GNE Myopathy is a rare, severe and progressive muscle disease that affects both the upper and lower limbs in adults. GNE Myopathy is caused due to a deficiency in enzyme (GNE/MNK) which hinders the biosynthesis of sialic acid, which is vital for the modification of muscle proteins and fats. When sialic acid levels are low, the muscles begin to weaken, resulting in loss of strength and muscle function.
GNE is an abbreviation for the mutated gene (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). The condition is described by several other names:
- Hereditary Inclusion Body Myopathy (HIBM) – for the characteristic features of inclusion bodies, in microscopic examination of muscle biopsy.
- Distal Myopathy with Rimmed Vacuoles (DMRV) – as the condition usually starts with weakness of distal muscles in the legs and rimmed vacuoles are typically seen in muscle.
- Quadriceps Sparing Myopathy (QSM) – as the large muscles on the top of the thigh remains strong while other leg muscles get weak.
- Nonaka Myopathy – as Dr Nonaka was the first clinician in Japan to recognize and describe the condition
GNE Myopathy is an autosomal recessive disease. Hence both parents (usually unaffected carriers) can pass on a defect copy of the GNE gene to their affected child. There is a 1 in 4 chance that an individual will develop GNE Myopathy if both parents are carriers.
The disease generally has an adult onset which usually starts around the age of 20-30 years, although onset of symptoms have been seen in individuals as young as 17 and as old as 52. It therefore affects the most productive time of a person’s life. Early symptoms typically include ‘foot drop’ (difficulty lifting the front part of the foot), which causes tripping and lack of balance. As the disease progresses, difficulties climbing stairs, getting up from a sitting position and weakness in hand and shoulder muscles is usually noticed. It can lead to severe disability within 10 – 15 years, confining many to a wheelchair. 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.
GNE myopathy is a disorder found worldwide, however, until recently it was mostly recognized in patients of Japanese and Persian Jewish ethnicity, where founder mutations are prevalent. The worldwide prevalence of GNE myopathy is estimated at 1/1,000,000 with higher prevalence seen in Middle Eastern Jews and Japanese population.
Owing to its ultra-rare status, diagnosis of GNE Myopathy is a challenge. It is often misdiagnosed for other conditions with similar symptoms, such as Limb-Girdle Muscular Dystrophy, Charcot-Marie-Tooth disease or Miyoshi myopathy. Diagnosis may require the efforts of a multidisciplinary team such as primary care physicians, neurologists, and neuromuscular specialists. a neurologist generally performs a detailed physical exam as well as tests to determine the cause of muscle weakness. If a myopathy is suspected, possible tests include:
- Blood test for a muscle enzyme called creatine kinase
- MRI and CT scan – reveal which specific muscles are being affected by GNE myopathy and which are being relatively spared (quadriceps).
- Electromyogram (EMG) to evaluate the electrical activity of the muscle
- Muscle biopsy – biopsy of an affected muscle can show the presence of small, encircled cavities in the muscle fibers called rimmed vacuoles, a signature feature of cells in people with GNE myopathy.
- Genetic testing.
Currently, there are no approved treatments for GNE Myopathy. It is managed by symptom treatment and evaluated and managed by a multidisciplinary team including neurologists, geneticists and physiatrists, as well as physical and occupational therapists.
Current treatment theories revolve around the following basic concepts:
- Substrate/Product based therapies: administration of small molecules that would increase intramuscular pools of Sialic Acid. It may involve administration of Sialic Acid rich compounds, Sialic Acid precursors, or other derivatives. Currently, this method is most likely to reach clinical trials in the shortest time.
- Gene therapy – delivery of a healthy GNE gene.
- Cell based therapies: These theories involve use of specialized stem cells capable of regenerating muscle and expressing the normal or hyperactive form of GNE/MNK.
- About GNE Myopathy. TREAT-NMD. Retrieved on 18-12-2016. www.treat-nmd.eu/gne/about/
- Ichizo Nishino et al 2015. GNE Myopathy: current update and future therapy. J Neurol Neurosurg Psychiatry. 2015 Apr; 86(4): 385–392.
- Erin K O’Ferrall, 2004 – Updated 2013. GNE-Related Myopathy. GeneReviews®
- GNE Myopathy. Orphanet. Retrieved on 18-12-2016. www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=602
- What is GNE myopathy? GNE Myopathy – In Focus. Retrieved on 18-12-2016. www.gnemyopathy.com/about-gne-myopathy-muscle-disease
- Marjan Huizing et al 2009. Hereditary Inclusion Body Myopathy: A decade of progress. Volume 1792, Issue 9, September 2009, Pages 881–887. Genetic Glycosylation Diseases
- Living with HIBM. ARM (Advancement of Research for Myopathies). Retrieved on 18-12-2016. www.hibm.org/arm/about_arm:about_arm
- About GNE Myopathy. GNE Myopathy International. Retrieved on 18-12-2016. www.gne-myopathy.org/about_gen_myopathy.html
- What Causes GNE Myopathy/HIBM? Neuromuscular Disease Foundation. Retrieved on 18-12-2016. www.curehibm.org/patients-scientists/for-patients/faqs.html
- Celeste FV et al. Mutation update for GNE gene variants associated with GNE myopathy. Hum Mutat. 2014;35(8):915-926.
- Broccolini A et al 2014. Hereditary inclusion-body myopathies. Biochim Biophys Acta. 2014:1-7.