Presence of Anti-LRP4 Antibodies in Blood May Be Common to Myasthenia Gravis and ALS, Case Study Suggests

Myasthenia gravis and amyotrophic lateral sclerosis (ALS) may share common underlying cellular mechanisms mediated by anti-LRP4 antibodies, a rare case report into both diseases being diagnosed in an elderly patient suggests.

The study, “Late-onset Myasthenia Gravis Accompanied by Amyotrophic Lateral Sclerosis with Antibodies against the Acetylcholine Receptor and Low-density Lipoprotein Receptor-related Protein 4,” was published at the journal Internal Medicine.

ALS, also known as Lou Gehrig’s disease, is a neurological disease characterized by the progressive damage to motor nerve cells. With time, due to the death of motor neurons, the brain loses the ability to control muscle movement, resulting in severe physical and functional disability.

Although ALS and myasthenia gravis are known to be caused by different biological processes, reports of these two diseases being found in a person on rare occasions do surface, indicating they might have a common background.

Japanese researchers detail the case of an 82-year-old women admitted to a hospital with unusual weakness in her neck and poor articulation.

An initial evaluation showed severe weakness in the neck muscles and moderate weakness in those that control the eyelids. Despite difficulties in articulating clearly when speaking, her speech was not slurred and tongue muscles were normal.

No alterations on other muscles or tendons were detected, and her sensorial nerves were found to respond normally.

Blood analysis showed that she was positive for anti-AChR antibodies, with levels about 67 times higher than usual — a hallmark of myasthenia gravis. To confirm a possible myasthenia gravis diagnosis, the team performed an edrophonium test, which — in a sign indicative of disease — temporarily strengthened her eyes and neck muscles.

“Based on these findings, she was diagnosed with seropositive late-onset generalized myasthenia gravis,” the scientists wrote.

The patient started treatment with plasmapheresis to lower blood levels of the anti-AChR antibodies. After eight treatment sessions she showed significant improvement, resulting in disease remission without any clinical manifestation. She started maintenance immunosuppressive therapy with prednisolone and tacrolimus  (brand names Prograf, and Protopic, among others).

One year later, while on maintenance therapy, she started to experience progressive muscle weakness  in her neck and limbs, and impaired speech.

A physical evaluation now found tongue muscle atrophy and spontaneous contraction. Her tendon reflexes were brisk, and she had nervous reflexes consistent with damage to motor neurons.

Further tests suggested severe loss of nerve cells that controlled limb and eye muscles, supporting a diagnosis of possible ALS.

New analysis of blood samples collected at the first and second hospital admission showed the woman positive for anti-LRP4 antibodies, and a drop to closer to normal range in anti-AChR antibody levels with treatment.

Recent studies suggest that anti-LRP4 antibodies may contribute to the development and progression of myasthenia gravis, and they are also linked to ALS. (LRP4 is a protein important for neuromuscular function.)

The woman was treated again with plasmapheresis and immunosuppressive therapy for myasthenia gravis, but her symptoms did not improved. Her condition worsened progressively, and she died of respiratory failure.

“The anti-LRP4 antibody seems to be associated with both ALS and myasthenia gravis, although the role and importance of the antibody in the [underlying mechanism] of these two diseases are different,” the researchers stated.

“The anti-LRP4 antibody may be important not only as an important diagnostic marker for myasthenia gravis but also as a marker of pathological changes in the neuromuscular junction in both ALS and myasthenia gravis,” they added.

Additional studies are warranted to better understand the role of anti-LRP4 antibody in these two diseases, and to clarify its potential utility as a diagnostic or prognostic biomarker.