GeneticsTier 1Medical Sciences concept

Duchenne muscular dystrophy - mutation types and genetics

Core concept

X-linked recessive; DMD gene at Xp21 - the largest human gene (2.4 Mb, 79 exons) -> high spontaneous mutation rate
Dystrophin links the actin cytoskeleton to the dystrophin-glycoprotein complex in the sarcolemma
- dec dystrophin -> membrane tears with contraction -> Ca influx -> necrosis, regeneration, then fibrofatty replacement

The reading-frame rule

	Mutation	Dystrophin	Phenotype
Duchenne	Out-of-frame deletion/duplication or nonsense	Absent (<3%)	Wheelchair ~10-12 yr
Becker	In-frame deletion	Reduced/abnormal but present	Ambulant beyond 16 yr, may be near-normal lifespan

~65-70% deletions (hotspots exons 45-55 and 2-20), ~10% duplications, ~20-25% point mutations
~1/3 of cases are de novo; ~2/3 have a carrier mother

Recurrence risk arithmetic

Obligate carrier = a woman with an affected son AND another affected male relative in the maternal line (or an affected father)
Standard exam chain - a woman whose brother and maternal uncle are affected:
- her mother is an obligate carrier -> she is 1/2 a carrier
- 1/2 (carrier) x 1/2 (transmits the allele) x 1/2 (child is male) = 1 in 8 that the child is affected
- Halve it again if you are asked about a pregnancy already known to be female (and the answer becomes "1/4 chance of a carrier daughter")
Germline mosaicism - the explanation when two maternal-line males are affected but the connecting woman tests carrier-negative on blood; empiric recurrence risk quoted up to ~10% for DMD, so prenatal testing is still offered
Manifesting female carriers (~10%) - skewed X-inactivation, Turner syndrome (45,X), or an X-autosome translocation disrupting DMD
- Usually mild proximal weakness or isolated dilated cardiomyopathy; carriers need cardiac surveillance regardless of skeletal muscle symptoms
Testing sequence: CK first (10-100x normal, often >10,000), then MLPA/array for deletion-duplication, then sequencing if negative; muscle biopsy is now rarely needed

Boy, delayed walking, Gowers' sign, calf pseudohypertrophy, toe-walking, raised transaminases (from muscle, not liver) -> check CK before anything else
Glucocorticoids (prednisolone or deflazacort) prolong ambulation and delay scoliosis and cardiomyopathy - the single most effective intervention
- Vamorolone is a newer dissociative steroid with less growth and bone toxicity
Cardiac and respiratory surveillance drives adult outcome
- ACE inhibitor +/- beta-blocker started before LV dysfunction; annual echo/cardiac MRI
- FVC monitoring -> nocturnal non-invasive ventilation
- Cardiomyopathy is now the leading cause of death
Mutation-specific therapy
- Exon-skipping antisense oligonucleotides (eteplirsen exon 51, golodirsen exon 53, casimersen exon 45) restore the reading frame -> Becker-like dystrophin
- Ataluren for nonsense mutations
- Delandistrogene moxeparvovec - AAV micro-dystrophin gene transfer
Bone: steroid-induced osteoporosis, vertebral fractures - monitor and treat
Avoid depolarising neuromuscular blockade and volatile anaesthetics - risk of rhabdomyolysis and hyperkalaemic arrest

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