calf hypertrophy, joint contractures. Onset between 2-5 yrs. Cardiomyopathy occurs later and a common cause of death. Males do not reproduce
- BMD affects 1 in 18,000 males. Milder than DMD. Later onset muscle weakness, but heart failure still a common cause of death.
- Female carriers at increased risk of DCM. Depending on XCI, females can be unaffected to severe
- Complete penetrance in males
5
Q
Other methods to diagnose DMD
A
- High serum creatine kinase levels
- Absent dystrophin staining in muscle
6
Q
Genetics behind dystrophinopathies
A
- Mutations in DMD gene.
- Dystrophin is almost absent in DMD (<5%) and low in BMD (20%)
- 3 independently regulated promoters control expression: B (brain), M (muscle), P (purkinje).
7
Q
Disease mechanism in DMD/BMD
A
- Dystrophin is a rod-shaped cytoskeletal protein, essential for sarcolemma stability in muscle
- Forms part of Dystrophin-associated protein complex (DAPC), which links actin cytoskeleton and extracellular matrix.
- Disruption to Dystrophin structure/function destabilises DAPC and causes membrane disruption and fibre damage.
8
Q
What proportion of DMD mutations are dels/dups
A
- DMD= 65-70%
- BMD= 80-85%
9
Q
Where are the 2 deletion/dup hotspots in DMD
A
- Central region (exons 44-53). 80% deletions, 20% dups occur here
- 5’ region (exons 2-20). 20% deletion, 80% dups occur here.
10
Q
What is the frameshift hypothesis in DMD
A
- Predicts disease severity
- Out of frame dels/dups cause severe DMD (related to absence of protein production)
- In frame dels/dups cause mild BMD (shorter but partially functional protein)
11
Q
Exceptions to the frameshift hypothesis in DMD
A
- Inframe dels/dups can lead to severe disease if they remove a functionally important domain of protein or affect mRNA/protein stability
- Out of frame dels/dups cause mild phenotype due to alternative splicing or use of a new cryptic translational start codon
- Some deletions have been associated with DMD and BMD
12
Q
What complicates recurrence risk of dystrophinopathies
A
- High new mutation rate. 1/3 of isolated cases are due to de novo mutations
- Incidence of germline mosaicism in mothers is 15-20%. So sibs of proband are at increased risk of inheriting variant. (8.6% recurrence risk)
- High recombination rate- 10%.
13
Q
Treatment of DMD/BMD
A
- Steroids. Improve strength and motor function
- Physical therapy. improve mobility
- Cardiac transplantation
- Molecular-based therapies.
1) PTC read through using aminoglycoside antibiotics. Gentamicin.
2) Exon skipping using ASOs (antisense oligonucleotides). Exondys51
14
Q
Review of SBMA
A
- Spinal-bulbar muscular atrophy
- Prevalence= 1 in 50,000
- Late onset, progressive neuromuscular disorder. Proximal muscle weakness and wasting, fasiculations, reduced fertility, gynecomastia. Onset between 30-50s.
- Degeneration of motor neurons.
- CAG expansion in AR gene.
- Inverse correlation between CAG length and disease severity. Longer= more severe
- Female carriers are usually asymptomatic.
15
Q
Disease mechanism in SBMA
A
- Gain of function.
- Possible disease mechanism is polyQ is cleaved into peptide fragments that are retained in nucleus to form neuronal intranuclear inclusions or interfere with transcription.
