Pain in Patients on Enzyme Replacement Therapy Unlikely Due to Nerve Damage

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

Share this article:

Share article via email
Enzyme Replacement Therapy | Pompe Disease News | illustration of joint pain

Pain is relevant but appears to be unrelated to damage to small nerve fibers in the skin of late-onset Pompe disease patients who are using enzyme replacement therapy, a study found.

The study, “Small fiber involvement is independent from clinical pain in late-onset Pompe disease,” was published in the Orphanet Journal of Rare Diseases by a team of researchers in Germany, Belgium, and Austria.

Pain is a common symptom of Pompe disease, and can frequently be severe in the shoulders, lower back, and in the legs.  It sometimes can be caused by damage to the small nerve fibers that detect pain, heat, and itching sensations in the skin.

To understand whether small nerve fibers play a role in the pain experienced by Pompe patients, the researchers investigated the link between pain and the amount of the skin’s small nerve fibers.

Recommended Reading
macroglossia | Pompe Disease News | illustration of woman with megaphone

Enlarged Tongue Leads to Severe Symptoms in Elderly LOPD Patients

Their study enrolled 35 people with late-onset Pompe disease (LOPD), who first experienced symptoms at a mean age of 34.9. They were diagnosed at a mean age of 42.3, and started enzyme replacement therapy a mean of 1.5 years later. At the time of the study, all were on regular treatment with Myozyme (alglucosidase alfa), marketed as Lumizyme in the U.S.

Pompe is caused by mutations in GAA, a gene with instructions to make an enzyme, a type of protein, called alpha-glucosidase. Of these patients, 34 (97.1%) had a known disease-causing mutation in one copy of GAA; genetic data were missing for the remaining person.

No clinical signs of damage to the many nerve fibers running through most of the body (polyneuropathy) was evident in the group, even though eight (22.8%) had a coexisting condition that could be a low risk factor for damage.

However, 24 people (68.6%) reported pain within the last four weeks, most often in a joint or the trunk. One patient reported pain in the lower legs. Fourteen patients (40.0%) experienced pain attacks, and 10 (28.6%) had persistent pain.

“Pain was a relevant symptom in over two-thirds of our patients,” the researchers wrote.

Patients rated their pain intensity on a scale from zero (no pain) to 10 (the worst possible pain) points. Mean pain intensity was 4.1 points, ranging from one to seven. Their current pain intensity was a mean of 2.8 points, and the maximum reported was a mean of 6.2 points.

To distinguish neuropathic pain, that arising from damaged or poorly working nerve fibers, from nociceptive pain — that caused in response to damage to tissues — the researchers used a questionnaire called painDETECT. This questionnaire also assigns points on a scale, and scores of 19 points or more are considered to indicate neuropathic pain. In general, the scores correlate positively with pain intensity, meaning that the higher the scores, the more intense the pain.

Questionnaire results showed neuropathic pain likely in one patient.

“The pain characteristics and distribution did not indicate of neuropathic pain … in our cohort of patients with LOPD,” the team wrote.

Researchers also looked at anxiety and depression, which can occur along with pain in people with Pompe disease. The Hospital Anxiety and Depression Scale used found eight patients (22.8%) with symptoms of anxiety and 11 (31.4%) with those of depression. These scores correlated positively with pain intensity.

They then counted the number of nerve fibers in small sections of skin taken in punch biopsies. As a control group for comparison, they used skin samples obtained from 20 healthy individuals. Late-onset Pompe patients had an average 3.98 fibers per millimeter of skin area, while control samples had an average 7.50 fibers per millimeter.

Nerve fiber density was also lower than normal in 57.1% of patients compared with reference data from a population of age- and sex-matched individuals. The scientists noted that the one likely neuropathic pain patient had reduced nerve fiber count in the lower leg.

In general, this reduction in nerve fibers was seen regardless of when patients started and how long they used enzyme replacement therapy.

“We found reduced small nerve fiber density in a large number of LOPD patients under ERT. Thus, our results indicate that the peripheral nervous system may represent another system affected in Pompe disease,” the researchers wrote. The peripheral nervous system is the system outside of the central nervous system, that of the brain and spinal cord.

Yet, they noted that there was no evidence of neuropathic pain arising from damaged nerve fibers.

“Future studies … may give further information both on the underlying mechanisms of small nerve fiber degeneration and pain generation,” they added.