Diagnosis And Differential Diagnosis Of GNE Myopathy

Objective: Mutations in the GNE gene(GNE) lead to GNE myopathy which is caused by the decrease of bifunctional enzyme uridine diphospho-N-acetylgucosamine(UDP-Glc NAc)2-epimerase/N-acetyl-mannosamine(Man NAc) kinase(GNE/MNK). It is a kind of autosomal recessive inherited neuromuscular disorders caused by the sialic acid reduction. Sialic acid plays a very important role in glycosylation of muscle fibers. Typical clinical manifestation of GNE myopathy: early adult-onset slowly progressive distal weakness and muscle atrophy, usually begin with anterior tibial muscle and with quadriceps spared at advanced stage. Typical muscle pathology includes rimmed vacuoles and filamentous inclusions but without infiltration of inflammatory cells. With the development of gene detection technique, more and more atypical GNE myopathy was found. Rimmed vacuoles are not specific to the diagnosis of GNE myopathy. RV myopathy was put forward to summary all kinds of skeletal muscle diseases which contain rimmed vacuoles in pathological section. Collect 14 patients’ whose pathological section showing rimmed vacuoles clinical data, skeletal muscle pathological results and gene detection results. 7 patients were diagnosed GNE myopathy though gene detection. By analysis these patients features, to discuss skeletal muscle MRI, RV, gene test’s meaning to GNE myopathy’s diagnosis and differential diagnosis.Methods:1 Collect the clinical information of these patients from the department of neuromuscular disease of the Third Hospital of Hebei Medical University. Following the diagnostic criteria : 1) containing rimmed vacuoles in pathological section.;2)slowly progressive weakness and atrophy of skeletal muscle; 3) creatine kinase mild or moderate increased in all patients; electromyogram(EMG) showed myogenic lesion with or without neurogenic lesion. 2 Gene test: GNE mutation was found in 7 patients. 3 Summarize and analyze the 7 patients’ clinical data, auxiliary examination, pathological data, which are including onset-ages, mode of onset, gender, family history, muscular strength, distribution of involved muscles, creatine kinase, electromyogram, double lower limbs skeletal muscle MRI and pathological features to make definite clarify to RV’s meaning to diagnosis and differential diagnosis of GNE myopathy.Result: 1 Summary and analysis of clinical characteristics of 7 GNE myopathy patients: 1.1 Clinical characteristicsIn the 7 GNE myopathy patients, 5 people are female, 2 people are male. The onset ages range from 24 years old to 39 years old. The average age of onset is 30.57. The course of disease ranges from 1to 20 years. Family survey shows that case 2 and case 3 are immediate sisters, besides case 6’s parents are proximity of blood. 2 patients’ first manifestation is hand weakness. The other 5 patients’ first manifestation is anterior tibial muscle weakness(one case begin to appear symptoms after postpartum, one case’s symptom increased after postpartum, and they are sisters). As advances, proximal muscles are involved. Case 1, case 2 and case 3 appear cervical muscles weakness. Distal muscles atrophy is prominent. All the 7 patients keep the ability to walk independently. 1.2 The analysis of auxiliary examination resultsThe creatine kinase level of 7 patients ranges from 163U/L to 1060U/L, higher than normal. It is mild or moderate increased. 7 patients’ EMG is myogenic lesion, 3 of which has neurogenic lesion at the same time. All patients got thought double skeletal muscle MRI examination. As a result, musculi biceps femoris, adductor muscles and tibialis anterior muscle are badly involved. 1.3 The analysis of muscular pathology results 1.3.1The histochemical stain pathological analysis of muscle biopsy under light microscopy:All 7 cases showed slightly muscle fiber degeneration, regeneration and necrosis on muscle pathology. Connective tissues are different degrees of hyperplasia. More or less rimmed vacuoles can be observed. In AMP stains, the edge of rimmed vacuoles was dark dyed. The activities of NADH dehydrogenase(NADH), succinate dehydrogenase(SDH) and cytochrome c oxidase(COX) are partly decreased in the part of rimmed vacuoles and show myofibrillar network disorder at the same time. The activity of acid phosphatase(ACID) was raised in degeneration, regeneration muscle fibers and the rimmed vacuoles. In adenosine triphosphatase(ATPase) stains,3 cases showed advantage of type Ⅰmuscle fibers, 2 cases showed advantage of type Ⅱ muscle fibers, the other 2 patients showed muscle fibers distribution like mosaic. 1.3.2 Monoclonal antibody immunohistochemistry stains pathological analysis of muscle biopsy under light microscopyIN monoclonal antibody immunohistochemistry stains, anti-dysferlin and anti-desmin are noemal in the 7 cases. 2 Summary and analysis of clinical characteristics of the other 7 patients:The onset symptom of 4 patients is the weakness and atrophy of proximal muscle, the other 3 patients is the weakness and atrophy of distal muscle. Among the 7 patients, 2 patients only have proximal weakness. 5 patients have the symptom of distal muscle weakness, and 3 patients the weakness of distal muscle is severer than the proximal muscle. The creatine kinase level is mild or moderate increased(149 U/L~947 U/L). 7 patients’ EMG is myogenic lesion accompany or un-accompany neurogenic lesion at the same time. 6 patients got thought double skeletal muscle MRI examination. As a result, 3 patients’ MRI like GNE myopathy patients’, the other 3 patients’ quadriceps femoris had different degrees fatty change. Skeletal muscle biopsy pathology, all cases show rimmed vacuoles like GNE myopathy patients.Conclusion:1 Typical clinical manifestation of GNE myopathy: early adult-onset, autosomal recessive inheritance. Preferential involve distal muscles of limbs, especially the anterior tibial muscles with sparing of the quadriceps muscle. The blood CK mildly to moderately increased. EMG is myogenic lesion accompany or un-accompany neurogenic lesion at the same time.2 Skeletal muscle MRI can directly display the extent and degree of involved muscles. This is useful to doctor to know the extent and degree of involved muscles. Combined clinical examination, doctors can judge the subtype of myopathy and decide which muscle to do biopsy. It is essential to raise the positive rate of diagnosis. Chose which muscle to do biopsy is important to find rimmed vacuoles in pathological analysis. Skeletal muscle is recommended to clinical application of the diagnosis of hereditary skeletal muscle disease.3 RV is still very important to GNE myopathy, but it can prompt other RV myopathy. According to the clinical manifestation, if the distal muscles were more seriously affected, Desminopathy, Laing distal myopathy, distal titin myopathy, should be considered. If the proximal muscles were more seriously affected, Filaminopathy, DNAIB6 myopathy should be considered.4 In the past, GNE myopathy was diagnosed by direct nucleotide sequencing. With the future understanding of RV myopathy, only doing direct nucleotide sequencing to diagnose RV myopathy cannot meet the requirement of diagnosis. Gene enrichment(exon trapping) and next generation sequencing technology apply to clinic that will simplify molecular biology diagnosis procedures of RV myopathy. That is worth study and clinical application.