Skip to content

Neuromuscular junction disorders: Pathology review




Musculoskeletal system

Pediatric musculoskeletal conditions
Musculoskeletal injuries and trauma
Bone disorders
Joint disorders
Muscular disorders
Neuromuscular junction disorders
Other autoimmune disorders
Musculoskeletal system pathology review

Neuromuscular junction disorders: Pathology review


1 / 7 complete

USMLE® Step 1 style questions USMLE

7 questions

A 65-year-old man comes to his outpatient provider because of a chronic cough for the past 3 months. It is occasionally accompanied by flecks of blood-tinged sputum. Review of systems is significant for weakness in the hips and thighs bilaterally and 15 lbs (6.8 kg) weight loss. Past medical history is notable for hypertension. He only takes hydrochlorothiazide. Social history is notable for a 50-pack-year smoking history. In the office, his temperature is 37.0°C (98.6°F), pulse is 76/min and blood pressure is 157/85 mmHg. Pulmonary examination reveals expiratory wheezing on the left side in 5th intercostal space. A chest radiograph is ordered and reveals the following:

Reproduced from:   

Laboratory testing reveals a creatinine kinase level of 75 U/L. Which of the following additional examination findings will most likely be present in this patient?  


Content Reviewers:

While doing your rounds, you see Kira, a 23-year-old female who presents with a series of recurrent symptoms that get worse as the day progresses. These include slurring of speech, difficulty swallowing, and double vision. She also mentions that her head feels heavy and is hard to hold up. She also complained that her arms are so weak she can’t even brush her hair. Additionally, she reports severe fatigue and shortness of breath. On examination, sensation and reflexes are normal. Next, you see a 62-year-old man named Jonathan, who presents with a history of leg muscle weakness that prevents him from doing simple things like climbing stairs or standing up, which gets better the more he uses his legs. He also reports shortness of breath, fatigue, dry mouth, impotence, and unintentional weight loss. Examination reveals a severely underweight man with dilated pupils. Reflexes are initially absent, although these are obtainable after a brief period of exercise. Blood tests were obtained, detecting anti-acetylcholine receptor antibodies in Kira and anti-voltage-gated calcium channels antibodies in Jonathan.

Now, both seem to have some type of neuromuscular junction disease. But first, a bit of physiology. In normal neuromuscular function, a nerve impulse is carried down the axon from the spinal cord, to the nerve endings, in the neuromuscular junction, where the impulse is transferred to the muscle cell. Here, the nerve impulse leads to the opening of voltage-gated calcium channels, causing an influx of calcium ions into the nerve terminal, which triggers synaptic vesicle fusion with plasma membrane. These synaptic vesicles contain a neurotransmitter called acetylcholine, which is released into the synaptic cleft. The neurotransmitter then binds to nicotinic acetylcholine receptors on muscle cell membranes and activates a chain reaction in the muscles that ultimately results in their contraction.

Ok, so there are two commonly tested diseases affecting the neuromuscular junction. First we have myasthenia gravis which is the most common. It’s an autoimmune disease that leads to varying degrees of skeletal muscle weakness, especially in women in their 20s and 30s and men in their 60s and 70s. The cause of this odd “bimodal” distribution of age-of-onset is unclear. What’s clear, though, is that the disease is marked by an antibody-mediated type II hypersensitivity. This begins when B cells get inappropriately activated, and they start making antibodies against the nicotinic acetylcholine receptors on the muscle cells. The antibodies bind to these receptors, and once they do that, the receptors are unable to bind acetylcholine. Without acetylcholine, muscles don’t contract as they should when they receive the “contract” signal from the central nervous system.

Anti-acetylcholine receptor antibodies can also activate the classical pathway of the complement. The complement system is a family of small proteins that work in an enzymatic cascade to fight off pathogens. The activation of complement causes inflammation and destruction of the muscle cells, reducing the number of acetylcholine receptors on the muscle cell surface, which impairs contraction even more. Now, a minority of people with myasthenia gravis produces another type of antibody called muscle-specific receptor tyrosine kinase antibody, which attacks proteins inside myocytes instead of nicotinic acetylcholine receptors, and this leads to muscle cells impairment as well.

The trigger for autoantibody production is unknown, but the disorder can be associated with other diseases. For example, myasthenia gravis can present as a paraneoplastic syndrome, which is a condition that arises as a result of cancer elsewhere in the body. The culprit is usually bronchogenic carcinoma or a thymic neoplasm, also called a thymoma, which generates an immune response that results in autoantibody production. Other conditions associated with the disease include hyperthyroidism, thymus hyperplasia, and autoimmune disorders like rheumatoid arthritis, systemic lupus erythematosus, and pernicious anemia.

Regarding symptoms, the high-yield hallmark of myasthenia gravis is muscle weakness that worsens after periods of activity and improves after rest. Manifestations also fluctuate in intensity over minutes, to hours, to days, and tend to get better in cold weather. Ok, so myasthenia can initially affect the muscles around the eyes, which might be the only signs of disease. When this occurs, the disease is called ocular myasthenia gravis, and it typically evolves into generalized myasthenia after a few years.

These muscles control movement of the eye as well as the eyelids, so because they can’t contract, individuals might develop diplopia or double vision, as well as ptosis, or drooping eyelids. Neck muscles can become weak too, and these individuals might feel their head is heavy and it’s hard to keep upright.

When arm and leg muscles are involved, people might experience difficulties in walking, climbing stairs, and performing simple tasks such as hair combing and brushing their teeth. In other cases, individuals might present with bulbar symptoms, which are caused by weakness in the muscles of the mouth and throat responsible for speech and swallowing. These symptoms can include a change in voice and slurred speech, nasal regurgitation, difficulties chewing, choking, and dysphagia, or difficulty swa