AChR stands for acetylcholine receptor. Acetylcholine is a neurotransmitter that is important for muscle contraction and memory. AChRs are proteins on the surface of muscle cells and neurons that bind to acetylcholine. When acetylcholine binds to AChRs, it triggers a response in the cell such as muscle contraction or activation of neurons.
High AChR refers to having an abnormally high number or concentration of AChRs. There are several conditions that can cause high AChR levels including:
Myasthenia gravis
Myasthenia gravis is an autoimmune disease where the immune system mistakenly attacks the body’s own AChRs, especially those at the neuromuscular junction. This impairs the signaling between nerves and muscles leading to muscle weakness and fatigability.
In myasthenia gravis, the body produces antibodies against AChRs which leads to fewer AChRs available for acetylcholine binding. As a compensatory mechanism, the muscles increase AChR production. This results in a high concentration of AChRs overall, although the functioning is still impaired.
Congenital myasthenic syndromes
Congenital myasthenic syndromes are a group of inherited genetic disorders that affect the neuromuscular junction, leading to muscle weakness similar to myasthenia gravis.
In some types of congenital myasthenic syndrome, mutations in genes alter the structure or function of AChRs. This impairs signaling at the neuromuscular junction. As a compensatory response, the body increases AChR density, leading to a high concentration of AChRs.
Lambert-Eaton myasthenic syndrome
Lambert-Eaton myasthenic syndrome is caused by autoantibodies against presynaptic voltage-gated calcium channels at the neuromuscular junction. This reduces the release of acetylcholine.
As a compensatory mechanism, the postsynaptic muscle cell increases the number of AChRs. This leads to a high concentration of AChRs due to the upregulation.
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons. In some cases of ALS, the degenerating motor neurons release excessive glutamate which overstimulates muscle cells.
As a response, the muscle cells increase the number of AChRs. This leads to high levels of AChRs as a compensatory mechanism, although it does not prevent the progression of muscle weakness.
Botulism
Botulism is caused by botulinum toxin produced by Clostridium botulinum bacteria. The toxin blocks the release of acetylcholine from motor neurons.
This leads to a compensatory upregulation of AChRs in the muscle in an attempt to increase acetylcholine signaling. However, with the continued blockade of acetylcholine release, this does not resolve muscle weakness.
Normal Range
In a healthy individual, the concentration of AChRs at the neuromuscular junction is around 10,000-20,000 receptors per square micrometer. This number can vary slightly between different muscles.
On a blood test, the normal reference range for the number of AChR autoantibodies is:
| Age | Normal Range |
|---|---|
| 0-2 years | 0.00-0.02 nmol/L |
| 3-11 years | 0.00-0.03 nmol/L |
| >11 years | 0.00-0.05 nmol/L |
Higher levels outside of this reference range indicate an abnormal increase in circulating AChR autoantibodies.
Causes
Some key causes of increased AChR levels and AChR autoantibodies include:
Myasthenia gravis
Myasthenia gravis involves autoantibodies directed against the AChR receptors. This leads to both a lower number of functioning AChRs as well as an upregulation of AChR production as a compensatory response. 85% of myasthenia gravis patients test positive for anti-AChR antibodies.
Other autoimmune conditions
Other autoimmune conditions like lupus and rheumatoid arthritis are occasionally associated with increased AChR autoantibodies, even in the absence of overt symptoms of neuromuscular junction disorders. The reasons for this are not entirely clear.
Congenital myasthenic syndromes
As discussed previously, mutations in genes regulating AChRs can lead to abnormal increases in AChR density in an attempt to compensate for the defect. Various subtypes of congenital myasthenic syndrome stem from genetic defects impacting AChR subunits, receptors, or regulatory proteins.
Nerve agents
Exposure to nerve agents like sarin irreversibly binds and blocks AChRs. This initially leads to accumulation of acetylcholine in the synaptic cleft. Afterwards, the body tries to compensate by increasing AChR production and density.
Denervation
When a muscle loses its neural input, denervation atrophy occurs. This involves upregulating AChR production as an attempt to increase sensitivity to acetylcholine in the absence of innervation.
Excess acetylcholine
In some situations, increased acetylcholine release can prompt a compensatory increase in AChRs. This includes using drugs that prolong acetylcholine actions like an anticholinesterase.
Inflammation
Inflammation near the neuromuscular junction may stimulate upregulation of AChRs. Inflammatory cytokines may play a role in signaling this upregulation.
Symptoms
Symptoms of conditions causing high AChR depend on the underlying disease process. However, muscle weakness and fatigability are characteristic features.
Myasthenia gravis
In myasthenia gravis, weakness classically fluctuates during the day, becoming more profound with repeated use of muscles. Ocular weakness like ptosis and diplopia are common initial symptoms. Eventually this can progress to weakness in facial muscles, throat, and extremities in more advanced cases.
Congenital myasthenic syndromes
Congenital myasthenic syndromes present early in childhood with various patterns of muscle weakness including ocular, bulbar, proximal limb, and generalized weakness. Symptoms are often present at birth but may worsen over time.
Lambert-Eaton myasthenic syndrome
Lambert-Eaton typically involves proximal muscle weakness in the hips and shoulders first. Other symptoms may include dry mouth, erectile dysfunction in men, and changes in reflexes. Symptoms worsen with exertion but improve with rest.
Amyotrophic lateral sclerosis
In ALS, increasing muscle weakness and atrophy eventually leads to paralysis and death from respiratory failure, typically within 2-5 years from symptom onset. Upper and lower motor neurons are affected.
Botulism
Botulism causes descending, symmetric flaccid paralysis beginning with bulbar weakness like diplopia and dysarthria. This progresses to respiratory paralysis if untreated, requiring mechanical ventilation.
Diagnostic Testing
Several tests can help diagnose the cause of elevated AChRs:
Blood tests
Serum can be tested for autoantibodies directed against AChR. A positive result supports the diagnosis of myasthenia gravis. Quantitative measurements outside the reference range indicate abnormal levels.
Electrodiagnostic tests
– Repetitive nerve stimulation – This measures the size of muscle responses to a series of nerve stimuli. A decrementing response is seen in myasthenia gravis and LEMS.
– Single fiber EMG – This measures jitter in the muscle fiber action potentials, which may be increased with impaired neuromuscular transmission.
Edrophonium test
This test involves injecting edrophonium chloride, a short-acting cholinesterase inhibitor. Improvement in strength after injection helps confirm a diagnosis of myasthenia gravis. Worsening indicates cholinergic crisis.
Genetic testing
Genetic testing can detect mutations associated with congenital myasthenic syndromes and help guide treatment.
Muscle biopsy
A muscle biopsy may show increased AChR density on microscopic examination using fluorescent tagged bungarotoxin.
Treatment
Treatment focuses on the underlying cause:
Myasthenia gravis
– Cholinesterase inhibitors like pyridostigmine to prolong acetylcholine activity at the neuromuscular junction
– Immunosuppression with corticosteroids, cyclosporine, azathioprine, or thymectomy surgery
– Plasmapheresis or IVIG to remove antibodies
Congenital myasthenic syndromes
– Cholinesterase inhibitors
– 3,4-DAP to prolong acetylcholine actions
– Treatment tailored based on genetic mutation
Lambert-Eaton myasthenic syndrome
– 3,4-DAP to increase acetylcholine release
– Immunosuppression like myasthenia gravis
– Treat underlying cancer if applicable
Amyotrophic lateral sclerosis
– Riluzole to reduce glutamate levels
– Physical therapy and assistive devices
– Breathing support if needed
Botulism
– Antitoxin to neutralize unbound toxin
– Supportive care including mechanical ventilation
Prognosis
The prognosis depends on the specific etiology:
Myasthenia gravis
With treatment, most can achieve good control of symptoms and normal life expectancy. About 15% may have refractory weakness requiring long term immunosuppression.
Congenital myasthenic syndromes
This varies widely depending on the genetic mutation. Some forms may respond well to treatment while others progress to disability.
Lambert-Eaton myasthenic syndrome
If associated with underlying cancer, prognosis depends on successful tumor treatment. Most can achieve remission and good symptom control with appropriate therapy.
Amyotrophic lateral sclerosis
ALS progresses rapidly and leads to death within 2-5 years on average. Riluzole may modestly prolong survival. Supportive care aims to optimize quality of life.
Botulism
With prompt antitoxin, the prognosis for recovery is good but hospitalization is often prolonged due to slow nerve regeneration. Delayed treatment can lead to extended paralysis or death.
Conclusion
In summary, a high AChR level refers to an abnormally increased concentration or density of acetylcholine receptors. This occurs as a compensatory response in diseases that impair neuromuscular transmission like myasthenia gravis, congenital myasthenic syndrome, and LEMS. Testing blood AChR antibodies and electrodiagnostics aid diagnosis. Treatment focuses on the specific underlying etiology. Further research into these conditions may help develop novel therapies targeting the AChR abnormalities.
