GNE Myopathy is a rare and debilitating genetic disorder that manifests itself as progressive muscle weakness in young adults; starting with foot drop and eventually, severely affecting the use of all muscles of the legs, neck, arms and hands.
The disease is a result of a number of different mutations in the GNE gene, which reduces the activity of the protein that is coded by this gene. The GNE protein (or enzyme) is needed for production of a small sugar called sialic acid, which is found in all cells and tissues of our body. Sialic acid is essential for the proper functioning of the body. Although we obtain small amounts of sialic acid from our food (milk, meat etc.), most of it is made by our cells with the help of the protein coded by the GNE gene. Therefore, mutations in this gene result in Sialic acid deficiency. The GNE gene mutations preferentially affect muscle cells leading to progressive loss of muscle function.
Mutations in this gene were first reported in Japanese and Persian Jewish populations. These mutations have now been reported worldwide and do not seem to be limited to any particular region or ethnicity. Patients with GNE Myopathy can be found in every corner of the world - Asian (Chinese, Indian, Korean, Japanese, and others), European, South American, African, and Middle Eastern (Muslim, Palestinian, Jewish, Iranian) origins. However, accurate diagnosis of the disease requires genetic testing that is inaccessible to most patients in the developing world, leading to misdiagnosis, under reporting and lack of disease awareness.
At present, a cure for the disease does not exist, although clinical trials are ongoing.
For more information on how GNE Myopathy is inherited, please refer to the Ultragenyx website:
A gene is a unit of inheritance. When we are born, we inherit from our parents their entire set of genes. These come in pairs and we get one set from the mother and one from the father. A gene is also a unit of information composed of a four-letter code (A, T, G, C). Each gene differs from the other in the number of ATGCs present in it (the number could vary from hundreds to thousands of letters), and their sequence, much like an entire dictionary of words, is made by just changing the sequence of a small number of alphabets. The sequence of letters in each gene conveys a unique meaning and this code is decoded in the form of a protein. Any errors in the code, for example, if a letter is missed or replaced by another, can profoundly change the meaning and give rise to a defective protein. A genetic defect or disorder arises due to such an error (called mutation) in the sequence of letters in a gene.
If you want to learn more about the chemical nature of genes and how proteins are made and consequences of genetic defect please refer to:
Generally, if only one member (called allele) of a gene pair carries a mutation and the other does not, the normal protein is made in sufficient amounts and the individual does not notice any effect. However, if both alleles have a mutation, the protein made is defective and disorder sets in. Thus, each healthy parent could be the carrier of a mutated allele.
Myopathy is a general term referring to any disease of muscles. Myopathies can be acquired or inherited, and can occur at birth or later in life. HIBM (Hereditary Inclusion Body Myopathies) are a group of rare/orphan genetic disorders, and GNE myopathy is one of these. Other names for GNE myopathy are ‘Distal Myopathy with Rimmed Vacuoles’ (DMRV), ‘Nonaka Myopathy’ or ‘Quadriceps Sparing Myopathy’ (QSM).
GNE myopathy causes progressive muscle weakness and wasting, which usually starts between the age of 20 and 30 years, although onset of symptoms have been seen in individuals as young as 17 and as old as 52. As such, it affects the most productive time of a person's life. It can lead to severe disability within 10-15 years, leading to many patients depending on the use of a wheelchair. The weakness and severity can vary from person-to-person. In some individuals, weakness in the legs is noticed first. In others, the hands are weakened more rapidly than the legs. Weakness is progressive, which means the muscles become weaker over time. It does not seem to affect the brain, internal organs or nerve sensation. The quadriceps are relatively spared, and remain strong until the late stages of disease.
Symptoms generally start with weakness of the distal muscles of hands and feet. Other typical symptoms include the following:
Initially, individuals may feel fatigued doing very light physical activity. Walking and climbing stairs may be difficult because of weakness in the pelvic and leg muscles that stabilize the torso/upper body. Patients often find it difficult to rise from a chair. As the myopathy progresses, there may be muscle wasting, loss of movement etc.
Foot drop is one of the most common early symptoms of GNE Myopathy - Please see a video below of a person with foot drop to understand how this symptom may be presented.
At present, there is no specific treatment or cure for a number of myopathies, particularly those that are hereditary or genetic. Scientists and clinicians are working on various approaches that include finding small molecules (or drugs) that can rectify the defect, replace the DNA or the defective gene with a good gene (gene therapy) and replace defective nerve or muscle cells with good healthy cells (stem cell therapy). All of these are currently in the development stage and no approved therapy is still available. However, one need not despair, as there are important developments that show promise for halting of the progress of disease ordevelopment of a cure.
In the absence of a definitive cure, a lot can still be done to help the patient. Careful management of the condition can have a beneficial effect on the long-term prognosis. Proper exercises with the guidance of a physiotherapist and a doctor can help to keep your good muscles active and not damage your bad musclesfurther. It is important to get proper guidance in doing exercises. Control of diet is important to keep your weight in check so that there is less pressure on the legsand to control other metabolic diseases, such as diabetes.
The prognosis for individuals with GNE Myopathy is highly variable and there is no scientific way yet to predict the long-term outcome for a patient. This is because a large number of factors may determine the progression of disease. These include the genetic background of the individual, environmental and nutritional factors, lifestyle, mental and emotional health, and societal factors. Some patients may lead almost a normal and reasonably active life whereas others with the same genetic defect may suffer from progressive and disabling disease. Given these caveats, it is considered that patients could become wheelchair users between ten and twenty years from onset of the disease.
Scientific progress in the area of regenerative medicine has been tremendous and we are all hoping that therapy for myopathies will be available within the next few years.
GNE Myopathy is caused due to deficiency of sialic acid. Therefore a possible cure could be achieved by increasing the levels of sialic acid in the body by supplementing it. Several research groups have tested this possibility in animal models in which the GNE mutation has been introduced. Based on encouraging results with these studies which showed that supplementation with ManNAc/sialic acid could improve and/or stop progression of the disease,two major clinical trials have been initiated to test the efficacy of these molecules for treatment of GNE Myopathy in patients.
Ultragenyx trial is in the phase three stage. The preliminary results suggest that it helps in the improvement of the muscles in the upper body and reduces progression in the lower limbs. For more : http://www.ultragenyx.com/pipeline/aceneuramic-acid/ ManNAc (DEXM74) supplementation by National Institutes of Health, USA NIH has completed their phase 1 study on the safety and efficacy of ManNAc supplementation. Phase II study is underway. For more and to know about enrolment for phase III: https://ncats.nih.gov/trnd/projects/active/dex-m74-gne-myopathy
This study is being conducted by National Human Genome Research Institute (NHGRI), National Institutes of Health, U.S.A. The purpose is to collect genetic and medical information from GNE Myopathy patients from all over the world. This will help for evaluation of therapies and to understand progression of disease. For more to know about participation in this study: http://hibmstudy.nhgri.nih.gov/
A promising future therapy is to correct the genetic defect by introducing a copy of the normal gene into the body. Safe methods for such gene therapy are being developed for a number of genetic disorders. Recently the Neuromuscular Disease Foundation (NDF) has taken an initiative to support gene therapy trial for GNE Myopathy.