• BMD is rarer than DMD because the specific mutation types that allow partial dystrophin expression (in-frame deletions) are less common than the out-of-frame/nonsense mutations causing DMD.
• Worldwide distribution with no significant racial or ethnic predilection.
• In Hong Kong, dystrophinopathies are the most common hereditary neuromuscular disorder. Genetic testing services are available through clinical genetics services at public hospitals (e.g., QMH). The carrier frequency in the general female population is approximately 1 in 2,500.
• De novo mutations account for approximately one-third of cases (no prior family history), which is important because a negative family history does NOT exclude the diagnosis.

• Typically asymptomatic, but ~8–10% of female carriers ("manifesting carriers") develop some degree of:
  • Mild proximal weakness
  • Dilated cardiomyopathy (this is important — can occur even without skeletal muscle symptoms)
  • Elevated CK
• Mechanism: skewed X-inactivation (lyonization) — if the normal X chromosome is preferentially inactivated in muscle cells, the mutant allele is predominantly expressed.

Dystrophin is a large cytoskeletal protein (427 kDa) located on the inner surface of the sarcolemma (muscle cell membrane). It is the product of the DMD gene on Xp21.2 — one of the largest genes in the human genome (~2.4 Mb, 79 exons) ^[2].

Function: Dystrophin acts as a molecular shock absorber — it links the internal cytoskeleton (actin filaments inside the muscle cell) to the extracellular matrix (via the dystrophin-associated glycoprotein complex, DAGC) through the sarcolemma.

[Extracellular Matrix (Laminin-α2)]
        ↕
[DAGC: Dystroglycans + Sarcoglycans] ← embedded in sarcolemma
        ↕
[Dystrophin] ← subsarcolemmal scaffold
        ↕
[F-actin cytoskeleton]

Structural Domains of Dystrophin

Why this matters for BMD: In BMD, mutations (usually in-frame deletions) most commonly affect the central rod domain. Because the rod domain is a flexible spacer with repeating units, deleting some repeats still allows the protein to fold and connect the N-terminal (actin-binding) and C-terminal (membrane-binding) domains → the protein is shorter but retains partial function. This is why BMD is milder than DMD.

During muscle contraction, enormous mechanical forces are generated. Dystrophin:

1. Stabilises the sarcolemma during eccentric contractions (lengthening under load)
2. Prevents contraction-induced membrane tears (without it, the sarcolemma tears → Ca²⁺ influx → myofibre necrosis)
3. Organises signalling molecules (nNOS, syntrophins) at the sarcolemma
4. Maintains the DAGC — without dystrophin, the entire complex disassembles

Dystrophin is also expressed in cardiac myocytes. This is why cardiomyopathy is a major feature of dystrophinopathies. In BMD, the partially functional dystrophin may be sufficient for skeletal muscle for years but eventually insufficient for cardiac muscle — hence cardiac involvement may be the presenting or predominant feature in some BMD patients.

The type of mutation determines whether the patient develops DMD or BMD. This is governed by the reading-frame rule (Monaco's rule), which holds true in ~90% of cases:

Common Mutation Types in BMD

Hotspot regions: Deletions cluster in two hotspot regions:

1. Exons 45–55 (most common, ~80% of deletions) — central rod domain
2. Exons 2–20 (~20% of deletions) — N-terminal/proximal rod domain

Why in-frame deletions in the rod domain are tolerated: The rod domain consists of 24 spectrin-like repeats. Deleting several repeats (if in-frame) simply shortens the "shock absorber" — it's less effective but still bridges actin to the DAGC. Think of it like removing some links from a chain — the chain is shorter but still connects both ends.

• ~1/3 of cases are de novo (new mutations not inherited from mother)
• The DMD gene's enormous size makes it vulnerable to spontaneous mutations
• Germline mosaicism in the mother is possible — even if her blood-derived DNA tests negative for the mutation, her eggs may carry it (~7–10% risk of recurrence)

• Genetic testing in HK is available via the Clinical Genetic Service (Department of Health) and molecular diagnostic labs at QMH and PWH
• Multiplex ligation-dependent probe amplification (MLPA) is the first-line genetic test for detecting deletions/duplications in the DMD gene
• Next-generation sequencing (NGS) panels are used for point mutations not detected by MLPA
• Carrier testing and prenatal diagnosis are routinely offered to at-risk families
• Newborn screening for DMD/BMD is NOT currently part of the HK newborn screening programme (as of 2026), though CK-based pilot programmes are being evaluated internationally

1. Genetic mutation → partially functional dystrophin → reduced but not absent DAGC stability
2. Sarcolemma fragility: During muscle contraction (especially eccentric), the membrane undergoes mechanical stress. Without full dystrophin support, micro-tears occur in the sarcolemma → this is why BMD is milder (some dystrophin = some protection, but not complete)
3. Calcium influx: Membrane tears allow extracellular Ca²⁺ to flood in. Intracellular calcium overload activates:
   • Calpains (calcium-dependent proteases) → digest myofilaments
   • Phospholipase A₂ → membrane phospholipid breakdown
   • Mitochondrial dysfunction → energy failure → more necrosis
4. CK leak: Damaged membranes also leak intracellular enzymes (CK, LDH, ALT, AST) into the blood → elevated serum CK (a hallmark finding, though less dramatically elevated than in DMD)
5. Necrosis-regeneration cycles: Satellite cells (muscle stem cells) initially regenerate damaged fibres. Over years/decades, satellite cell pools become exhausted.
6. Fibrosis and fatty infiltration: As regenerative capacity fails, necrotic muscle is replaced by fibrous tissue and fat → this explains:
   • Pseudohypertrophy (calf muscles look big but are actually fat/fibrosis, not functional muscle)
   • Progressive weakness
   • Contractures (fibrotic tissue is inelastic)
7. Cardiac involvement: The same process occurs in cardiac myocytes → dilated cardiomyopathy (DCM) ^[4]. Fibrosis typically begins in the posterobasal and lateral LV wall (detected on cardiac MRI as late gadolinium enhancement).
8. Respiratory involvement: Diaphragm and intercostal muscle weakness → restrictive ventilatory defect (less severe and later than DMD).

Becker muscular dystrophy is listed as a neuromuscular disorder causing familial dilated cardiomyopathy ^[4].

• Dystrophin deficiency in cardiac myocytes → membrane instability → progressive cardiomyocyte loss → ventricular dilatation → dilated cardiomyopathy (DCM)
• The cardiomyopathy in BMD can be disproportionately severe compared to skeletal muscle involvement
• Fibrosis pattern: subepicardial, starting in inferolateral wall (detectable on cardiac MRI before echocardiographic changes)
• Heart failure and arrhythmias (especially ventricular tachycardia) are the leading cause of death in BMD

BMD sits within the broader classification of muscular dystrophies. This classification has been tested heavily in exams.

Clinical classification of muscular dystrophies: Duchenne (DMD), Becker (BMD), Facioscapulohumeral (FSHD), Limb-girdle (LGMD), Myotonic dystrophy (MyoD) ^[1][5]

Old definition of muscular dystrophy ^[1][5]:

1. Inherited disease
2. All symptoms due to muscle weakness
3. Progressive
4. No histopathological abnormalities other than degeneration and regeneration

The modern definition incorporates molecular genetics — muscular dystrophies are now defined by their underlying genetic mutations rather than purely clinical patterns ^[2].

Dystrophinopathies exist on a continuum:

BMD: usually later onset with milder symptoms and better prognosis ^[2][3]

• Continue to ambulate beyond 15 ^[2][3]
• Death between 40–60 ^[2][3]

General myopathy features: symmetrical proximal muscle weakness, normal reflex, no fatigability, no sensory loss ^[2]

These features help distinguish BMD (a myopathy) from:

• Neuropathy: would have sensory loss, distal > proximal weakness, absent reflexes early
• NMJ disorder (myasthenia gravis): would have fatigability, fluctuating weakness, ptosis/diplopia
• Motor neuron disease: would have UMN signs (spasticity, hyperreflexia) + LMN signs (fasciculations, wasting)

Muscular dystrophy is listed under "Congenital" causes in the pathological differential of lower limb weakness ^[6]

• The mildest end of the dystrophinopathy spectrum
• Males present with isolated DCM (no/minimal skeletal weakness)
• Due to mutations affecting cardiac-specific promoters or 5' exons of the DMD gene
• Female carriers can also develop isolated DCM

• Some patients are identified incidentally by elevated CK (e.g., during routine blood tests or pre-operative workup)
• If a young male has unexplained persistent CK elevation → consider BMD even without overt weakness

• BMD patients have an increased risk of rhabdomyolysis under general anaesthesia (particularly with succinylcholine and volatile agents)
• Not classic malignant hyperthermia (which is RYR1-related), but a "malignant hyperthermia-like" reaction due to sarcolemma fragility → massive Ca²⁺ release → rhabdomyolysis
• Anaesthetic precaution: avoid succinylcholine and volatile agents; use total intravenous anaesthesia (TIVA) ^[7]

These are the conditions most commonly confused with BMD because they share a genetic, progressive, proximal weakness pattern.

These are critical differentials because they are treatable — missing them has major consequences.

Hypothyroidism can mimic inflammatory myopathy with subacute onset of proximal muscle weakness and elevated CK ^[10]. Always check TFT in the workup of any proximal myopathy.

Drug-induced myopathy: glucocorticoids, statins, colchicine ^[6][9]

These are easily distinguished from BMD by their acute onset, systemic infection features, and temporal relationship with illness.

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

BMD does NOT have fatigability or ocular involvement. This is a fundamental distinction.

SMA Type 3 (Kugelberg-Welander) can present with proximal weakness in childhood/adolescence and may mimic BMD. Key distinguishers: fasciculations, areflexia (LMN pattern), and EMG showing denervation (not myopathic pattern). Genetic testing for SMN1 confirms SMA.

Periodic paralysis is episodic, not progressive — this is the key distinction from BMD.

Diseases where familial dilated cardiomyopathy forms part of a greater syndrome: Duchenne muscular dystrophy, Becker muscular dystrophy, Myotonic dystrophy, Mitochondrial diseases ^[4]

When a young man presents with DCM, consider:

• BMD (even with minimal skeletal weakness)
• DMD carrier state (in females)
• X-linked dilated cardiomyopathy (mildest dystrophinopathy)
• Myotonic dystrophy
• Laminopathy (LMNA mutation — more important in Chinese ^[4])
• Idiopathic / familial DCM (TTN most common gene, LMNA 6% of cases ^[4])
• Viral myocarditis / post-myocarditis DCM
• Alcoholic/toxic cardiomyopathy

Differential diagnosis of floppy infant syndrome ^[7]:

Note: BMD rarely presents as a floppy infant (it is typically later-onset), but severe BMD can present with early hypotonia and delayed motor milestones, entering this differential.

A patient found incidentally to have elevated CK (e.g., pre-operative blood test):

• BMD (especially mild/subclinical)
• DMD carrier (female)
• Statin myopathy
• Hypothyroidism
• Post-exercise
• Idiopathic hyperCKemia (some of these are eventually diagnosed with mild BMD on genetic testing)

A clinical diagnosis of BMD should be strongly suspected when ALL of the following are present:

The definitive diagnosis requires one of the following:

Since cardiac involvement is a major feature of BMD, you should also know when to diagnose the associated DCM ^[4][11]:

Familial DCM diagnostic criteria: ≥ 2 first- or second-degree relatives with DCM, OR a first-degree relative who had sudden death at < 50 years old with DCM clinically proven at autopsy ^[4]

Echocardiographic criteria for DCM: LV end-diastolic volume/diameter > 2SD from normal according to age and body-surface-area corrected nomograms; LVEF < 50% ^[4]

CK: released from damaged muscle membrane ^[2][3] CK 200–1,000 IU/L: most myopathies, SMA/MND, rigorous exercise, IM injection, after EMG/muscle biopsy, tonic-clonic seizures, statin/neuroleptic-induced ^[2][3] CK 1,000–10,000 IU/L: inflammatory myopathies, acute rhabdomyolysis, DMD/BMD ^[2][3]

Other muscle enzymes to check: ALT, AST, LDH — these are also released from damaged muscle. A common pitfall: elevated ALT/AST in a BMD patient is from muscle, NOT liver. Always check CK alongside "liver enzymes" in any patient with myopathy to avoid unnecessary hepatological workup.

This is the first-line and definitive diagnostic test for BMD ^[2][3][5].

Key investigations for muscular dystrophy: genetic testing (dystrophin – Xp21.2) ^[5]

Stepwise approach:

1. MLPA first — cheap, fast, detects the most common mutations (large deletions/duplications)
2. If MLPA negative → NGS / Sanger sequencing — detects point mutations
3. If both negative but clinical suspicion remains high → muscle biopsy (see below) and/or RNA studies

Interpreting the result — the reading-frame rule:

• In-frame mutation → dystrophin mRNA is translated into a shorter but partially functional protein → BMD
• Out-of-frame (frameshift) mutation → premature stop codon → truncated, non-functional protein rapidly degraded → DMD
• This rule holds in ~90% of cases. The ~10% exceptions include unusual splice effects, internal translation re-initiation, and exon-skipping events

Genetic studies are listed as a key investigation for lower limb weakness workup ^[6]

NCS: to rule out neuropathy (can also cause reduced motor response) ^[2][5] EMG: polyphasic, low-amplitude motor unit potential ^[5]

These are neurophysiological tests used to confirm the localisation is myopathic and exclude neuropathic mimics.

Neurophysiological tests: nerve conduction studies, electromyography — used to confirm lesion location and cause of presentation ^[6]

Muscle biopsy: at muscle that is most affected ^[2] Site: done on weak but not atrophied muscle, guided by P/E, EMG ± MRI ^[12]

Muscle biopsy is no longer the first-line diagnostic test for suspected dystrophinopathy (genetic testing has replaced it), but it remains critical when:

• Genetic testing is inconclusive (no mutation found on MLPA + NGS)
• Clinical phenotype is atypical and you need to differentiate from LGMD or inflammatory myopathy
• You need to quantify dystrophin for prognostication or trial eligibility

Biopsy site selection:

• Choose a muscle that is clinically weak but NOT severely atrophied — a completely wasted muscle will show only end-stage fibrosis and fat with no diagnostic information
• Common sites: vastus lateralis (quadriceps), biceps brachii, deltoid
• Avoid muscles recently tested with EMG needle (causes artefactual changes)

Cardiac assessment is mandatory in ALL BMD patients because cardiomyopathy is the leading cause of death and can be disproportionately severe relative to skeletal muscle involvement.

ECG / echo: detect cardiac muscle involvement ^[2][5] Key investigations for muscular dystrophy: ECG / echo: dilated cardiomyopathy ^[5]

Frequency of cardiac screening:

• At diagnosis, then annually (or more frequently if abnormalities detected)
• Echocardiography ± cardiac MRI from age 10 onwards (some guidelines recommend from diagnosis regardless of age)
• Earlier and more frequent if symptoms develop

In BMD, respiratory involvement is typically later and milder than in DMD, but should still be monitored from diagnosis onwards with annual PFTs.

Basic blood tests: CBC, inflammatory markers, basic biochemistry, other metabolic markers — vitamin B12, thyroid function tests, lipid profile, glucose etc., creatine kinase ^[6]

Further blood tests: autoimmune markers (ANA, anti-dsDNA, anti-ENA, anti-AChR Ab, anti-HMG-CoA reductase Ab…), genetic studies ^[6]

• Dystrophin isoforms (Dp71, Dp140) are expressed in the brain
• Mutations affecting distal exons/promoters may impair brain-specific isoforms → cognitive impairment
• ~10–20% of BMD patients have some degree of learning difficulty (milder than the ~1/3 rate in DMD)
• Formal neuropsychological testing should be offered, particularly in children, to guide educational support

For idiopathic DCM: genetic counselling → 3-generation family tree, genetic screening ^[4]

Respiratory failure develops later and more gradually in BMD than DMD, but still requires monitoring.

This is a life-saving management point that must be communicated to every BMD patient and documented prominently in their medical record:

These represent the future of BMD management and are increasingly examined:

In DMD, corticosteroids ↓risk of scoliosis ^[3] — partly by prolonging ambulation. This benefit is less well-studied in BMD.