Limb Girdle Muscular Dystrophy

Introduction

Limb Girdle Muscular Dystrophy (LGMD) is not a single category but a group of inherited genetic diseases characterized by progressive weakness of the shoulder and hip muscles. LGMD is defined as a neurological manifestation of primarily proximal weakness without facial extraocular and distal extremity muscles (at least in the early stages of the disease[1]. LGMD has an autosomal pattern of inheritance that can be dominant or recessive in nature.The classification is alphanumeric with assignment of number ‘1’ or ‘2’ depending on whether they do primarily inherited or retrograde. A letter is included in order of discovery. To date, more than 50 genetic loci have been identified.Predominantly inherited LGMD is rare and is reported to account for only 5–10% of all LGMDs.[2] Examples of weakness may be variable – Scapuloperoneal or distal weakness or respiratory failure.

To summarize the common types[2],

• LGMD1A (myotilinopathy) – LGMD 1A is an allelic and myotilin variant associated with myofibrillar myopathy. Symptoms begin to occur more frequently in adult life with mildly elevated CPK protein. Features include respiratory failure cardiomyopathy as well as dysarthric speech. The semimembranosus muscle is strongest it is affected in the hamstring group while the semitendinosus muscle is usually well preserved.
• LGMD1B (laminopathy) – Occurs between the first to fourth decade of life. In addition to weakness, severe myocardial infarction and life-threatening heart failure are common. The most commonly affected muscles include the hip girdle muscle group.
• LGMD1C (caveolinopathy) – Symptoms begin in the first decade of life including rippling muscles (elicited with tendon hammer) proximal muscle weakness and myalgia.
• LGMD1E 2R (The desminopathies) – Mutations in the DES gene (Desmin a structural protein) are strongly associated with myofibrillar myopathy and cardiomyopathy (dominant gene) and cardiac arrhythmias (dominant and recessive gene). Patient usually presents in adulthood.
• LGMD2A (calpainopathy) – This is the most common form of LGMD worldwide with a typical age ranging from 2–40 years. Respiratory distress is common in late stages but not as severe as in LGMDs associated with the dystrophin-glycoprotein complex. Patients do not show cardiac involvement and the muscles of the shoulder girdle and the posterior aspects of the legs are most affected while the sartorius gracilis and vastus medialis muscles are slightly spared.
• LGMD2B (dysferlinopathy) – It is also one of the most common. The age of onset varies (usually the second to third decade of life) and progress is often slow. Cardiac involvement is rare. Dysferlin-deficiency with significantly greater involvement of the lower leg muscles is also known as Miyoshi mild myopathy. It commonly affects the hamstrings and triceps surae.
• LGMD2C 2D 2E 2F (The sarcoglycanopathies) – The four types (2C 2D 2E 2F) involve loss of the specific sarcoglycan protein γ α β δ. It resembles dystrophinopathy with progressive proximal muscular weakness. The baseline changes significantly from 4 yr old to the 7th decade. Respiratory failure and cardiomyopathy are common features.
• LGMD2G (telethoninopathy) – Rare and common in adolescence. The diagnosis can be confirmed by the expression of telethonin in biopsies that often show a dystrophic pattern.
• LGMD2I 2K 2M 2N 2O 2P 2T 2U (The dystroglycanopathies) – Dystroglycanopathies result from defects in the dystroglycan complex primarily through abnormal glycosylation of α-dystroglycan. Dystroglycan is found in many tissues throughout the body and is important in the function of myocytes and membrane stability. The onset is usually between the 1st-4th decade. Respiratory failure cardiomyopathy myoglobinuria and myalgia are frequently reported. The hamstrings and triceps surae are usually involved.
• LGMD2J (titinopathy) – Due to interference of the TTN gene. Serum CK may be significantly elevated. Patients with TTN gene mutations may also present with severe respiratory failure and distal manifestations of myofibrillar myopathy. The disease is difficult to diagnose.
• LGMD2L – Symptoms appear from the third decade and primarily affect males. Cardiac involvement is rare and serum CPK is significantly elevated.
• The other subtypes of LGMD – LGMD1D 1F and 1G are both very rarely described, sometimes in single families. The age of onset varies, but usually presents in adulthood with proximal muscle weakness. LGMD2H 2Q 2S 2V 2W is a very rare subtype of LGMD that occurs only in Although LGMD2H is frequently diagnosed in Hutterites due to a co-founder mutation, few cases

Clinically Relevant Anatomy

LGMD is caused by multiple genes that encode proteins in the cytoplasm or nucleus of muscle cells. The result of the deficiency is that the muscles cannot properly form certain proteins needed for normal muscle function. Several different proteins may be affected, specific proteins The absence or deficiency identifies a specific type of muscular dystrophy. Proteins affected in LGMD include alpha beta gamma and delta sarcoglycan. Sarcoglycans are a family of transmembrane proteins involved in proteins (α β γ δ or ε) Complex responsible for linking the muscle fiber cytoskeleton to the extracellular matrix, preventing damage to the muscle fiber sarcolemma by shear forces.

The dystrophin glycoprotein complex (DGC) is a transmembrane complex that connects the inner cytoskeleton to the extracellular matrix in muscle. The sarcoglycan complex is a subcomplex within the DGC consisting of several muscle-specific transmembrane proteins, namely (α β γ δ or ε). Sarcoglycan is an asparagine-linked glycosylated protein with a single transmembrane domain. [3]

Pathology

It is likely that most subtypes of LGMD will eventually develop membrane instability similar to muscular dystrophy, eventually leading to muscle fiber degeneration. High levels of intracellular calcium are associated with muscle cell damage, but the exact mechanism is unknown. Some Theory suggests that an influx of calcium ions activates proteolysis, ultimately leading to myocyte apoptosis/necrosis. Damage to muscle fibers leads to the release of inflammatory cytokines, and neutrophils and macrophages are dispatched in succession to degrade cellular debris. muscle Satellite cells (undifferentiated muscle cell progenitors) replace damaged or necrotic tissue. Eventually muscle repair mechanisms and satellite cell populations become overwhelmed, and fibrotic (collagen) tissue and adipose tissue are deposited [2]

Clinical Presentation

General features include weakness and atrophy of the shoulder and hip girdle muscles. The onset of symptoms and the exact cause can vary from type to type.

1. Muscle cramps and myalgia
2. The most typical presentation is symmetrical weakness due to scapula-humeral-pelvic weakness, which may resemble the presentation of FSHD but without the facial weakness.
3. Muscle wasting
4. Slow progression
5. Intelligence and cognition are usually normal
6. Staggering gait – hip muscle weakness Gait dysfunction Foot drop
7. Scapular Winging
8. Joint stiffness
9. Contractures
10. Frequent falls
11. Difficulty walking for longer distances
12. Loss of ability to perform transfers
13. Decreased stamina and tolerance for activities
14. Difficulty climbing stairs and lifting objects
15. They cannot perform superficial activities that are progressively more difficult in terms of self-care and movement
16. Scoliosis / Lordosis
17. Dysphagia may occur
18. Gower’s sign may be present in femoral hernias
19. Pseudohypertrophy of calf muscles
20. Cardiomyopathies
21. Conduction abnormalities, arrhythmias
22. The latter may cause difficulty breathing in respiratory failure

Diagnostic Procedures

• History and examination are important in the initial examination procedures that must be done thoroughly. It should include age of onset of myocardial infarction or symptoms of ‘rippling’ simple muscles or stiffness of the spine.
• Serum CK level
• Genetic testing – DNA testing is the gold standard for LGMD
• Electrophysiology nerve imaging and nerve biopsy analysis (immunohistochemical stains and Western blot analysis) .
• MRI or CT for musculoskeletal abnormalities
• Echocardiography/Electrocardiography for simple heart failure
• NCV and NCS (Neural Velocity and Conduction Studies) .
• Electromyography
• Holter monitoring and event monitoring
• Pulmonary Function Tests

Outcome Measures

Outcome measures used 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 Analysis Measurement and Functional Independence Measurement (FIM + FAM) .

One limitation of these interventions is the fact that they target interventional or non-ambulatory patients

(see Outcome Measures Database)

Management

Medical Management

There is no specific protocol for the management of LGMD syndromes and management depends on the presentation of the case. Strong supportive care is needed.

Heart involvement – Installation of a pacemaker can be a life-saving procedure. If it is known to contribute, the case should be referred to a cardiologist or surgeon. Other methods of treatment include anticoagulants, implantable defibrillators and so on.

Respiratory Symptoms – Early intervention to treat respiratory failure with noninvasive ventilation can help improve function and prolong patient survival.

Dysphagia and nutrition – Feeding or enteral feeding (gastrostomy tube).

Skeletal Abnormalities – Abnormal posture due to muscle weakness can lead to later scoliosis/lordosis/kyphosis deformities, which can be corrected with orthopedic procedures such as spinal decompression, spinal fusion, orthopedics.

Pain and inflammation – corticosteroids may be given to slow the progression of the disease.

Physiotherapy

• The goal of physical therapy is to prevent contractures and to function for as long as possible.
• Low-impact aerobic exercise with submaximal strength training is generally safe and beneficial to overall health.
• Gentle, low-impact aerobic exercise to improve heart function and endurance (swimming and stationary bike or treadmill)
• Exercise programs can include simple exercises such as sit to stand, side step, step back, walk, step in place, stride, stride, play football
• Upper limb exercises – sitting upright, scapula retraction, neck flexion, neck retraction, shoulder rolling, shoulder resistance exercise, wrist exercise, light grip, upper limb movement range, exercise to achieve different goals
• Trunk Exercises – Assisted Crunches Trunk Rotations Lateral Trunk Bends Picking Objects from Floor Log Rolls
• Quadriceps Hamstrings Piriformis Lateral Trunk Stretch Hip Adductors and Abductors Gastrocnemius Hip Flexors Deltoids Biceps Brachii Triceps Brachii Hand Stretch Fingers.
• Lower body exercises – abducted legs, quadruped walking, donkey kicking straight legs, raising knees, quadruped superman, low-intensity squats, sidewalking, toes different points, kicking crabs, walking, heel lifting, toe raising
• Coordination activity – shuffling cards thumbs opposing performance craft picking beads writing
• Warning Signs – Excessive muscle soreness, shortness of breath, severe muscle spasms in extremities, feeling weaker rather than stronger after 30 minutes of exercise.

Occupational Therapy

Occupational therapy helps with ergonomic assessment and modification of self-care activities

• Home evaluation
• Adaptive dressings, eg. Dressing Stick Sock Helper
• Reach activity modification – items can be placed at a lower height or use a reach device
• Strengthening of large group muscles
• Mobility exercises
• Energy conservation techniques

Orthosis (Assistive devices)

• 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

Gene therapy and stem cell therapy introduce genetic material into cells to help them function in the normal way. Stem Cell Therapy Shows Promising Results, and Visible Improvements Can Be Seen With Exercise

[4]

Differential Diagnosis

LGMD is a large and heterogeneous group of disorders. The differential diagnosis of these disorders includes –

• Duchenne muscular dystrophy and Beckers muscular dystrophy – more common than LGMD
• Facioscapulohumeral dystrophy – The 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 – lack or reduced glucosidase activity
• Bethlem myopathy – skin changes and contractures due to collagen involvement
• Acquired muscle disorders (polymyositis dermatomyositis and inclusion body myositis)