Muscular Dystrophies

Muscular dystrophies are inherited progressive muscle diseases characterized by fiber necrosis, regeneration, fibrosis, and fatty replacement. The clinical phenotypes are diverse — from severe early-onset Duchenne dystrophy to milder late-onset limb-girdle and oculopharyngeal forms — but share the histopathologic dystrophic pattern. Specific molecular defects in structural proteins of the sarcolemma, contractile machinery, or nuclear envelope produce specific clinical syndromes. Modern molecular genetics has transformed diagnosis and is beginning to deliver disease-modifying therapy. This page covers the major dystrophies and their pathology.

Dystrophinopathies (X-Linked)

Duchenne Muscular Dystrophy (DMD)

  • Most common X-linked dystrophy.
  • Dystrophin gene (Xp21); largest gene in the human genome.
  • Out-of-frame deletions/duplications/point mutations → no functional dystrophin.
  • Boys: onset 2-5 years; difficulty walking; Gower sign; calf pseudohypertrophy.
  • Wheelchair-bound by ~12 years; respiratory failure by 20s.
  • Cardiomyopathy + intellectual disability + skeletal deformity.

Pathology

  • Dystrophic pattern: variable size fibers + necrosis + regeneration + fibrosis + fatty replacement.
  • Hyalinized “opaque” fibers.
  • Connective tissue increases progressively.
  • Absent dystrophin on IHC (all three domains: N-terminus, rod, C-terminus).
  • Western blot: no detectable dystrophin.

Treatment

  • Corticosteroids (prednisone, deflazacort): standard; slows decline.
  • Eteplirsen, golodirsen, casimersen, viltolarsen: exon-skipping antisense oligonucleotides for specific mutations; small benefit but disease-modifying.
  • Delandistrogene moxeparvovec (Elevidys): AAV9-delivered micro-dystrophin gene therapy; approved 2023.
  • Ataluren: read-through of nonsense mutations (limited approval).
  • Cardiac (ACE inhibitors, BB) and respiratory (NIV) support.

Becker Muscular Dystrophy (BMD)

  • Same gene as DMD; in-frame deletions → reduced or abnormal but partly functional dystrophin.
  • Milder phenotype than DMD.
  • Onset variable: childhood to adulthood.
  • Ambulation often preserved into adulthood.
  • Cardiomyopathy common.
  • Dystrophin IHC: reduced or patchy expression.

Limb-Girdle Muscular Dystrophies (LGMD)

Heterogeneous group with proximal weakness. 30+ subtypes. Now classified by inheritance pattern (LGMD-D for dominant, LGMD-R for recessive) and gene.

Sarcoglycanopathies (LGMD-R3, R4, R5, R6)

  • Mutations in α, β, γ, or δ sarcoglycan.
  • Childhood / adolescent onset.
  • Severe weakness; cardiomyopathy.
  • Sarcolemma sarcoglycan IHC: absent or reduced.

Dysferlinopathy (LGMD-R2 / Miyoshi Myopathy)

  • Dysferlin mutations.
  • Distal (Miyoshi) or proximal (LGMD-R2) presentations.
  • Onset late teens/twenties.
  • Dysferlin IHC: absent.

Calpainopathy (LGMD-R1)

  • Calpain-3 mutations.
  • Pelvic and shoulder girdle weakness.
  • Calpain-3 Western blot: deficient.

Other LGMDs

Caveolinopathy (LGMD-D1), titinopathies (LGMD-R10), anoctaminopathy (LGMD-R12), and many others.

Facioscapulohumeral Muscular Dystrophy (FSHD)

  • Autosomal dominant.
  • FSHD1: shortened D4Z4 repeat on chromosome 4q35 (with permissive 4qA haplotype) → ectopic DUX4 expression in muscle.
  • FSHD2: SMCHD1 mutation + 4qA haplotype.
  • Onset typically adolescent/young adult.
  • Asymmetric weakness: face + scapular winging + humeral muscles + later truncal and lower extremity.
  • Often “preserved” extraocular and bulbar muscles.
  • Hearing loss, retinal vasculopathy in some.
  • Biopsy: dystrophic with often patchy inflammation.
  • Treatment: supportive; trials targeting DUX4 expression.

Oculopharyngeal Muscular Dystrophy (OPMD)

  • Autosomal dominant; PABPN1 trinucleotide repeat expansion.
  • Late onset (50s-60s).
  • Ptosis (often first symptom), dysphagia.
  • Later proximal weakness.
  • Biopsy: rimmed vacuoles + intranuclear filamentous inclusions on EM.

Emery-Dreifuss Muscular Dystrophy (EDMD)

  • X-linked (EMD/emerin) or autosomal (LMNA/lamin A/C).
  • Triad: early contractures (elbows, ankles, neck) + slowly progressive muscle weakness + cardiomyopathy with conduction defects.
  • Cardiomyopathy often disproportionate to muscle weakness; sudden death risk.
  • Biopsy: emerin or lamin A/C IHC abnormal.

Myotonic Dystrophy

Myotonic Dystrophy Type 1 (DM1, Steinert Disease)

  • Autosomal dominant; CTG expansion in DMPK 3′ UTR.
  • RNA toxicity from expanded RNA hairpins sequestering RNA-binding proteins (MBNL1, CUGBP1).
  • Anticipation common; congenital DM1 with very large expansions (maternal transmission).

Clinical

  • Distal weakness early.
  • Myotonia (delayed muscle relaxation): grip, percussion.
  • Facial weakness; ptosis.
  • Cardiac conduction abnormalities.
  • Cataracts.
  • Frontal balding.
  • Diabetes mellitus.
  • Cognitive impairment.
  • Hypersomnolence.
  • Testicular atrophy.

Pathology

  • Central nuclei (often in long chains).
  • Sarcoplasmic masses.
  • Ring fibers.
  • Type 1 fiber atrophy in some.

Myotonic Dystrophy Type 2 (DM2)

  • CCTG expansion in ZNF9 (CNBP) intron 1.
  • Milder; later onset.
  • Proximal weakness predominant.
  • Similar systemic features (cataracts, conduction, diabetes).
  • No congenital form.

Congenital Muscular Dystrophies (CMD)

  • Merosin-deficient CMD (LAMA2): merosin (laminin α2) deficiency; white matter hyperintensities on MRI; severe weakness from birth.
  • α-dystroglycanopathies: Walker-Warburg, muscle-eye-brain (Santavuori), Fukuyama. Cobblestone lissencephaly + eye + muscle.
  • Collagen VI-related: Bethlem (mild) and Ullrich (severe); follicular hyperkeratosis.
  • Selenoprotein N-related: rigid spine syndrome.

Other Dystrophic Conditions

  • Spinal muscular atrophy (SMA): actually a neurogenic disease but with secondary muscle changes; SMN1 mutations; nusinersen/Zolgensma transformative.
  • Distal myopathies: Welander, Markesbery-Griggs, GNE myopathy, others.
  • Myofibrillar myopathies: with cytoplasmic inclusions; desmin, αB-crystallin, others.

Diagnostic Workflow

  1. Clinical history + examination.
  2. CK elevation pattern.
  3. EMG.
  4. Genetic testing (NGS panels increasingly first-line).
  5. Muscle biopsy if genetics negative or to confirm.
  6. Cardiac and respiratory evaluation.

🔍 Did You Know?

The 2023 FDA approval of delandistrogene moxeparvovec (Elevidys) as a gene therapy for Duchenne muscular dystrophy marked a historic transition. The therapy uses an AAV9 viral vector to deliver a “micro-dystrophin” gene — a shortened but functional dystrophin variant — to skeletal muscle. Because the full dystrophin gene is too large to fit in an AAV vector, the micro-dystrophin retains the critical functional domains while omitting the dispensable middle region. The treatment is given as a single IV infusion. Outcomes have been mixed in clinical trials, with some patients showing improvement in motor function and others showing less benefit, but the FDA approval was based on biomarker evidence (increased micro-dystrophin expression) and modest clinical benefit. The treatment costs over $3 million, raising profound questions about access and equity. The approval represents a real first: a one-time gene therapy that addresses the underlying genetic cause of DMD, in contrast to the symptomatic treatment that has been the standard for decades. Other gene therapy approaches for DMD (CRISPR-mediated exon skipping, full dystrophin restoration) are in development. The era of treatable dystrophies has begun. The lesson generalizes: gene therapy for monogenic neuromuscular diseases is no longer theoretical — it is clinical reality with all its promise and challenges. SMA, Friedreich ataxia, and selected other diseases now have or will soon have disease-modifying therapies. The diagnostic accuracy of muscle biopsy and molecular testing has never been more important, because effective treatment depends on precise genetic diagnosis.

Pitfalls and Pearls

  • Dystrophic pattern: variable size + necrosis + regeneration + fibrosis + fatty replacement.
  • Duchenne: X-linked; absent dystrophin; severe; gene therapy (Elevidys) and exon-skipping ASOs.
  • Becker: X-linked; reduced/abnormal dystrophin; milder; ambulatory longer.
  • Calf pseudohypertrophy + Gower sign: classic DMD/BMD.
  • LGMD subtypes: now classified LGMD-D (dominant) and LGMD-R (recessive); 30+ genes.
  • Sarcoglycanopathies: sarcoglycan IHC absent.
  • FSHD: asymmetric face/scapular/humeral; D4Z4 repeat contraction.
  • OPMD: ptosis + dysphagia; PABPN1 expansion; rimmed vacuoles + nuclear filaments.
  • Emery-Dreifuss: contractures + slow weakness + cardiomyopathy with conduction defects.
  • Myotonic dystrophy 1: CTG expansion in DMPK; distal weakness + myotonia + multisystem.
  • Myotonic dystrophy 2: CCTG in ZNF9; proximal weakness; milder.
  • Anticipation in DM1: especially maternal congenital form.
  • Walker-Warburg + muscle-eye-brain: α-dystroglycanopathies; cobblestone lissencephaly.
  • Merosin-deficient CMD: white matter changes on MRI.
  • SMA: SMN1 deletion; nusinersen, Zolgensma, risdiplam transformative.

References

  1. Dubowitz V, Sewry CA, Oldfors A. Muscle Biopsy: A Practical Approach. 5th ed. Elsevier; 2020.
  2. Mercuri E, Bönnemann CG, Muntoni F. Muscular dystrophies. Lancet. 2019;394(10213):2025-2038.
  3. Birnkrant DJ, Bushby K, Bann CM, et al. Diagnosis and management of Duchenne muscular dystrophy. Lancet Neurol. 2018;17(3):251-267.
  4. Mendell JR, Sahenk Z, Lehman K, et al. Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with Duchenne muscular dystrophy. JAMA Neurol. 2020;77(9):1122-1131.
  5. Thornton CA. Myotonic dystrophy. Neurol Clin. 2014;32(3):705-719.
  6. Straub V, Murphy A, Udd B; LGMD workshop study group. 229th ENMC international workshop: limb girdle muscular dystrophies — nomenclature and reformed classification. Neuromuscul Disord. 2018;28(8):702-710.