Last updated:
7/18/2025
Years published: 2020, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Carmen Bertoni, PhD, former Associate Professor, Department of Neurology, University of California Los Angeles; CEO NMD BioConsulting; Scientific Director, Neuromuscular Disease Foundation, for assistance in the preparation of this report.
Summary
GNE myopathy, also known as HIBM, Nonaka myopathy, IBM2 and distal myopathy with rimmed vacuoles, is a genetic disorder that primarily affects the skeletal muscles (muscles that the body uses to perform daily physical activity). The first signs of the disease appear between 20 and 40 years of age and affect males and females at the same rate. This condition is characterized by progressive muscle weakness which typically worsens over time, decreased grip strength and frequent loss of balance.1,2
GNE myopathy is caused by changes (variants) in the GNE gene which encodes for an enzyme known as glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase. The enzyme is responsible for the production of sialic acid (SA), a sugar required by all cells including muscle to produce energy. It is also an important part of cell membranes. The condition is inherited in an autosomal recessive manner.3
Currently, there is no cure for the disease and treatment is focused on managing the symptoms. However, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. In March 2024, Japan approved SA-ER (Acenobel) as the first drug for GNE myopathy but it has not yet been approved in the United States.4
Introduction
The term GNE myopathy refers to a group of diseases described worldwide over the last few decades. In 1984, Nonaka et al. were the first to describe a rare muscle disorder mainly affecting the muscles of the lower leg (anterior tibialis muscles) and characterized by increased creatine kinase in the blood (serum CK) and loss of muscle mass (atrophy). Under a microscope, muscle biopsies often showed characteristic histopathological changes including abnormal empty spaces inside muscle cells (rimmed vacuoles), lack of inflammation and no evidence of regeneration.5,6
Because of those findings, they initially called the disease distal myopathy with rimmed vacuoles (DMRV) to describe a familial myopathy with onset in early adulthood. Reports by Argov and Yarom described a similar pathology found in Iranian Jewish families and characterized by autosomal recessive inheritance. In addition to showing the typical presence of rimmed vacuoles in muscle biopsies, these studies also suggested that the disease did not impact the thigh muscles (quadriceps).3 This led the group to name the condition hereditary inclusion body myopathy (HIBM).7 Other historical names include Nonaka myopathy, inclusion body myopathy 2 (IBM2) and quadriceps sparing myopathy (QSM). In the early 2000’s, GNE gene variants were identified as the cause of these diseases. This led to the grouping of these disorders under the same name now known and commonly referred to as GNE myopathy.8-10
This condition is classified as a “congenital disorder of glycosylation (CDG)” because it disrupts the biosynthesis of sialic acid, a sugar crucial for protein glycosylation.4
The signs and symptoms of GNE myopathy start developing between the second and third decade of life and are characterized by progressive muscle wasting often accompanied by severe disability affecting walking within 10 to 20 years after onset.
Even at early stages of the disease, people with GNE myopathy have a characteristic foot drop in both feet which is caused by weakness of the tibialis anterior muscle (muscle that is connected to the knee and the foot). Early-stage muscle weakness in people with GNE myopathy can include not being able to walk typically (disturbed gait) and decreased stability, frequent falls, difficulty climbing stairs, running, and getting up from a seated position. Most people end up wheelchair-bound within 10-20 years of disease onset. Lower limb muscles are affected first. Quadriceps muscles are typically not affected until later stages, which is a diagnostic hallmark of this disease.11
As the disease progresses, 5 to 10 years after the onset of symptoms, most people experience progressive weakness and loss of the upper limb muscles. In advanced stages of the disease, neck muscles can also be affected.1,10,12 Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers.1,13,14
Non-muscular symptoms include:11
Importantly, cognitive function is not affected, which sets GNE myopathy apart from other congenital disorders of glycosylation (CDGs).
GNE myopathy is caused by changes (variants) in the GNE gene. This gene is responsible for the production of an enzyme needed to make sialic acid (SA). People with GNE myopathy consistently show lower levels of SA in their muscle biopsy analyses. It is believed that the loss of SA is one of the main contributors in the typical muscle wasting observed in patients, but further studies are needed to figure out the purpose of the GNE enzyme in muscle. Variants in GNE can occur anywhere along the sequence of the gene. Scientists have found over 200 variants in the GNE gene. Most of the reported variants are called missense variants. These are changes of the genetic code that only produce a small difference in the genetic sequence but affect the function of the GNE enzyme.
Some variants, called null variants, are so severe that they prevent development altogether. This shows that the GNE gene is essential for life.
There are also “founder variants” which are changes in the gene that are more common in certain populations. For example:11
Researchers have seen that certain variants can lead to different symptoms:
People in the same family who have the same gene variant can show different symptoms. This means that other things might be influencing how the condition appears. These could include small changes in nearby parts of the DNA (for example, Alu-mediated recombination, which is a natural way the DNA can rearrange itself). Other influences might be environmental factors (like diet, stress, or toxins) or epigenetic factors, which are changes in how genes work without changing the DNA sequence.
GNE myopathy is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene from each parent. If an individual receives one working gene and one disease-causing gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. If one parent is a carrier and the other parent has GNE myopathy, the risk of having an affected child is 50% with each pregnancy. The risk is the same for males and females.
GNE myopathy has been reported worldwide in approximately 4,000 patients. Prevalence estimates vary from 18-95 cases per million people. This suggests that there may be many people who remain undiagnosed.1
People with GNE myopathy have been identified in Asia, Europe, the Middle East, Australia and North America. Clusters of specific gene variants among different ethnicities are prevalent in Japanese and Persian Jewish descendants, suggesting an ancestral origin of these specific variants. The disease affects males and females equally.16,17
The diagnosis of GNE myopathy may be suspected in young adults who have foot drop, a condition where lifting the front part of the foot becomes difficult, leading to frequent tripping or difficulty walking. As the disease progresses, affected people may experience increasing weakness in the muscles of the arms and legs, particularly those farthest (distal) from the center of the body, such as the hands and feet. When these symptoms are present, a genetic test is usually requested.¹
Genetic testing is typically the first recommended step for assessing GNE myopathy. This testing can be done either with a blood or saliva sample and does not require any surgical or invasive procedures. Results are usually available within hours or days. However, it’s important to understand that identifying certain genetic changes, such as missense variants, which are single-letter changes in the DNA sequence, does not always mean the function of the enzyme produced by the gene is affected. Because of this, genetic testing alone cannot always confirm the diagnosis or rule out other muscle-related conditions.²
In these cases, to confirm GNE myopathy and to determine the severity and progression of the disease, additional evaluations are necessary.
Several tools are used to monitor how the disease progresses over time. These include:
Additionally, people with GNE myopathy can report their own experiences and how the disease affects their everyday life using standardized questionnaires such as the IBM functional rating scale (IBMFRS).⁶
Treatment
Currently, there is no cure for GNE myopathy and treatment is limited to managing the symptoms. In March 2024, Japan approved SA-ER (Acenobel) as the first drug for GNE myopathy. However, it is not currently approved in the United States by the FDA.
Early diagnosis ensures that patients receive the best optimal care which could ultimately play an important role in slowing down disease progression. Muscle overuse through strenuous activity or underuse due to prolonged inactivity could significantly accelerate the rate of progression. Patients should be followed by a neuromuscular specialist. Periodic physical therapy sessions along with balanced physical activity have shown to slow down progressive muscle wasting. Physical and occupational therapists as well as physiatrists, specialized doctors trained to treat patients with physical impairments or disabilities, are often helpful in addressing issues due to muscle weakness. Their involvement can have a significant impact on functional ability and quality of life of people affected by the disease. Annual follow up visits with the neuromuscular specialist are usually sufficient to evaluate disease progression and address muscle strength, mobility, function and activities of daily living.15,18
Genetic counseling and carrier testing are strongly encouraged for family members of affected individuals.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
View reportMedlinePlus has information about this condition that may include a description, frequency, causes, inheritance, and links to more information. The information is written for the public, including patients, caregivers and families. MedlinePlus is a service of the National Library of Medicine (NLM), which is part of the National Institutes of Health (NIH).
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