Limb Girdle Muscular Dystrophy
Top Contributors - Shreya Pavaskar, Rucha Gadgil, Kim Jackson, Vidya Acharya, Kehinde Fatola, Lucinda hampton and Kirenga Bamurange Liliane
Introduction[edit | edit source]
Limb Girdle Muscular Dystrophy (LGMD) is not a single, but a rare group of inherited genetic disorders which are characterizes by progressive weakening of shoulder and hip muscles. LGMD is defined as a muscular dystrophy presenting with predominantly proximal weakness, sparing facial, extraocular, and distal extremity muscles (at least early in the course of the disease. LGMD has an autosomal pattern of inheritance which can be either dominant or recessive in nature. The classification is alphanumeric with assignation of number ‘1’ or ‘2’ depending on whether they are inherited dominantly or recessively. A letter is added in order of discovery. To date over 50 genetic loci have been identified. Dominantly inherited LGMD is less common and reported to be only 5–10% of all LGMD. Patterns of weakness can be variable - Scapuloperoneal or distal weakness or respiratory failure.
To summarize the common types,
- LGMD1A (myotilinopathy) - LGMD 1A is allelic with myotilin-associated myofibrillar myopathy. Symptoms start occuring usually in adult life with mildly elevated CPK protein. Features include respiratory failure, cardiomyopathy and dysarthric speech as well. Semimembranosus muscle is most severely affected among the hamstring group whereas semitendinosus muscle is often well preserved.
- LGMD1B (laminopathy) - Occurs between first to fourth decade of life. Along with weakness, severe cardiomyopathy and potentially life threatening cardiac arrhythmias tend to occur. The most affected muscles include the hip girdle muscle group.
- LGMD1C (caveolinopathy) - Symptoms start with first decade of life which include "rippling" of muscles (elicited with tendon hammer), proximal muscle weakness and myalgia.
- LGMD1E, 2R (The desminopathies) - Mutations in the DES gene (Desmin which is a structural protein) is closely associated with myofibrillar myopathy and cardiomyopathy (dominant gene) and cardiac arrhythmias (dominant and recessive gene). Patient typically presents in adult life.
- LGMD2A (calpainopathy) - This is the most common form of LGMD worldwide, typically presents from 2–40 years. Respiratory compromise is common at later stages, but less severe than in the LGMDs associated with the dystrophin-glycoprotein complex. Patients don’t show cardiac involvement and muscles of the shoulder girdle and of the posterior compartments of the legs are most severely affected, with relative sparing of the sartorius, gracilis and vastus medialis muscles.
- LGMD2B (dysferlinopathy) - It is also one of the common types. Age of onset is variable (typically second to third decade of life) and progression is often slow. Cardiac involvement is rare. Dysferlin-deficiency with more prominent involvement of the lower legs muscles is also known as Miyoshi myopathy. Hamstrings and triceps surae are commonly affected.
- LGMD2C, 2D, 2E, 2F, (The sarcoglycanopathies) - The four types (2C, 2D, 2E, 2F) relate to the specific sarcoglycan protein which is missing, γ, α, β, δ, respectively. It resembles dystrophinopathy, with severe, progressive proximal muscular weakness. Onset is highly variable ranging from 4 yr old to 7th decade. Respiratory failure and cardiomyopathy are common features.
- LGMD2G (telethoninopathy) - Rare and tends to occur in adolescence period. The diagnosis can be suggested by the lack of telethonin expression in biopsies, which typically show a dystrophic pattern.
- LGMD2I, 2K, 2M, 2N, 2O, 2P, 2T, 2U (The dystroglycanopathies) - Dystroglycanopathies are caused by defects in the dystroglycan complex, mainly through abnormalglycosylation of α-dystroglycan. Dystroglycan is present in many tissues throughout the body and is essential in function of myocytes and membrane stability. Onset is generally between 1-4th decade. Respiratory failure, cardiomyopathy, myoglobinuria and myalgia are commonly reported. Hamstrings and triceps surae are usually involved.
- LGMD2J (titinopathy) - Caused by the involvement of TTN gene. Serum CK can be highly raised. Patients with mutations in the TTN gene may also present with distal weakness, severe respiratory involvement and characteristic features of a myofibrillar myopathy. It is difficult to diagnose.
- LGMD2L - Symptoms occur from third decade of life and predominantly affects males. Cardiac involvement is rare and serum CPK is highly elevated.
- Other LGMD subtypes - LGMD1D, 1F, and 1G are all described in very small numbers, and sometimes within single families. The age of presentation is varied, but typically onset is with proximal muscle weakness in adulthood.LGMD2H, 2Q, 2S, 2V, 2W are very rare LGMD subtypes and have only been described in a few cases, although LGMD2H is frequently diagnosed in the Hutterites due to a common founder mutation
Clinically Relevant Anatomy[edit | edit source]
LGMD is caused by multiple genes encoding for proteins within the sarcolemma, cytosol or nucleus of the myocyte. The result of the defect is that the muscles cannot properly form certain proteins needed for normal muscle function. Several different proteins can be affected, and the specific protein that is absent or defective identifies the specific type of muscular dystrophy. Among the proteins affected in LGMD are α, β, γ and δ sarcoglycans. The sarcoglycans are a family of transmembrane proteins (α, β, γ, δ or ε) involved in the protein complex responsible for connecting the muscle fiber cytoskeleton to the extracellular matrix, preventing damage to the muscle fiber sarcolemma through shearing forces.
The dystrophin glycoprotein complex (DGC) is a membrane-spanning complex that links the interior cytoskeleton to the extracellular matrix in muscle. The sarcoglycan complex is a sub complex within the DGC and is composed of several muscle-specific, transmembrane proteins namely (α, β, γ, δ or ε). The sarcoglycans are asparagine-linked glycosylated proteins with single transmembrane domains.
Pathology[edit | edit source]
It is likely that the majority of the LGMD subtypes eventually develop membrane instability, similar to dystrophinopathies, which ultimately leads to muscle fibre degeneration. High levels of intracellular calcium have been implicated in myocytic damage although the exact mechanism unknown. Some theories suggest that the influx of calcium ions activates proteolysis, eventually leading to apoptosis/necrosis of the myocytes. Damage of muscle fibres leads to the release of inflammatory cytokines and consecutively neutrophils and macrophages are dispatched to degrade cellular debris. Muscle satellite cells (undifferentiated myocyte progenitor cells) replace the damaged or necrotic tissue. Eventually muscular repair mechanisms and satellite cell populations are overwhelmed and deposition of fibrotic (collagen) tissue and adipose tissue occurs
Clinical Presentation[edit | edit source]
The general features include weakness and atrophy of shoulder and hip girdle muscles. Onset of symptoms and precise etiology can vary according to different types.
- Muscle cramps and myalgia
- Most typical presentation is of symmetrical weakness due to scapular-humeral-pelvic weakness, which may be similar to the presentation of Facioscapulohumeral Dystrophy (FSHD), but without facial weakness.
- Muscle wasting
- Slow progression
- Intelligence and cognition is usually normal
- Waddling gait - weakness of hip musculature, gait dysfunction, foot drop
- Scapular Winging
- Joint stiffness
- Frequent falls
- Difficulty walking for longer distances
- Loss of ability to perform transfers
- Decreased endurance and tolerance to activity
- Difficulty climbing stairs and lifting objects
- Unable to do overhead activities with progressive difficulty for self-care and movements
- Scoliosis / Lordosis
- Dysphagia may occur
- Gower's sign may be present in hip muscle weakness
- Pseudohypertrophy of calf muscles
- Conduction abnormalities, arrhythmias
- Late stages may involve difficulty in breathing, respiratory insufficiency
Diagnostic Procedures[edit | edit source]
- History and examination is vital in the first line of investigating procedures which should be done thoroughly. It should include age of onset, presence of cardiomyopathy or arrhythmia, ‘rippling’ muscles, or symptoms of rigid spine.
- Serum CK level
- Genetic investigation - DNA testing is gold standard for LGMD
- Electrophysiology, muscle imaging and muscle biopsy analysis (immunohistochemical stains and Western blot analysis)
- MRI or CT for muscle and bone abnormality detection
- Echocardiography/Electrocardiography for cardiac arrhythmias
- NCV and NCS (Nerve Conduction Velocity and Nerve Conduction Study)
- Holter monitoring and event monitoring
- Pulmonary Function Tests
Outcome Measures[edit | edit source]
Outcome measures to quantify disease progression, including:
- 6‐minute walking test
- North Star ambulatory assessment scale,
- Time taken to climb four steps
- Time taken to rise from the floor
- Performance of upper limb.
- VAS (Visual Analog Scale)
- Manual Ability Measure
- Action Research Arm Test
- Functional Assessment Measure and Functional Independence Measure (FIM + FAM)
One of the limitations of these measures is the fact they target either ambulant or non‐ambulant patients
Management[edit | edit source]
Medical Management[edit | edit source]
There is no specific management protocol for LGMD syndromes and management is based on presentation of the case. An aggressive supportive care is essential.
Cardiac Involvement - Placement of a pacemaker can be a life-saving procedure. With known involvement, the case should be referred to cardiologist or surgeon. Other methods of treatment include anticoagulant drugs, implantable defibrillator, etc.
Respiratory Symptoms - Early intervention to treat respiratory insufficiency with non-invasive ventilation can help improve function and prolong the patient's life expectancy.
Dysphagia and nutrition - Nutritional supplementation or enteral feeding (gastrostomy tube).
Skeletal abnormalities - Abnormal posture due to weakness of muscles can lead to scoliosis/lordosis/kyphosis in later stages can be corrected via orthopedic procedures like spinal decompression, spinal fusion, spinal correction.
Pain and inflammation - Corticosteroids can be given to delay the progression of the disease.
Physiotherapy[edit | edit source]
- The goal of physiotherapy is to prevent contractures and maximize function for as long as possible.
- Low impact aerobic exercise with submaximal strength training is usually safe and beneficial to overall health.
- Gentle low impact aerobic exercise improves cardiac function and endurance (swimming and stationary cycle or treadmill)
- Exercise protocol can include simple exercises like sit to stand, side step, backward walk, marching in place, step-ups, step-taps, step-overs, soccer kicks
- Upper limb exercises - Straight sitting, scapular retraction, neck lateral flexion, neck retraction, shoulder rolls, shoulder resistive exercise, wrist movements, gentle gripping activities, range of motion exercises of upper limb, reaching different targets,
- Trunk exercises - Assistive crunches, trunk rotations, lateral bending of trunk, picking up objects from floor, log rolls
- Stretching exercises for quadriceps, hamstrings, piriformis, lateral trunk stretch, hip adductors and abductors, gastrocnemius, hip flexors, deltoids, Biceps Brachii , triceps brachii, hand stretches for fingers.
- Lower limb exercises - Abduction of legs, quadruped walking, walking, donkey kicks, straight leg raise, knee walking, quadruped superman, low intensity squats, side walks, toe taps on different points, crab walks, heel raises, toe raises
- Co-ordination activities - Shuffling cards, opposition of thumbs, performing crafts, picking beads, writing
- Warning signs - Excessive muscle soreness, prolonged shortness of breath, severe muscle cramping, heaviness in extremities and feeling weaker rather than stronger within 30 minutes of exercise.
Occupational Therapy[edit | edit source]
Occupational therapy helps in ergonomic evaluation and modification of self care activities
- Home evaluation
- Adaptive dressing eg. dressing stick, Sock aide
- Reaching activities modification - Things can be placed at lower height or use of a reacher device
- Strengthening of large group muscles
- Mobility exercises
- Energy conservation techniques
Orthosis (Assistive devices)[edit | edit source]
- Arm slings
- Lumbar corset
- Lumbosacral orthosis
- Hip knee ankle foot orthosis (HKAFO)
- Knee Ankle Foot Orthosis (KAFO)
- Spinal Brace
- Wheelchair - Non-powered or powered
Gene Therapy[edit | edit source]
Gene therapy and stem cell therapy can introduce genetic material in cells helping them to function in a normal manner. Stem cell therapy shows promising results and with exercises, a definite improvement can be seen
Differential Diagnosis[edit | edit source]
LGMD is a large heterogenous group of disorders. The differential diagnosis of these disorders include -
- Duchenne Muscular Dystrophy and Beckers Muscular Dystrophy - More common than LGMD
- Facioscapulohumeral Dystrophy - Pattern of muscle weakness is variable.
- Spinal muscular atrophy (SMA) types II and III - Genetic testing
- Emery Dreifuss muscular dystrophy (EDMD) - Genetic testing
- Pompe disease - Deficiency or reduction of glucosidase enzyme activity
- Bethlem myopathy - Skin changes and contractures due to collagen involvement
- Acquired muscle diseases (polymyositis, dermatomyositis and inclusion body myositis)
Resources[edit | edit source]
References[edit | edit source]
- Darras BT, Jones Jr HR, Ryan MM, Darryl C, editors. Neuromuscular disorders of infancy, childhood, and adolescence: a clinician's approach. Elsevier; 2014 Dec 3.
- Murphy AP, Straub V. The classification, natural history and treatment of the limb girdle muscular dystrophies. Journal of neuromuscular diseases. 2015 Jan 1;2(s2):S7-19.
- Chockalingam PS, Cholera R, Oak SA, Zheng Y, Jarrett HW, Thomason DB. Dystrophin-glycoprotein complex and Ras and Rho GTPase signaling are altered in muscle atrophy. American Journal of Physiology-Cell Physiology. 2002 Aug 1;283(2):C500-11.
- ASGCT. Limb-Girdle Muscular Dystrophy and Gene Therapy. Available from: http://www.youtube.com/watch?v=a1OitIarHYo [last accessed 29/3/2021]