Innovations in GNE Myopathy Research

GNE myopathy is an inherited neuromuscular disease with an estimated prevalence of 1 to 9 in 1 million. It usually starts between the ages of 20 and 40. The first sign is often trouble lifting the front part of the foot (foot drop) because of weakness in the lower leg muscles. Over time, the weakness spreads to other muscles in the legs and then the upper body.

In 2001, the GNE gene was discovered to cause GNE myopathy, also called hereditary inclusion body myopathy, distal myopathy with rimmed vacuoles, or Nonaka myopathy. Since then, researchers have learned more about the mechanisms of the disease and are exploring different pathways for potential therapies.

To learn more, we spoke with three researchers at the National Human Genome Research Institute (NHGRI) who are involved in GNE myopathy research: Marjan Huizing, PhD; May Malicdan, MD, PhD; and Francis Rossignol, MD.

What do we know about the cause of GNE myopathy?

Marjan Huizing, PhD

Dr. Huizing: We know that it’s autosomal recessive. This means a person gets the disease if they inherit two mutated copies of the GNE gene, one from each parent. We also know that the GNE gene codes for an enzyme that helps produce sialic acid, a substance found on the surface of cells and proteins. We found evidence that the amount of sialic acid on proteins in muscle membranes is lower than normal in people with two GNE gene mutations. We have also seen in mouse models of GNE myopathy that if we give them sialic acid or N-acetylmannosamine (ManNAc), a sugar molecule that is converted by cells into sialic acid, the sialic acid on muscle proteins and muscle symptoms seemed to improve in the mice. This suggests that sialic acid is an important part of the disease mechanism. However, there might be other factors involved, like problems with how the GNE protein interacts with other proteins or pathways that we don’t fully understand yet.

How does the disease typically progress?

Dr. Rossignol: There’s a wide variability in GNE myopathy — even members of a single family may experience the disease differently. Typically, symptoms start with foot drop, which causes problems with walking. Then there’s progression from the lower to upper legs. We may see weakness in the muscles that help bend the knee or the muscles that move the leg from the hip, but the quadriceps (front thigh muscles) are usually less affected.

About five to 10 years after the leg weakness starts, people may notice upper extremity involvement, which does not follow a clear distal to proximal pattern as in the legs. Weakness may start with the shoulders rather than the hands.

About 10 to 20 years after disease onset, we may see loss of ambulation (ability to walk) and less ability to do activities of daily living. Breathing can be involved as the disease progresses. However, GNE myopathy typically does not affect facial muscles, swallowing, or the heart.

How is GNE myopathy diagnosed?

Dr. Rossignol: Many people go through several diagnoses before finding out they have GNE myopathy. At first, it can seem more like a nerve problem than a muscle problem. Because of the non-specific first symptoms and the rarity of GNE myopathy, some people are misdiagnosed with other conditions first, such as the nerve-related condition Charcot-Marie-Tooth disease (CMT).

Francis Rossignol, MD

Doctors familiar with GNE myopathy may recognize it by noticing the typical symptoms, like foot drop, and the fact that the quadriceps are not affected as much as other leg muscles.

Some doctors suspect the diagnosis when a muscle MRI shows most of the lower limb muscles are affected except for the quadriceps. Doctors who suspect a myopathy may do a muscle biopsy. If the biopsy shows rimmed vacuoles (small holes in the muscle tissue), it’s a strong clue for GNE myopathy.

Currently, most people are diagnosed through genetic testing. This might happen after tests for neuropathies don’t provide answers, leading to broader tests like exome or genome sequencing.

Dr. Huizing: More patients are getting a diagnosis in the last five years, but we think the disease is still underdiagnosed. If we look at mutations that occur in patients and the general exome databases we have access to, we can do a calculation for autosomal recessive disease with the mutations that are occurring in the general population. The prevalence of GNE myopathy should be much higher than the number of patients diagnosed so far.

How are researchers looking for GNE myopathy therapies?

Dr. Huizing: Therapies being tested in clinical trials for GNE myopathy are based on increasing the amount of sialic acid in muscle cells. There have been clinical trials for treatment with the sialic acid molecule in the US and worldwide. In 2024, slow-release sialic acid was approved as a GNE myopathy therapy in Japan. Also, sialyllactose,
a highly sialylated protein therapy, was used in a clinical trial in Korea, and the analysis of the results is still ongoing.

Our group at NHGRI is studying ManNAc therapy to enable the body to produce sialic acid. We’ve gone through phase 1 and 2 clinical trials to test ManNAc’s safety and efficacy, and a pivotal multicenter study is ongoing.

May Malicdan, MD, PhD

Dr. Malicdan: Gene therapy efforts are also underway in different stages of preclinical development, but it will still require some time before these therapies can be tested in humans. One big challenge is that there are few patients with GNE myopathy and a small number of doctors involved in GNE myopathy research. Because of this, much of the focus has been on the sialic acid-increasing therapies that show promise.

However, researchers are also considering other forms of therapy. Current studies include looking at how the GNE protein interacts with other proteins and creating simpler animal models or new cell models based on induced pluripotent stem cells (iPSCs) to help test new treatments. These efforts are helping to find more options for future therapies.

What is promising in the GNE myopathy field right now?

Dr. Huizing: The field has evolved into collaborations and sharing resources. You see this happening in many rare disease fields: Different research groups interested in the disease start out competitive. Then, a patient advocacy group brings different stakeholders together and encourages collaborations, sometimes by offering research grants, resulting in interactions and collaborations. That very much happened in the GNE myopathy field, where advocacy groups continue to play a large role in bringing international research groups together.

Amy Bernstein is a writer for Quest Media.