Limb-girdle muscular dystrophies

Overview

LGMDs are a genetically diverse group of inherited muscle disorders with progressive proximal (shoulder and pelvic girdle) weakness. Autosomal recessive forms (LGMD-R) are more common; calpainopathy (LGMD-R1) is the most prevalent subtype worldwide.

Pathophysiology

All subtypes share a common mechanism: membrane instability → fibre necrosis → attempted regeneration → progressive fibrosis and fatty replacement. Key proteins involved:

•Calpain-3 (LGMD-R1) - muscle protease; loss impairs sarcomere remodelling

•Dysferlin (LGMD-R2) - membrane repair protein; absence prevents patching of contraction-induced micro-tears

•Sarcoglycans (LGMD-R3 to R6) - loss destabilises the dystrophin-associated protein complex (DAPC); mimics Duchenne MD clinically but dystrophin staining on biopsy is normal

•FKRP (LGMD-R9) - defective glycosylation of alpha-dystroglycan reduces laminin-binding; wide clinical spectrum including severe cardiomyopathy

Presentation

•Pelvic girdle weakness - difficulty rising from chair, climbing stairs, Gowers' sign; typically earliest symptom

•Shoulder girdle weakness - difficulty lifting arms above head, scapular winging

•Waddling (Trendelenburg) gait - weak hip abductors

•Calf pseudohypertrophy - particularly in sarcoglycanopathies

•Muscle cramps and myalgia - especially in dysferlinopathy, often preceding weakness

•Facial muscles spared - key differentiator from facioscapulohumeral MD (FSHD)

•Cardiac involvement - cardiomyopathy and arrhythmias most prominent in LGMD-D2 (laminopathy) and LGMD-R9

•Early joint contractures (elbows, ankles, spine) - particularly LGMD-D2 (laminopathy)

•Dyspnoea/orthopnoea - respiratory muscle involvement, especially LGMD-R9 and sarcoglycanopathies

🎯

Facial sparing distinguishes LGMD from FSHD. Absence of early cardiac conduction disease distinguishes most LGMDs from Emery-Dreifuss MD - but LGMD-D2 (laminopathy) is a notable exception.

Investigations

🥇 First-line

•serum CK - markedly elevated (10-50x ULN) in most subtypes; near-normal CK should prompt reconsideration

•EMG - myopathic pattern (short-duration, low-amplitude, polyphasic MUPs); excludes neurogenic causes

•ECG and echocardiogram - baseline cardiac assessment (essential given cardiac risk in LGMD-D2 and LGMD-R9)

•spirometry (FVC) - baseline respiratory assessment; identifies restrictive pattern

•muscle MRI - characteristic pattern of muscle group involvement; guides biopsy site

🏆 Gold standard

•muscle biopsy with immunohistochemistry and western blot - confirms dystrophic change and identifies absent/reduced protein

•next-generation sequencing (NGS) neuromuscular gene panel / whole exome sequencing - confirms causative variant; enables genetic counselling

Differential diagnosis

Key differentials for proximal muscle weakness

Condition	Distinguishing feature
Becker MD	X-linked; males; dystrophin reduced (not absent) on biopsy
FSHD	Facial weakness present - absent in LGMD
Emery-Dreifuss MD	Early contractures + cardiac conduction disease + humeroperoneal distribution
Polymyositis	Raised inflammatory markers; irritative EMG; inflammatory infiltrate on biopsy; responds to immunosuppression
SMA	Neurogenic EMG; SMN1 deletion on genetic testing
Pompe / McArdle disease	Episodic exercise intolerance and cramps rather than progressive weakness; specific enzyme assays

Management

No disease-modifying therapy is approved for LGMD in routine UK practice. Management is multidisciplinary and supportive within a specialist neuromuscular centre.

🥇 First-line

•physiotherapy and low-impact exercise - maintains function, prevents contractures; avoid excessive high-intensity exercise

•orthotic devices (AFOs for foot drop) and mobility aids as weakness progresses

•annual ECG and echocardiogram - more frequent in LGMD-D2 and LGMD-R9

•ramipril (ACE inhibitor) or bisoprolol (beta-blocker) - when dilated cardiomyopathy develops; start early in laminopathy given risk of sudden cardiac death

•annual spirometry (FVC); non-invasive ventilation (NIV) when FVC falls below 50% or symptomatic hypoventilation

🥈 Second-line

•ICD or CRT - for LGMD-D2 with significant arrhythmia or severe LV dysfunction

•spinal surgery for scoliosis - especially childhood-onset subtypes

🚨

In LGMD-D2 (laminopathy), sudden cardiac death from arrhythmia can precede severe skeletal muscle weakness - early cardiology review and ICD consideration are essential even in ambulatory patients.

Complications

•Dilated cardiomyopathy and heart failure - especially LGMD-D2 and LGMD-R9

•Sudden cardiac death from arrhythmia - most significant in laminopathy (LGMD-D2)

•Type 2 respiratory failure - nocturnal hypoventilation precedes daytime failure

•Progressive scoliosis - worsens respiratory compromise

•Loss of ambulation - sarcoglycanopathies may cause wheelchair dependence in second decade; dysferlinopathy often allows walking into mid-adulthood

Prognosis

•Sarcoglycanopathies (especially gamma/delta) - Duchenne-like course; loss of ambulation in adolescence, early death from cardiac/respiratory failure

•Calpainopathy and dysferlinopathy - more slowly progressive; many remain ambulatory into 4th-5th decade

•LGMD-R9 (FKRP) - wide spectrum; some mild, others develop severe cardiomyopathy requiring transplant

•LGMD-D2 (laminopathy) - significant risk of sudden cardiac death independent of skeletal muscle severity