NORD gratefully acknowledges 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.
GNE myopathy, also known as HIBM, Nonaka myopathy, IBM2 and distal myopathy with rimmed vacuoles, is a genetic disorder that affects primarily the skeletal muscles (muscles that the body uses to perform daily physical activity). 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 (mutations) 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 as well as an important component 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.
The term GNE myopathy refers to a group of diseases described worldwide by different investigators and physicians over the last few decades. In 1984, Nonaka et al. were the first to describe a rare muscle disorder predominantly affecting the anterior tibialis muscles and characterized by mild serum creatine kinase (CK) elevation and muscle atrophy. Under a microscope, muscle biopsies often showed characteristic histopathological changes including rimmed vacuoles, lack of inflammation, and no evidence of regeneration. 4,5 As such, they initially termed the disease distal myopathy with rimmed vacuoles (DMRV) to describe a familial myopathy with onset in early adulthood. Reports followed by from Argov and Yarom describing 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 spared the quadriceps.3 This led the group to name the condition hereditary inclusion body myopathy (HIBM).6 Other historical names include Nonaka myopathy, inclusion body myopathy 2 (IBM2) and quadriceps sparing myopathy (QSM). Finally, the identification in the early 2000’s of GNE gene mutations being responsible for these diseases has led to a grouping of the disorders under the same name now known and commonly referred to as GNE myopathy.7-9
GNE myopathy manifests between the second and third decade of life and is characterized by progressive muscle wasting often accompanied by severe incapacitation within 10 to 20 years after onset. Even at early stages of the disease, GNE myopathy patients exhibit a characteristic bilateral foot drop which is caused by weakness of the tibialis anterior muscle (one of the frontal muscles that is connected to the knee and the foot). Early stage muscle weakness in GNE myopathy patients can include disturbed gait and decreased stability, frequent falls, difficulty in climbing stairs, running and getting up from a seated position. Most patients end up wheelchair-bound within 10-20 years of disease onset. Lower limb muscles are affected first with the exception of the quadriceps which appears to be relatively spared. As the disease progresses, 5 to 10 years after the onset of symptoms, the majority of patients experience progressive weakness and loss of the upper limb muscles. In advanced stages of the disease, neck muscles can also be affected. 1, 10, 11 Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers 1, 12, 13
GNE myopathy is caused by mutations in the GNE gene. This gene is responsible for the production of an enzyme needed to make SA. Patients consistently express lower levels of SA as clearly demonstrated by analyses performed on muscle biopsies. It is believed that the loss of SA is one of the main contributors in the typical muscle wasting observed in patients, although further studies are required to determine the specific mechanisms of action of the GNE enzyme in muscle. Mutations in GNE can occur anywhere along the sequence of the gene. The majority of mutations reported are so-called missense mutations. These are alterations of the genetic code that only produce a small change in the genetic sequence but affect the function of the GNE enzyme.
GNE myopathy is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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 to have an affected child is 50% with each pregnancy. The risk is the same for males and females.
Mutations in the GNE gene have been reported worldwide in approximately 4,000 patients although the incidence of the disease has been estimated to be 1-9/100,000 individuals (Orphanet; http://www.orpha.net/). This suggests that the vast majority (approximately 40,000) of GNE myopathy patients still remain undiagnosed. 1
GNE myopathy patients have been identified worldwide including Asia, Europe, Middle East, Australia and North America. Clusters of specific mutations among different ethnicities are prevalent in Japanese and Persian Jewish descendants, suggesting an ancestral origin of these specific mutations. The incidence of the disease is similar in males and females. 14
Patients presenting with foot drop (young adults) and distal extremity muscle weakness (in individuals at more advance stages of the disease) are good candidates for GNE myopathy testing.
Genetic testing represents an ideal first option to assess GNE myopathy in patients. This involves the use of minimal or no invasive procedures, only requires a blood or a saliva sample and results can be obtained in a matter of hours or days. However, because missense mutations don’t necessarily imply defects in enzyme function, the genetic testing alone cannot be considered definitive to provide a diagnosis or to rule out other neuromuscular disorders. Additional testing is needed to confirm GNE myopathy, to rule out the presence of other pathologies as well as to determine the stage of the disease. Tests include a muscle biopsy, which necessitates taking a small sample of muscle using a needle. A magnetic resonance imaging (MRI) will help determine the extent of the damage to lower and upper limb muscles. Echocardiogram and pulmonary function tests are also recommended in non-ambulatory individuals.
Currently, there is no effective cure for GNE myopathy and treatment is limited to managing the symptoms. 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 a 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.14, 15
Genetic counseling and carrier testing are strongly encouraged for family members of affected individuals.
A number of clinical trials have been implemented to evaluate the safety and efficacy of enzyme replacement therapy for the treatment of GNE myopathy. Some of those trials have concluded while others are still ongoing (for detail information on recruitment and inclusion/exclusion criteria for participant enrollment refer to https://clinicaltrials.gov/). All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
Below is a summary and information on the major studies conducted worldwide in GNE myopathy patients.
1-Intravenous Immune Globulin (IVIG) to Treat hereditary inclusion body myopathy (ClinicalTrials.gov: NCT00195637) was conducted at the National Institutes of Health (NIH) to evaluate the effects of immune globulin (IG) treatment on muscle and muscle function. IG is a protein in the blood that carries a large amount of SA. IVIG was infused in four GNE myopathy patients over a period of 2 consecutive days and improvements on muscle strength and other functional parameters were detected in the quadriceps and in the shoulders suggesting that enzyme replacement therapy and SA supplementation in particular has detectable beneficial effects in patients.
2-A phase 1 clinical trial administering N-acetylneuraminic acid (NeuAc), a precursor of SA was conducted at Tohoku University in Japan in three patients in 2010-2011 (ClinicalTrials.gov: NCT01236898). The trial was only focused on evaluating the safety of 800 mg of NeuAc three times a day up to five consecutive days and was not intended to demonstrate therapeutic efficacy. Results showed no significant adverse effects in any of the patients tested throughout the duration of the study.
3-Phase 1/2 and phase 3 trials were conducted by the pharmaceutical company Ultragenix, to evaluate the safety and efficacy of an extended release formulation of SA (SA-ER). The phase 1/2 trial recruited 47 patients that received either a low dose (3gr) or a high dose (6gr) for up to 48 weeks (ClinicalTrials. gov: NCT01517880). Results showed modest although positive improvement in the upper limb muscle function compared to the placebo control group. No serious side effects and minimal adverse events were observed.
Similar results were obtained in the phase 2 extension studies in patients enrolled in the phase 1/2 trial. Studies were conducted to evaluate the additional long-term safety of SA-ER treatment of participants with GNE myopathy previously treated with SA-ER at dose of 6 grams/day as well as to evaluate the safety of a 12 grams/day SA over a 6-month treatment period (ClinicalTrials. gov: NCT01830972). In the first part of the extension study, all 46 patients from the 48-week phase 1/2 study crossed over to 6 grams/day for a variable period of time that was on average 24 weeks. In the second part of the extension study, all 46 patients and 13 treatment-naïve patients received 12 grams/day of SA-ER for 24 weeks. SA-ER appeared to be generally safe and well tolerated with no drug-related serious adverse events although few patients experienced mild to moderate gastrointestinal adverse events.
However, phase 3 study (ClinicalTrials. gov: NCT02377921) failed to meet its primary endpoint in demonstrating a statistically significant difference in the upper extremity muscle strength compared to placebo. The study also did not meet its key secondary endpoints. The disappointing result has led Ultragenyx to discontinue its plan for further clinical development of SA-ER.
4-Phase 1 and phase 2 clinical trial of ManNAc (N-acetyl-D-mannosamine monohydratehave also been conducted in GNE myopathy patients by the NIH. ManNAc is a precursor in the biosynthesis of Neu5Ac and a substrate of the GNE enzyme. In phase 1 studies (ClinicalTrials.gov NCT01634750), ManAc was administered orally as a liquid solution to 3 cohorts of 6 subjects (Cohorts A, B, C) at doses of 3 grams, 6 grams, and 10 grams ManNAc, respectively. The most common reported symptoms were gastrointestinal problems, such as abdominal cramps and diarrhea. A total of 22 participants were enrolled in the safety, pharmacokinetics and SA production after oral administration of ManNAc study in subjects with GNE myopathy.
The phase 2 studies were focused on determining the efficacy of ManAc in GNE myopathy patients (ClinicalTrials.gov NCT02346461A). A total of 12 patients were enrolled in the studies and were divided into two cohorts. Cohort A received oral ManNAc 3 grams twice daily (6 grams/day) for 7 days and, then the dose was escalated to 6 grams twice daily (12 grams/day) for the remainder of the study. Cohort B received oral ManNAc 6 grams twice daily (12 grams/day) for the duration of the study.
A multi-center study of ManNAc for GNE myopathy (MAGiNE) has also been planned (ClinicalTrials.gov NCT04231266). Details for these studies are expected to be released in the next few months.
5-Natural history and patient registry studies have been carried out independently by Ultragenyx in collaboration with TREAT-NMD (ClinicalTrials.gov: NCT04009226) and the NIH (ClinicalTrials.gov: NCT01417533). The scope of these studies is to assess and better understand the rate of progression of GNE myopathy, its clinical variability as well as identifying markers of progression that can be used to evaluate the efficacy of ongoing and future clinical trials. These studies have also the potential to identify new patients worldwide and to generate a patient registry. Information on trial status, enrollment, inclusions and exclusion criteria can be found at https://clinicaltrials.gov/
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:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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2. Huizing M, Malicdan MC, Krasnewich DM, Manoli I, Carrillo-Carrasco N. GNE Myopathy. In: Valle D, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, editors. OMMBID – The Online Metabolic and Molecular Bases of Inherited Diseases.New York: McGraw-Hill; 2014.
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8. Nishino I, Noguchi S, Murayama K et al. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 2002;59(11):1689-1693.
9. Huizing M, Carrillo-Carrasco N, Malicdan MC et al. GNE myopathy: new name and new mutation nomenclature. Neuromuscul Disord. 2014;24(5):387-389.
10. Pogoryelova O, Cammish P, Mansbach H et al. Phenotypic stratification and genotype-phenotype correlation in a heterogeneous, international cohort of GNE myopathy patients: First report from the GNE myopathy Disease Monitoring Program, registry portion. Neuromuscul Disord. 2018;28(2):158-168.
11. Mori-Yoshimura M, Oya Y, Yajima H et al. GNE myopathy: a prospective natural history study of disease progression. Neuromuscul Disord 2014;24(5):380-386.
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13. Cho A, Hayashi YK, Monma K et al. Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy). J Neurol Neurosurg Psychiatry 2014;85(8):914-917.
14. Nishino I, Carrillo-Carrasco N, Argov Z. GNE myopathy: current update and future therapy. J Neurol Neurosurg Psychiatry 2015;86(4):385-392.
15. Carrillo N, Malicdan MC, Huizing M. GNE Myopathy. 2004 Mar 26 [Updated 2020 Apr 9]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1262/ Accessed May 6, 2020.
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