20.03.03 X-linked recessive

Question 1

Features of X-linked recessive inheritance

Answer 1

• 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

Question 2

What can affect variable expressivity of X-linked disorders (e.g. affected females)

Answer 2

• Skewed X chromosome inactivation

- Somatic mosaicism

Question 3

Other times when females could be affected

Answer 3

• XCI
• Deletion on X chromosome
• Aneuploidy (Turner syndrome)
• 2 variants (compound het)
• UPD

Question 4

Review of dystrophinopathies

Answer 4

• 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

Question 5

Other methods to diagnose DMD

Answer 5

• High serum creatine kinase levels

- Absent dystrophin staining in muscle

Question 6

Genetics behind dystrophinopathies

Answer 6

• 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).

Question 7

Disease mechanism in DMD/BMD

Answer 7

• 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.

Question 8

What proportion of DMD mutations are dels/dups

Answer 8

• DMD= 65-70%

- BMD= 80-85%

Question 9

Where are the 2 deletion/dup hotspots in DMD

Answer 9

• Central region (exons 44-53). 80% deletions, 20% dups occur here
• 5’ region (exons 2-20). 20% deletion, 80% dups occur here.

Question 10

What is the frameshift hypothesis in DMD

Answer 10

• 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)

Question 11

Exceptions to the frameshift hypothesis in DMD

Answer 11

• 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

Question 12

What complicates recurrence risk of dystrophinopathies

Answer 12

• 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%.

Question 13

Treatment of DMD/BMD

Answer 13

• 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

Question 14

Review of SBMA

Answer 14

• 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.

Question 15

Disease mechanism in SBMA

Answer 15

• 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.

Question 16

Review of Androgen insensitivity syndrome (AIS)

Answer 16

• Mutations in AR gene.
• 3 types: complete, partial or mild AIS.
• Prevalence of complete AIS is 2-5 in 100,000 males. Also partial. Mild rare.
• Characterized by feminisation of external genitalia at birth (genetically male), infertility.

Question 17

Disease mechanism in AIS

Answer 17

• Androgen receptor allows cells to respond to androgens (hormones that direct male sexual development).
• Mutations prevent androgen receptors working properly, lower ligand-binding or reduced transactivation potential. Cells less sensitive to androgens.

Question 18

Review of haemophilia A and B

Answer 18

• Haem A= mutations in F8. Prevalence= 1 in 6,000 male births
• Haem B= mutations in F9. Prevalence= 1 in 30,000 male births
• Clinically indistinguishable, diagnosed by deficiency in clotting activity of relevant factor.
• Characterised by prolonged bleeding after injury/surgery, spontaneous bleeding.
• Females can be biochemically abnormal but clinically unaffected. 10% of carrier females are at risk of bleeding, usually mild.

Question 19

Genetics of Haemophilia A and B

Answer 19

• F8 (haem A) is large 26 exons.
• Inversions are most common- inversion of intron 22 accounts for 45%, intron 1 inversion accounts for 5%. Testing of F8 will identify path variants in 98% haem A patients
• F9 (haem B) smaller, 8 exons. Predominantly single base changes (90%), throughout gene. Testing F9 will identify path variants in 90% of haem B patients.

Question 20

Management of haemophilia

Answer 20

• Prophylactic intravenous infusions of Factor 8 or 9

- Gene therapy using intravenous infusions of adeno-associated viral vectors expressing F8 or 9.

Question 21

Review of X-linked retinitis pigmentosa (XLRP)

Answer 21

• Characterised by night blindness and decreased peripheral vision in 3rd or 4th decade.
• 6 genes identified to cause x-linked form.
• 70% cases have RPGR mutations

Question 22

Review of Fabrys

Answer 22

• GLA mutations. Envoces alpha-galactosidase A enzyme.
• GLA is active in lysoosmes, breaking down GL-3 (globotriaosylceramide). Mutations leads to GL-3 build up damaging cells.
• Characterised by episodes of pain, angiokeratomas, reduced sweating, hearing loss, heart and kidney damage.
• Prevalence= 1-5 in 100,000.