STEPTRACKERGENETICS + NEUROLOGY + PATHOLOGY | MUSCLE & MITOCHONDRIA | HIGH-YIELD REVIEW

Muscular Dystrophies & Mitochondrial Disease

Dystrophin — the largest human gene — and mitochondrial DNA inherited only from the mother: two routes to weak muscle and failing energy.

FOCUS ON
Duchenne: XR, frameshift (or nonsense) in dystrophin → no protein → onset < 5 y, Gowers sign, calf pseudohypertrophy, death from dilated cardiomyopathy/respiratory failure. Becker: in-frame deletion → some dystrophin → milder, later. ↑ CK; genetic testing confirms. Mitochondrial: maternal, heteroplasmy, ragged red fibers, lactic acidosis — MELAS, MERRF, LHON.
DISORDER
GENETICS
FEATURES
CLUE · LABS
Duchenne muscular dystrophy
XR · DMD
Frameshift/nonsense → absent dystrophin (links actin to the membrane dystroglycan complex)
Boys < 5 y: proximal weakness (pelvic first), waddling gait, Gowers sign, calf pseudohypertrophy (fibrofatty), scoliosis, ID in some
Death ~20s–30s: dilated cardiomyopathy, respiratory failure
Becker muscular dystrophy
XR · DMD
In-frame deletion → truncated, partly functional dystrophin
Adolescent/adult onset, slower progression, cardiomyopathy common
"Becker = Better"
Dystrophin gene
Largest protein-coding human gene (Xp21) → high rate of new mutations
Many cases de novo
Deletions are most common mutation type
Myotonic dystrophy type 1
AD · CTG
DMPK repeat expansion
Myotonia, distal weakness, cataracts, balding, testicular atrophy, arrhythmia, insulin resistance
See 5.04
Facioscapulohumeral & limb-girdle
FSHD: AD (DUX4 derepression) · LGMD: AR/AD, various genes
FSHD: facial weakness, scapular winging · LGMD: hip and shoulder girdle
Normal dystrophin
MELAS
mtDNA tRNA-Leu mutation (often)
Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like episodes; seizures, short stature
Stroke-like lesions not in vascular territories
MERRF
mtDNA tRNA-Lys mutation
Myoclonic Epilepsy with Ragged Red Fibers; ataxia, myopathy
Ragged red fibers on Gomori trichrome
Leber hereditary optic neuropathy
mtDNA complex I mutations
Young men: acute/subacute painless bilateral central vision loss
Maternal inheritance; incomplete penetrance
Mitochondrial myopathy findings
Defective oxidative phosphorylation
Exercise intolerance, ↑ lactate, ragged red fibers (subsarcolemmal mitochondria)
Tissues with highest energy demand suffer most
Mitochondrial inheritance
All mitochondria come from the oocyte
Affected mother → all children at risk; affected father → none
Heteroplasmy → variable severity

Mechanism — reading frame decides severity

Frameshift deletionNot a multiple of 3
→
No dystrophin
→
DuchenneSevere, early
In-frame deletionMultiple of 3
→
Shorter dystrophinWorks partly
→
BeckerMilder, later

Exon-skipping drugs (eteplirsen) restore the reading frame — turning Duchenne toward Becker.

Duchenne vs Becker

FEATURE
DUCHENNE
BECKER
Mutation
Frameshift / nonsense
In-frame deletion
Dystrophin
Absent
Reduced, abnormal
Onset
< 5 years
Adolescence–adulthood
Walking lost
~12 years
Later or never
Heart
Dilated cardiomyopathy
Dilated cardiomyopathy

How it's tested

COMMON CONFUSIONCalf enlargement in Duchenne is pseudohypertrophy — fat and fibrous tissue replacing muscle, not strong muscle.
THE TRAPA mitochondrial disease never passes from an affected father; if a man's children are affected, look for another pattern.
YOUR APPROACHBoy + proximal weakness + ↑ CK → dystrophin (frame decides severity). Maternal pattern + lactate + ragged red fibers → mitochondrial syndrome by its letters.

If you see… think…

Boy uses hands to climb up his legs to stand → Gowers sign (Duchenne)
Large firm calves with weakness → pseudohypertrophy
Frameshift in dystrophin → Duchenne
In-frame deletion in dystrophin → Becker
Death in DMD → dilated cardiomyopathy / respiratory failure
Ragged red fibers on muscle biopsy → mitochondrial myopathy
Stroke-like episodes, lactic acidosis in a child → MELAS
Myoclonic seizures + ragged red fibers → MERRF
Young man with sudden bilateral central vision loss, maternal relatives too → LHON
Drug that skips an exon to restore dystrophin frame → eteplirsen