• Incidence: approximately 1 in 3,500 live male births worldwide — this makes DMD the most common lethal genetic disorder diagnosed in childhood ^[2][3]
• DMD is the most common neuromuscular disease in children — SMA is the 2nd most common neuromuscular disease following DMD ^[4]
• Prevalence: approximately 4.8 per 100,000 males (lower than incidence because of premature mortality)
• No racial or ethnic predilection — equally affects all populations globally

• Almost exclusively affects males (X-linked recessive inheritance)
• Females are typically carriers — most are asymptomatic, but ~2.5–7.8% of female carriers develop some degree of skeletal or cardiac muscle involvement ("manifesting carriers"), due to skewed X-inactivation (lyonisation)
• Very rare affected females: can occur in Turner syndrome (45,X with DMD mutation on the single X), uniparental disomy, or balanced X-autosome translocations disrupting the DMD gene

• Prevalence mirrors global figures
• Genetic counselling and prenatal diagnosis are available through clinical genetics services (e.g., HKU Department of Obstetrics & Gynaecology, QMH Clinical Genetics Service)
• No universal newborn screening for DMD in Hong Kong as of 2026 (unlike some European countries/US states that have pilot programmes using CK-based screening)

• Located at Xp21.2 (short arm of X chromosome, band 21.2)
• The largest known human gene: spans 2.4 megabases (Mb) of genomic DNA — this enormous size partly explains its high spontaneous mutation rate
• Contains 79 exons but the mature mRNA is only ~14 kb (i.e., > 99% of the gene is intronic)
• Encodes the protein dystrophin (427 kDa, 3,685 amino acids)

Dystrophin has four functional domains — think of it as a molecular shock absorber that links the internal cytoskeleton of the muscle fibre to the extracellular matrix:

[N-terminal] ——— [Central rod domain] ——— [Cysteine-rich domain] ——— [C-terminal]
     |                    |                          |                        |
Binds F-actin       24 spectrin-like repeats    Binds β-dystroglycan      Binds syntrophins
(intracellular      (acts as spring/shock       (connects to              and dystrobrevins
 cytoskeleton)       absorber)                   extracellular matrix      (signalling)
                                                 via DGC)

Dystrophin is the central component of the DGC (also called dystrophin-glycoprotein complex, DGC). The DGC bridges the muscle cell interior to the extracellular matrix:

Why does this matter?

• During muscle contraction, the sarcolemma (muscle cell membrane) is subjected to enormous mechanical stress
• Dystrophin acts as a molecular spring/shock absorber — it transmits force from the intracellular actin cytoskeleton through the DGC to the extracellular matrix, distributing mechanical stress and protecting the sarcolemma from contraction-induced damage
• Without dystrophin → the DGC disassembles → sarcolemma becomes fragile → repeated contraction-relaxation cycles cause membrane tears → catastrophic downstream consequences (see Pathophysiology below)

The DMD gene has multiple promoters producing tissue-specific isoforms:

This explains why DMD is not purely a muscle disease — cognitive impairment and behavioural issues occur because dystrophin isoforms are expressed in the CNS.

• X-linked recessive ^[1][2][3]
• Hemizygous males (only one X chromosome) are affected
• Heterozygous females are carriers (usually asymptomatic or mildly affected)
• ~1/3 of cases are de novo mutations (no family history) — this is crucial because it means a negative family history does NOT exclude DMD
  • The high de novo rate is because the DMD gene is so large that it is a "mutational hotspot"

• Two deletion hotspots: exons 2–20 and exons 44–55
• ~30–60% of mutations are deletions ^[2]

This is the single most important concept for understanding the DMD vs. BMD distinction:

• If a mother is a confirmed carrier:
  • 50% of sons will be affected
  • 50% of daughters will be carriers
• ~1/3 de novo mutations → mother may not be a carrier (germline mosaicism can still confer a recurrence risk of ~7–10% even if maternal blood testing is negative)
• Prenatal diagnosis: chorionic villus sampling (CVS) at 11–14 weeks or amniocentesis at 15–18 weeks with mutation-specific testing
• Preimplantation genetic testing (PGT) is available for known familial mutations

Let me walk through each step:

Step 1: Absent dystrophin → Sarcolemma instability

• Without the dystrophin "shock absorber," the sarcolemma cannot withstand the mechanical stress of repeated contraction
• The DGC complex falls apart (sarcoglycans, dystroglycans lose their scaffold)
• nNOS is displaced from the sarcolemma → impaired functional ischaemia regulation (see below)

Step 2: Membrane tears and calcium influx

• Each contraction cycle causes micro-tears in the fragile sarcolemma
• Extracellular calcium floods into the myofibre through these tears
• Intracellular calcium rises to toxic levels

Step 3: Calcium-mediated destruction

• Excess calcium activates calpains (calcium-dependent proteases) → proteolytic degradation of myofibrils
• Mitochondrial calcium overload → mitochondrial dysfunction → oxidative stress → further damage
• This is why CK (creatine kinase) levels are massively elevated — CK leaks out through the damaged sarcolemma

Step 4: Inflammation and failed regeneration

• Necrotic fibres attract inflammatory cells (macrophages, T cells)
• Chronic inflammation drives fibrosis (via TGF-β signalling)
• Satellite cells (muscle stem cells) initially attempt regeneration but eventually become exhausted
• The regenerative capacity is overwhelmed → fibres are progressively replaced by fibrotic tissue and fat

Step 5: nNOS displacement

• Dystrophin normally anchors neuronal nitric oxide synthase (nNOS) to the sarcolemma via syntrophins
• Without dystrophin → nNOS is mislocalised → impaired local vasodilation during exercise → functional muscle ischaemia → accelerated damage

• Cardiac muscle expresses the same Dp427m dystrophin isoform
• The same cascade occurs in cardiomyocytes → progressive fibrosis (begins in the posterolateral LV wall) → dilated cardiomyopathy (DCM) ^[5]
• DMD is listed as a neuromuscular disorder causing familial dilated cardiomyopathy ^[5]
• Cardiac fibrosis is initially subepicardial (unlike ischaemic cardiomyopathy which is subendocardial) — this pattern is detectable on cardiac MRI with late gadolinium enhancement

• Dp427c (cortical neurons), Dp140 (brain), and Dp71 (ubiquitous) are all expressed in the brain
• Absence of these isoforms disrupts:
  • Synaptic structure and function
  • GABA-A receptor clustering
  • Aquaporin-4 anchoring at astrocyte endfeet (blood-brain barrier function)
• Result: intellectual disability (mean IQ ~85, roughly 1 SD below normal), learning difficulties, and increased rates of ASD, ADHD, and OCD

• Proximal muscles are affected before distal muscles because proximal muscles (hip and shoulder girdles) generate greater forces and undergo more mechanical stress during activities like walking, climbing, and getting up from the floor
• Calf muscles develop pseudohypertrophy — the muscle fibres are replaced by fat and fibrous tissue, making the calves appear enlarged despite being weak

• CK is normally contained within myofibres
• In DMD, the sarcolemma is permeable even at rest (membrane integrity is compromised)
• CK leaks out constantly → serum CK is typically 50–100× the upper limit of normal (often > 10,000–20,000 IU/L)
• CK is elevated from birth — even before clinical symptoms appear
• CK gradually falls in later stages as muscle mass is replaced by fat and fibrosis (less muscle = less CK to leak)

Immunohistochemical classification ^[2]:

• Dystrophinopathy: DMD, BMD
• Sarcoglycanopathy: LGMD
• Others: laminin, caveolin, calpain, dysferin

Genetic classification — based on the underlying gene mutation ^[2]

From the lecture slides and senior notes, DMD must be differentiated from other causes of weakness ^[6][7]:

• Most female carriers are asymptomatic
• ~2.5–7.8% are "manifesting carriers" due to skewed X-inactivation:
  • Mild proximal limb weakness
  • Calf hypertrophy
  • Myalgia and exercise intolerance
  • Elevated CK (in ~50–70% of carriers, even if asymptomatic)
  • Dilated cardiomyopathy — this is the most clinically significant carrier manifestation; up to 7–10% of carriers develop DCM by age 40
• All known female carriers should undergo cardiac screening with echocardiography

A. Spinal Muscular Atrophy (SMA)

This is the second most important differential in a floppy/weak child ^[4].

Key distinguishing point: Absent reflexes + fasciculations + normal CK → anterior horn cell disease (SMA). Preserved reflexes + no fasciculations + massively elevated CK + pseudohypertrophy → myopathy (DMD).

A. Myasthenia Gravis (Congenital or Juvenile)

Distinguished from myositis by presence of facial muscle weakness, normal muscle enzymes, characteristic EMG changes and AChR antibodies ^[10]

These are acquired — usually present later, with subacute onset, and often have systemic features.

A. Juvenile Dermatomyositis (JDM) / Polymyositis (PM)

Drug-induced myopathies ^[6][7][9]:

• Corticosteroids (proximal weakness)
• Statins (HMG-CoA reductase inhibitors)
• Alcohol, cocaine, heroin, colchicine, antimalarials ^[2][9]

While statins and steroids are less relevant in a 3-year-old, steroid myopathy becomes a critical differential later in DMD management because corticosteroids are used therapeutically — worsening weakness on steroids may be drug-induced rather than disease progression.

These are upper motor neuron or chromosomal causes — they produce truncal hypotonia but not true weakness in the way DMD does ^[4]:

A. Charcot-Marie-Tooth Disease (CMT / Hereditary Motor and Sensory Neuropathy)

A diagnosis of DMD is established when ALL of the following are met:

The following should trigger investigation for DMD:

1. Motor delay — a boy not walking by 18 months, or walking but clumsy/falling frequently by age 2–3
2. Gower's sign in any child
3. Calf pseudohypertrophy in a boy with proximal weakness
4. Incidentally discovered elevated CK (e.g., elevated "liver enzymes" — ALT and AST — that are actually from muscle, not liver)
5. Elevated transaminases in a young boy with no liver disease — this is a classic trap: ALT and AST are present in skeletal muscle, so in DMD they may be elevated due to muscle damage, not hepatitis
6. Family history of muscular dystrophy, unexplained wheelchair use, or early death in males on the maternal side
7. Severe skeletal muscle disease causing a false positive troponin elevation — the GC CVS investigations lecture highlights that DMD/rhabdomyolysis can cause elevated troponin as a true false positive ^[12]

Management of complications: heart failure, arrhythmia, respiratory failure ^[3]

Why start cardiac medications prophylactically? Because cardiac fibrosis in DMD begins silently — by the time echo shows reduced LVEF, significant irreversible fibrosis has already occurred. Early treatment aims to slow fibrosis before it becomes clinically apparent. Cardiac MRI with LGE can detect fibrosis years before echo changes.

Why does respiratory failure occur? Diaphragm and intercostal muscle weakness → reduced vital capacity → ineffective cough → mucus retention → atelectasis → pneumonia. Scoliosis further restricts chest wall compliance. FVC declines ~6–10% per year after loss of ambulation.

Genetic counselling ^[3] is a critical component of DMD management, addressing: