Muscular Dystrophies
Muscular Dystrophies
What Do You Need to Know?
- 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
🚩 Don’t Miss — Test-Day Priorities
- 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)
🔍 Buzzwords & Pathognomonic FindingsClinical · 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
Myotonic Dystrophy
DM1 vs DM2 Comparison
| Feature | DM1 (Steinert Disease) | DM2 (PROMM / Ricker Disease) |
|---|---|---|
| Gene / Locus | CTG repeat in DMPK (chr 19q13) | CCTG repeat in CNBP/ZNF9 (chr 3q21) |
| Inheritance | AD | AD |
| Repeat size | Normal: 5–34; premutation: 35–49; affected: ≥50 (mild adult ~50–150; classic ~100–1,000; congenital >1,000) | Normal: ≤30 CCTG repeats; affected 75–11,000+ |
| Anticipation | Yes — worsens with generations (especially maternal transmission) | Minimal / absent |
| Congenital form | Yes — floppy infant, respiratory failure, facial diplegia, clubfeet; inherited from affected mother | No |
| Weakness pattern | Distal (hands, ankle dorsiflexors) + facial + neck flexors | Proximal (hip flexors, thighs) — unlike DM1 |
| Myotonia | Prominent (grip myotonia, percussion myotonia) | Mild / intermittent; may be absent clinically |
| Pain | Less prominent | More prominent (myalgia is a common complaint) |
| Cataracts | Posterior subcapsular (iridescent “Christmas tree” cataracts) | Posterior subcapsular cataracts (similar) |
| Cardiac | Conduction defects (1st degree AV block, bundle branch block); arrhythmias; sudden death | Conduction defects (less severe than DM1) |
| Endocrine | Insulin resistance / diabetes; testicular atrophy; frontal balding (men) | Insulin resistance (similar) |
| CNS | Cognitive impairment; excessive daytime somnolence (central hypersomnia) | Milder cognitive effects |
| CK | Normal or mildly elevated | Normal or mildly elevated |
| Severity | More severe overall | Generally milder; later onset |
Myotonia
- Clinical: delayed relaxation after voluntary contraction (grip myotonia — difficulty releasing handshake) or percussion (percussion myotonia of thenar eminence)
- EMG: myotonic discharges — waxing and waning amplitude/frequency = “dive bomber” sound
- Worsened by cold in DM1; improves with repeated activity (“warm-up phenomenon”)
- Treatment of myotonia (if symptomatic): mexiletine (first-line); alternatives: carbamazepine, phenytoin
Anesthesia Risks
- Succinylcholine can trigger generalized myotonic contraction (masseter spasm, difficult ventilation) and hyperkalemia — avoid depolarizing agents
- NOTE: this is NOT true malignant hyperthermia (MH is RYR1/CACNA1S-related); volatile anesthetics are generally tolerated but heightened sensitivity to respiratory depressants and prolonged neuromuscular blockade are concerns
- Cardiac arrhythmias under anesthesia — continuous monitoring required
- Prolonged respiratory depression with sedatives/opioids
- Always alert anesthesiology before any procedure in myotonic dystrophy patients
💎 Board Pearl
- DM1 = distal weakness; DM2 = proximal weakness — the single most tested distinction between the two
- Congenital DM1 is inherited from the MOTHER (massive CTG expansion during maternal meiosis) — father transmits smaller expansions
- Christmas tree cataracts on slit-lamp exam are virtually pathognomonic for myotonic dystrophy
- Cardiac sudden death is a leading cause of mortality in DM1 — annual ECG and Holter monitoring; low threshold for pacemaker/ICD
- Dive bomber sound on EMG = myotonia — seen in both DM1 and DM2 (also in myotonia congenita, paramyotonia congenita)
- Avoid succinylcholine in myotonic dystrophy — can trigger prolonged muscle contraction and hyperkalemia
Facioscapulohumeral Dystrophy (FSHD)
Genetics
- FSHD1 (~95%): contraction of D4Z4 macrosatellite repeats on chr 4q35 (Normal: 11–100 D4Z4 repeats; FSHD1: 1–10 repeats (contraction) on a permissive 4qA haplotype); AD; requires permissive 4qA haplotype for DUX4 expression
- FSHD2 (~5%): SMCHD1 mutations (epigenetic modifier) + permissive 4qA allele; D4Z4 repeat normal or borderline
- Common pathway: de-repression of DUX4 gene → toxic DUX4 protein expression in skeletal muscle
Clinical Features
| Region | Findings |
|---|---|
| Face | Inability to whistle, drink from a straw, or bury eyelashes; weak eye closure (may sleep with eyes partially open); transverse smile |
| Scapula | Scapular winging (difficulty raising arms above head); asymmetric; trapezius, serratus anterior, rhomboid weakness |
| Upper arm | Biceps/triceps weakness with relative sparing of deltoid and forearm (“Popeye arms”) |
| Lower extremity | Anterior compartment → footdrop; tibialis anterior weakness; hip girdle weakness later |
| Trunk | Abdominal weakness → Beevor sign (umbilicus moves cephalad with sit-up); lumbar lordosis |
Key Features
- Asymmetric involvement is characteristic (right-left asymmetry is the rule, not the exception)
- CK: normal or mildly elevated (rarely >5× normal)
- No cardiac involvement typically
- Coats-like retinal vasculopathy (telangiectasias ± exudative changes) — severe forms primarily affect infantile/early-onset FSHD with large contractions (1–3 repeats); screen with dilated fundoscopy
- Sensorineural high-frequency hearing loss — common (especially in early-onset/infantile FSHD where it approaches 100%); less frequent in typical adult-onset FSHD
- Onset: typically teens–20s; infantile-onset FSHD is severe (1–3 D4Z4 repeats)
💎 Board Pearl
- Can’t whistle + scapular winging + footdrop + asymmetric = FSHD — the classic board vignette
- Beevor sign (umbilicus migrates superiorly with sit-up) = lower abdominal weakness; highly associated with FSHD
- FSHD requires a permissive 4qA haplotype — D4Z4 contraction on 4qB does NOT cause disease
- Coats-like retinal vasculopathy + hearing loss are extra-muscular features that distinguish FSHD from other dystrophies
Limb-Girdle Muscular Dystrophies (LGMD)
Overview
- Definition: heterogeneous group of muscular dystrophies with predominant proximal (limb-girdle) weakness
- New nomenclature (2018): LGMD D (dominant) or LGMD R (recessive) + number + protein name
- Common features: proximal weakness (pelvic > shoulder girdle), elevated CK, myopathic EMG, onset teens–young adult
- Diagnosis: muscle biopsy with immunohistochemistry for specific protein deficiency → genetic confirmation
Board-Relevant LGMD Subtypes
| New Name | Gene / Protein | Inheritance | Key Features |
|---|---|---|---|
| LGMD R1 | CAPN3 / calpain-3 | AR | Most common AR LGMD; posterior thigh + hip girdle weakness; scapular winging in some; CK 5–20× |
| LGMD R2 | DYSF / dysferlin | AR | Also causes Miyoshi myopathy (distal — calf weakness/atrophy); allelic disorders; CK very high (often >10,000); defective membrane repair |
| LGMD R3 | SGCA / α-sarcoglycan | AR | Sarcoglycanopathies = “mini-dystrophinopathies”; phenotype mimics DMD/BMD but dystrophin is normal; progressive proximal weakness; calf pseudohypertrophy in some; cardiac involvement variable |
| LGMD R4 | SGCB / β-sarcoglycan | AR | |
| LGMD R5 | SGCG / γ-sarcoglycan | AR | |
| LGMD R6 | SGCD / δ-sarcoglycan | AR | |
| LGMD R9 | FKRP / fukutin-related protein | AR | Overlaps with congenital muscular dystrophies (dystroglycanopathies); variable severity; may have brain and eye involvement in severe forms |
| LGMD R12 | ANO5 / anoctamin-5 | AR | Common in Northern Europe; asymmetric quadriceps and calf involvement; high CK; allelic with Miyoshi-like distal myopathy |
| LGMD D1 | DNAJB6 | AD | Late-onset proximal weakness; rimmed vacuoles on biopsy (can mimic IBM) |
| LGMD D2 | TNPO3 / transportin-3 | AD | Rare; slowly progressive proximal weakness |
🎯 Clinical Pearl
- Dysferlinopathy (LGMD R2) can present as either proximal (LGMD) or distal (Miyoshi) — same gene, different phenotype; suspect when CK is very high (>10,000) in a young patient
- Sarcoglycanopathies look like dystrophinopathies clinically but dystrophin staining is normal on biopsy — always check sarcoglycan staining if dystrophin is preserved
💎 Board Pearl
- LGMD R1 (calpain-3) = most common AR LGMD worldwide
- LGMD R2 (dysferlin) = Miyoshi myopathy — distal calf weakness from the same gene; the board loves this allelic relationship
- Sarcoglycanopathies (R3–R6) = “mini-dystrophinopathies” — DMD-like phenotype with normal dystrophin; biopsy shows absent sarcoglycan staining
- FKRP mutations (LGMD R9) span a severity spectrum from mild LGMD to severe congenital MD with brain malformations
Emery-Dreifuss Muscular Dystrophy (EDMD)
Genetics
| Gene | Protein | Inheritance | Key Points |
|---|---|---|---|
| EMD | Emerin (inner nuclear membrane) | X-linked recessive | Classic EDMD; milder cardiac disease in some |
| LMNA | Lamin A/C (nuclear lamina) | AD (most common) | More severe cardiac involvement; higher risk of sudden cardiac death; also causes dilated CM, CMT2B1, lipodystrophy, progeria |
Clinical Triad
| Feature | Details |
|---|---|
| 1. Early contractures | Elbow flexion contractures, Achilles tendon tightening, cervical spine rigidity — appear BEFORE significant weakness (distinguishing feature) |
| 2. Humeroperoneal weakness | Biceps/triceps (upper arm) + peroneal (ankle dorsiflexion/eversion) — slowly progressive |
| 3. Cardiac conduction defects | AV block (1st → complete), atrial arrhythmias (atrial fibrillation/flutter, atrial standstill), dilated cardiomyopathy; pacemaker/ICD often required |
- CK: mildly elevated (2–10× normal)
- LMNA mutations are pleiotropic — can also cause: dilated cardiomyopathy (isolated), CMT type 2B1, familial partial lipodystrophy (Dunnigan), Hutchinson-Gilford progeria, restrictive dermopathy
💎 Board Pearl
- Early contractures BEFORE weakness = think EDMD — contractures precede weakness (opposite of most dystrophies where weakness comes first)
- LMNA cardiac disease can cause sudden death even with mild skeletal weakness — low threshold for ICD placement
- LMNA mutations are the most common cause of familial dilated cardiomyopathy with conduction defects — this gene appears in cardiology and neurology board questions
Oculopharyngeal Muscular Dystrophy (OPMD)
Overview
| Feature | Details |
|---|---|
| Gene | GCN trinucleotide repeat expansion in PABPN1 (poly(A) binding protein nuclear 1); chr 14q11 |
| Inheritance | AD (most common); rare AR form (homozygous — more severe) |
| Normal repeats | Normal: (GCN)10 encoding 10 alanines; AD OPMD: (GCN)12–17 (typically 12–13); (GCN)11 is a recessive modifier allele |
| Onset | >40 years (typically 5th–6th decade) |
| Ancestry | French-Canadian (1:1,000 in Quebec) and Bukharan Jewish populations; also worldwide |
| Ptosis | Bilateral, progressive, symmetric; patients compensate with head tilt and frontalis contraction; NO diurnal fluctuation (unlike MG) |
| Dysphagia | Progressive; main source of morbidity (aspiration pneumonia, malnutrition); may need cricopharyngeal myotomy |
| Proximal weakness | Mild; develops later; primarily hip girdle and shoulder |
| CK | Normal or mildly elevated |
| Biopsy | Intranuclear tubulofilamentous inclusions (8.5 nm diameter) on electron microscopy — pathognomonic |
- DDx: MG (but OPMD has no fluctuation, no antibodies, no response to AChEi); mitochondrial myopathy (CPEO); FSHD
💎 Board Pearl
- Ptosis + dysphagia + onset >40 + French-Canadian ancestry = OPMD — classic board vignette
- 8.5 nm intranuclear tubulofilamentous inclusions on EM are pathognomonic for OPMD — distinguish from 15–18 nm inclusions in IBM
- No diurnal fluctuation distinguishes OPMD from MG; OPMD ptosis is constant and progressive, not fatigable
Congenital Muscular Dystrophies (CMD)
Overview
- Definition: muscular dystrophies presenting at birth or early infancy with hypotonia, weakness, contractures, and elevated CK
- All autosomal recessive
- Two major groups: merosin-deficient CMD (LAMA2) and dystroglycanopathies (defective glycosylation of α-dystroglycan)
Key CMD Subtypes
| Type | Gene / Protein | Key Features | Brain MRI |
|---|---|---|---|
| Merosin-deficient CMD (MDC1A) | LAMA2 / laminin-α2 (merosin) | Most common CMD in Western countries; severe hypotonia at birth; rarely achieve independent ambulation; seizures in ~30% | Diffuse white matter abnormalities (T2/FLAIR hyperintensity); NO structural malformation |
| Walker-Warburg syndrome | Multiple genes (POMT1, POMT2, FKRP, others) | Most severe dystroglycanopathy; death usually by age 3; severe eye abnormalities (microphthalmos, retinal dysplasia) | Type II (cobblestone) lissencephaly; hydrocephalus; cerebellar malformations |
| Muscle-Eye-Brain disease | Primary gene: POMGNT1; secondary: POMGNT2, FKTN, FKRP, ISPD, others (allelic spectrum overlap) | Intermediate severity; eye abnormalities (myopia, glaucoma, retinal dysplasia); intellectual disability | Cobblestone lissencephaly (less severe than WWS); cerebellar cysts |
| Fukuyama CMD | FKTN / fukutin | Most common CMD in Japan; intellectual disability; seizures; rarely ambulatory; dilated cardiomyopathy | Cobblestone lissencephaly; cerebellar polymicrogyria; cerebellar cysts |
| Ullrich CMD | COL6A1/A2/A3 / collagen VI | Prominent proximal contractures + distal hyperlaxity; follicular hyperkeratosis (rough skin); respiratory failure | Normal |
💎 Board Pearl
- Merosin-deficient CMD = white matter abnormalities on MRI but no structural brain malformation — distinguishes from dystroglycanopathies which have cobblestone lissencephaly
- Cobblestone (type II) lissencephaly = dystroglycanopathy (Walker-Warburg, Muscle-Eye-Brain, Fukuyama) — due to overmigration of neurons through gaps in the pial-glial limitans
- Walker-Warburg = worst prognosis among CMDs; die by age 3; most severe brain + eye + muscle involvement
- Fukuyama CMD is the most common CMD in Japan (founder mutation); most common CMD overall in Western countries = merosin-deficient (LAMA2)
High-Yield Comparison Table
Muscular Dystrophies — Side-by-Side
| Feature | DMD | BMD | DM1 | DM2 | FSHD | LGMD | EDMD | OPMD |
|---|---|---|---|---|---|---|---|---|
| Inheritance | XR | XR | AD | AD | AD | AR or AD | XR or AD | AD |
| Gene | DMD | DMD | DMPK | CNBP | D4Z4 / DUX4 | Multiple | EMD / LMNA | PABPN1 |
| Onset | 2–5 yr | 5–15 yr | Teens–30s | 30s–60s | Teens–20s | Teens–adult | Childhood | >40 yr |
| Weakness | Proximal | Proximal | Distal | Proximal | Face → scapula → distal LE | Proximal (limb-girdle) | Humeroperoneal | Ptosis + pharyngeal |
| CK | 10,000–50,000+ | Typically 1,000–5,000 (can exceed); generally lower than DMD | Normal–mild ↑ | Normal–mild ↑ | Normal–mild ↑ | Moderate–high ↑ | Mild ↑ | Normal–mild ↑ |
| Cardiac | Dilated CM (universal) | Dilated CM (common) | Conduction defects; sudden death | Mild conduction defects | None typically | Variable | AV block; arrhythmias; sudden death | None |
| Myotonia | No | No | Yes | Mild | No | No | No | No |
| Unique feature | Gower sign; calf pseudohypertrophy | CM may precede weakness | Cataracts; frontal balding; anticipation | Pain; proximal; no congenital form | Asymmetric; Beevor sign; Coats-like retinal vasculopathy | Sarcoglycanopathies mimic DMD | Contractures before weakness | French-Canadian; 8.5 nm inclusions |
💎 Board Pearl
- Cardiac monitoring is mandatory in: DMD, BMD, DM1, EDMD — all carry risk of cardiomyopathy, conduction defects, or sudden death
- Myotonia narrows the differential to DM1 or DM2 (also non-dystrophic myotonias: myotonia congenita, paramyotonia congenita)
- Distal weakness pattern: DM1 (hands + ankle dorsiflexors); contrast with DM2 which is proximal despite being a “myotonic dystrophy”
- Highest CK: DMD > BMD > LGMD > EDMD/DM/FSHD/OPMD
- Asymmetry: FSHD is the most characteristically asymmetric muscular dystrophy
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