Muscular Dystrophies

What You'll Learn

DMD = absent dystrophin, BMD = reduced dystrophin: X-linked; out-of-frame deletions → DMD (severe), in-frame → BMD (milder); CK massively elevated (10,000–50,000+); cardiac monitoring mandatory in both
Myotonic dystrophy type 1 (DM1): CTG repeat in DMPK (chr 19); DISTAL weakness + myotonia + cataracts + cardiac conduction defects + frontal balding; anticipation (congenital DM1 = floppy infant from affected mother)
DM2 = PROXIMAL weakness: CCTG repeat in CNBP (chr 3); NO congenital form; pain more prominent than DM1; less severe myotonia
FSHD: D4Z4 repeat contraction on chr 4q35; facial weakness (can’t whistle) + scapular winging + footdrop; asymmetric; CK normal or mildly elevated
LGMD: Heterogeneous group; proximal weakness + elevated CK; new nomenclature LGMD R (recessive) / D (dominant); calpain-3 (R1) most common AR; sarcoglycanopathies = “mini-dystrophinopathies”
Emery-Dreifuss: Triad of early contractures + humeroperoneal weakness + cardiac conduction defects; LMNA mutations carry sudden death risk
OPMD: GCN repeat in PABPN1; normal (GCN)10 encoding 10 alanines; AD OPMD (GCN)12–17 (typically 12–13); (GCN)11 is a recessive modifier allele; onset >40 years; ptosis + dysphagia; French-Canadian and Bukharan Jewish ancestry; intranuclear tubulofilamentous inclusions (8.5 nm)
Congenital MDs: Hypotonia at birth; merosin-deficient CMD (LAMA2) = white matter abnormalities; Walker-Warburg = most severe dystroglycanopathy with lissencephaly

HighYield Pearls

DMD reading-frame rule: out-of-frame deletion → absent dystrophin = DMD; in-frame deletion → truncated dystrophin = BMD — classic exam stem
DMD clinical pentad: Gowers sign + calf pseudohypertrophy + onset 2–5 yr + loss of ambulation by 12 + dilated cardiomyopathy; CK 10,000–50,000+; ~1/3 have intellectual disability
DMD treatment hierarchy: glucocorticoids (deflazacort, prednisone) + ACEi/MRA for cardiac + exon-skipping antisense oligos (eteplirsen exon 51, golodirsen/viltolarsen exon 53, casimersen exon 45); ELEVIDYS (delandistrogene moxeparvovec-rokl) AAVrh74 micro-dystrophin gene therapy — indicated for AMBULATORY DMD ≥4 yr; contraindicated with exon 8/9 deletions; boxed warning for acute liver injury/failure; ataluren is NOT FDA-approved and the EU authorization was not renewed in 2025
DMD female carriers can manifest: ~5–10% with weakness/calf hypertrophy — ALL carriers need echo screening for dilated cardiomyopathy even if asymptomatic
DM1 anticipation rule: CTG repeat in DMPK (chr 19) expands with transmission; congenital DM1 (floppy infant, severe) inherited from AFFECTED MOTHER (maternal expansion bias)
DM1 vs DM2 weakness pattern: DM1 = DISTAL + facial diplegia + myotonia; DM2 = PROXIMAL + pain prominent + NO congenital form; CCTG in CNBP (chr 3)
DM1 anesthesia alert: AVOID propofol/succinylcholine — prolonged sedation, malignant-hyperthermia-like reactions, post-op respiratory failure; warn anesthesia preoperatively
FSHD genetics: D4Z4 contraction on chr 4q35 + PERMISSIVE 4qA haplotype (both required); FSHD2 = SMCHD1 mutation + 4qA; CK normal/mildly elevated
Emery-Dreifuss triad: early contractures (elbow flexors, neck extensors, achilles) + humeroperoneal weakness + cardiac conduction defects — LMNA mutations have HIGH SCD risk, need prophylactic pacemaker/ICD ± anticoagulation
Walker-Warburg = most severe α-dystroglycanopathy: cobblestone (type II) lissencephaly + eye anomalies + CMD + neonatal death; milder forms = MEB, Fukuyama (Japanese)

🔍 Quick ReferenceClinical · EMG / biopsy / imaging · Genetics / treatment

Clinical phenotype

Gowers sign + calf pseudohypertrophy + boy 2–5 yr → Duchenne muscular dystrophy
Dilated cardiomyopathy dominant, walking into 30s+ → Becker muscular dystrophy
Distal weakness + facial diplegia + frontal balding + cataracts + myotonia (grip release) → Myotonic dystrophy type 1 (DM1)
Floppy infant born to affected mother (anticipation) → Congenital DM1
Proximal weakness + prominent myalgia + calf hypertrophy + mild myotonia → Myotonic dystrophy type 2 (DM2)
“Popeye arms” sparing deltoid + biceps, scapular winging, can’t whistle → FSHD
Early elbow/neck/achilles contractures + humeroperoneal weakness + heart block → Emery-Dreifuss MD
Adult >40 yr with ptosis + dysphagia, French-Canadian/Bukharan Jewish/Hispanic → OPMD
Floppy infant + white matter changes on MRI → Merosin-deficient CMD (LAMA2)
Lissencephaly type II (cobblestone) + eye anomalies + CMD + neonatal death → Walker-Warburg syndrome

EMG / biopsy / imaging

Absent dystrophin on immunostain → DMD
Reduced / truncated dystrophin on immunostain → BMD
CK 10,000–50,000+ IU/L → Dystrophinopathy (DMD/BMD)
EMG “dive-bomber” myotonic discharges (waxing-waning amplitude) → Myotonic dystrophy
Ringed fibers + sarcoplasmic masses + type 1 fiber atrophy → DM1 biopsy
Intranuclear tubulofilamentous inclusions 8.5 nm on EM → OPMD (PABPN1)
Muscle MRI: selective involvement patterns differentiate → LGMD subtypes
Asymmetric face/scapular/humeral wasting on exam & MRI → FSHD

Genetics / inheritance / treatment

X-linked, DMD gene Xp21, out-of-frame deletion → Duchenne
CTG repeat expansion in DMPK chr 19, anticipation → DM1
CCTG repeat in CNBP chr 3, no congenital form → DM2
D4Z4 contraction chr 4q35 + permissive 4qA haplotype → FSHD1
SMCHD1 mutation + 4qA haplotype → FSHD2
Calpain-3 (R1) most common AR LGMD; dysferlin (R2) distal; sarcoglycanopathies (R3–6) “mini-dystrophinopathies”; FKRP (R9) → LGMD recessive
Emerin (X-linked) / LMNA (AD) / FHL1, prophylactic pacemaker/ICD → Emery-Dreifuss
PABPN1 GCN repeat chr 14 → OPMD
Eteplirsen exon 51 / golodirsen & viltolarsen exon 53 / casimersen exon 45 → DMD exon-skipping antisense
Delandistrogene moxeparvovec (ELEVIDYS) AAV micro-dystrophin → DMD gene therapy
Ataluren (nonsense mutation read-through) — NOT FDA-approved; EU authorization not renewed 2025 → DMD with premature stop codon
Avoid propofol & succinylcholine, prolonged sedation risk → Myotonic dystrophy anesthesia

Dystrophinopathies — DMD & BMD

Overview

Gene: DMD gene (Xp21) — largest human gene (~2.4 Mb); encodes dystrophin (connects cytoskeleton to extracellular matrix via dystrophin-associated glycoprotein complex)
Inheritance: X-linked recessive; 1/3 de novo mutations
Reading frame rule: out-of-frame deletions → no dystrophin = DMD; in-frame deletions → truncated but partially functional dystrophin = BMD
CK: massively elevated — 10,000–50,000+ IU/L (elevated from birth, even before symptoms)
Diagnosis: genetic testing first (multiplex ligation-dependent probe amplification [MLPA] or next-gen sequencing); biopsy if genetic testing inconclusive (absent dystrophin = DMD, reduced/truncated = BMD)

DMD vs BMD Comparison

Feature	DMD	BMD
Dystrophin	Absent (<3%)	Reduced / truncated (partially functional)
Reading frame	Out-of-frame deletion	In-frame deletion
Onset	2–5 years	5–15 years (variable, may be later)
Gower sign	Present (classic)	May be present, later onset
Calf pseudohypertrophy	Prominent	May be present
Loss of ambulation	By age 12	After age 16; many ambulatory into 20s–30s+
Cardiomyopathy	Dilated CM universal by late teens	Dilated CM may be predominant feature (even without significant skeletal weakness)
Cognitive	~1/3 have intellectual disability (mean IQ ~85)	Generally normal
Life expectancy	20s–30s (cardiac/respiratory failure)	40s–60s+ (variable)
Scoliosis	Common after loss of ambulation	Less common

Female Carriers

Manifesting carriers in ~5–10% due to skewed X-inactivation
May have: elevated CK, mild limb-girdle weakness, calf hypertrophy
Dilated cardiomyopathy — can occur even without skeletal weakness; echocardiographic screening recommended for ALL carriers

Treatment

Therapy	Mechanism	Key Details
Corticosteroids	Anti-inflammatory; prolongs ambulation 2–3 years	Deflazacort (preferred; less weight gain) or prednisone; standard of care since childhood
Exon-skipping (antisense oligonucleotides)	Restores reading frame → truncated but functional dystrophin (converts DMD → BMD phenotype)	Eteplirsen (exon 51), golodirsen (exon 53), viltolarsen (exon 53), casimersen (exon 45); each targets specific exon deletions (~30% of DMD patients amenable)
Gene therapy	AAV-delivered micro-dystrophin	Delandistrogene moxeparvovec-rokl (Elevidys); AAVrh74 vector micro-dystrophin gene therapy; currently FDA-indicated for AMBULATORY DMD patients age ≥4 years with a confirmed DMD mutation (after fatal acute liver injury in non-ambulatory patients, indication was restricted to ambulatory only); contraindicated with deletions in exons 8 and/or 9; boxed warning for acute serious liver injury / liver failure; also risk of immune-mediated myocarditis
Ataluren	Premature stop codon readthrough → full-length dystrophin	For nonsense (stop codon) mutations (~10–15% of DMD); NOT FDA-approved; historically had conditional EU authorization, but the EU marketing authorization was NOT renewed in 2025 (European Commission decision March 28, 2025)
Cardiac management	ACE inhibitors / ARBs ± beta-blockers	Start by age 10 or at first sign of dysfunction; mandatory annual echocardiography
Respiratory	Non-invasive ventilation (BiPAP)	Monitor FVC annually; initiate NIV when FVC <50% predicted or nocturnal hypoventilation

💎 Board Pearl

Reading frame rule: out-of-frame = DMD (severe); in-frame = BMD (milder) — the single most tested genetic concept in muscular dystrophies
CK is elevated from birth in DMD — an incidentally discovered CK >10,000 in a young boy should prompt dystrophin gene testing
BMD cardiomyopathy can be the presenting/dominant feature — may present with heart failure before significant skeletal weakness
Exon-skipping converts DMD → BMD by restoring the reading frame — produces truncated but partially functional dystrophin
Female carrier + dilated cardiomyopathy = classic board question; screen all carriers with echo regardless of symptoms

🔒

Continue reading — sign in

The full note has more clinical pearls, tables, and board-focused tips. Free account, no fee.