Aspect	Progressive Muscular Dystrophies	Myotonic Syndromes
Definition	A group of genetic disorders characterized by progressive muscle weakness and wasting.	Disorders characterized by muscle weakness along with myotonia (difficulty relaxing muscles after contraction).
Main Types	Duchenne, Becker	Type 1 (DM1) and Type 2 (DM2)
Inheritance	Often X-linked (e.g., Duchenne/Becker) or autosomal (e.g., Limb-Girdle).	Autosomal dominant. Trinucleotide repeat expansion diseases
Onset	Usually in childhood or adolescence.	Typically adolescence or adulthood.
Primary Symptoms	Muscle weakness, wasting, contractures, scoliosis, cardiac complications.	Muscle weakness, myotonia, cataracts, cardiac arrhythmias, endocrine issues.
Progression	Gradual; severity and speed depend on the subtype.	Gradual; multisystem involvement often worsens with age.
Pathophysiology	Defects in proteins like dystrophin (Duchenne/Becker) or other sarcolemmal proteins.	Expanded CTG (DM1) or CCTG (DM2) repeats causing RNA toxicity and protein misregulation.
Diagnosis	Genetic testing, muscle biopsy, creatine kinase (CK) levels, EMG.	Genetic testing, EMG (shows myotonic discharges).
Treatment	Symptomatic: physical therapy, steroids (e.g., Duchenne), assistive devices.	Symptomatic: medications for myotonia (e.g., mexiletine), physical therapy.
Cardiac Involvement	Common, especially in Duchenne and Becker (cardiomyopathy).	Common, often conduction abnormalities or arrhythmias.
Respiratory Complications	Can develop in advanced stages due to diaphragm involvement.	Can occur due to muscle weakness or central control issues.
Cognitive Impact	Rare	Can include mild cognitive and behavioral changes.
Prognosis	Varies by type; some forms (e.g., Duchenne) are life-limiting.	Varies by severity; generally better than PMD but depends on systemic involvement.

Epidemiology

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• Sex: only male individuals affected in DMD and BMD
• Age of onset
  • DMD: 2–5 years
  • BMD: adolescence or early adulthood, usually > 15 years

Etiology

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• Inheritance pattern (DMD and BMD): X-linked recessive
• Chromosomal mutations affecting the dystrophin gene on the short arm of the X chromosome (Xp21)
  • DMD: frameshift deletion or nonsense mutation → shortened or absent dystrophin protein
  • BMD: in-frame deletion → partially functional dystrophin protein
  • In about two-thirds of DMD or BMD cases, deleted segments are as large as one or more exons.

Pathophysiology

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• Dystrophin protein: anchors the cytoskeleton of skeletal and cardiac muscle cells to the extracellular matrix by connecting cytoskeletal actin filaments to membrane-bound α- and β-dystroglycan, which are connected to extracellular laminin
• Dystrophin gene: largest known protein-coding gene in the human DNA
  • Because of its size, the dystrophin gene is at increased risk for spontaneous mutations.
  • Mutations affecting the dystrophin gene→ alterations of dystrophin protein structure → partial (BMD) or almost complete (DMD) impairment of protein function → disturbance of numerous cellular signaling pathways → necrosis of affected muscle cells → replacement with connective tissue and fatty tissue → affected muscles are weak even though they appear larger (“pseudohypertrophy”)
  • Errors in splicing in the DMD gene can also cause DMD.

Clinical features

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Duchenne muscular dystrophy (DMD)

• Progressive muscle paresis and atrophy
  • Starts in the proximal lower limbs (pelvic girdle)
  • Extends to the upper body and distal limbs as the disease progresses
• Weak reflexes
• Waddling gait (i.e., Duchenne limp) with bilateral Trendelenburg sign
• Gower maneuver
  • The individual arrives at a standing position by supporting themselves on their thighs and then using the hands to “walk up” the body until they are upright.
  • Classic sign of DMD, but also occurs in inflammatory myopathies (e.g., dermatomyositis, polymyositis) and other muscular dystrophies (e.g., BMD)
• Calf pseudohypertrophy
  • Mutations affecting the dystrophin gene→ alterations of dystrophin protein structure → partial (BMD) or almost complete (DMD) impairment of protein function → disturbance of numerous cellular signaling pathways → necrosis of affected muscle cells → replacement with connective tissue and fatty tissue → affected muscles are weak even though they appear larger (“pseudohypertrophy”)

Becker muscular dystrophy (BMD)

• Symptoms similar to those of DMD, but less severe
• Slower progression (patients often remain ambulatory into adult life)

Mnemonic

Becker is better