An Algorithm for Diagnosing GNE Myopathy
The diagnosis of GNE-related myopathy is based on clinical, histopathological and DNA sequence analysis. Muscle histopathology typically shows rimmed vacuoles and characteristic filamentous inclusions. For differential diagnosis nerve conduction is done and it is generally normal. Mutations in the GNE gene is done to confirm the diagnosis.
The algorithm for diagnosis of GNE myopathy is described below (taken from https://www.ncbi.nlm.nih.gov/books/NBK1262).
The following clinical diagnostic criteria for GNE-related myopathy have been proposed [Griggs et al 1995, Argov et al 2003]:
- A primary skeletal muscle disease, usually presenting with weakness in the legs
- Sustained quadriceps sparing despite marked weakness of all other proximal lower-extremity muscles
- Onset in late teenage years or early adulthood
- Modest elevation of serum creatine kinase activity, between two and four times the normal value
- Muscle biopsy
- On cryostat sections, the most prominent finding is the presence of rimmed vacuoles, lined by basophilic granular material on H&E staining and purple-red in color with the modified Gomoritrichrome stain. The vacuoles themselves do not stain with oil red orange or PAS stains, and lack acid phosphatase activity; however, with the latter, a few vacuoles show faint activity in the periphery. The vacuoles either appear empty or contain granular or amorphous basophilic inclusions or congophilic masses. Fiber size varies, with both atrophic and hypertrophic fibers observed. Endomysial fibrosis may be considerable. Many fibers contain internal myonuclei and fiber splitting occurs [Mizusawa et al 1987, Sadeh et al 1993].
Note: The origin of the rimmed vacuoles and their contents remains controversial. It has been suggested that they may be autophagic in nature, but the lack of acid phosphatase activity argues against this suggestion. Some authors have suggested that they arise from the membranous structures of the cell (SR, T-tubules, Golgi). Others have suggested that they arise when myonuclei burst and discharge their basophilic content into the cytoplasm [Griggs et al 1995].
- On ultrastructural analysis, the vacuoles do not appear as empty spaces but are filled with membranous whorls and cytoplasmic debris. Certain fibers harbor cytoplasmic or nuclear tubulo-filamentous inclusions with a diameter of 16-18 nm.
- In general, inflammation is not observed in an affected muscle. However, a modest inflammatory response has been noted in a few individuals [Argov et al 2003, Krause et al 2003, Yabe et al 2003] and inflammatory cell invasion of non-necrotic muscle fibers is rarely reported [Krause et al 2003].
- Early changes in certain muscle groups (before clinical weakness is detected) visualized by the following [Mizusawa et al 1987, Sadeh et al 1993]:
- Electromyogram showing myopathic motor unit potentials in association with spontaneous activity, similar to the pattern seen in inflammatory myopathies
- CT or MRI examination of muscle showing fatty replacement of muscle
- Normal nerve conduction velocity studies
There is no treatment available at present for GNE myopathy. Most of the treatment given are supportive for alleviating some of the symptoms. It is believed that proper exercise, intake of anti-oxidants and muscle stimulating co-factors may have beneficial effect, but nothing is available currently that helps to slow down the progression of the disease. There are two clinical trials going ongoing in the United States and a third will start very soon. One hopes for positive outcomes out of these trials, so that at least a therapy is available soon.