Genetic and Clinical Spectrum of GNE Myopathy in Russia

Abstract

GNE myopathy (GNEM) is a rare hereditary disease, but at the same time, it is the most common distal myopathy in several countries due to a founder effect of some pathogenic variants in the GNE gene. We collected the largest cohort of patients with GNEM from Russia and analyzed their mutational spectrum and clinical data. In our cohort, 10 novel variants were found, including 2 frameshift variants and 2 large deletions. One novel missense variant c.169_170delGCinsTT (p.(Ala57Phe)) was detected in 4 families in a homozygous state and in 3 unrelated patients in a compound heterozygous state. It was the second most frequent variant in our cohort. All families with this novel frequent variant were non-consanguineous and originated from the 3 neighboring areas in the European part of Russia. The clinical picture of the patients carrying this novel variant was typical, but the severity of clinical manifestation differed significantly. In our study, we reported two atypical cases expanding the phenotypic spectrum of GNEM. One female patient had severe quadriceps atrophy, hand joint contractures, keloid scars, and non-classical pattern on leg muscle magnetic resonance imaging, which was more similar to atypical collagenopathy rather than GNEM. Another patient initially had been observed with spinal muscular atrophy due to asymmetric atrophy of hand muscles and results of electromyography. The peculiar pattern of muscle involvement on magnetic resonance imaging consisted of pronounced changes in the posterior thigh muscle group with relatively spared muscles of the lower legs, apart from the soleus muscles. Different variants in the GNE gene were found in both atypical cases. Thus, our data expand the mutational and clinical spectrum of GNEM.

Recessive GNE Mutations in Korean Nonaka Distal Myopathy Patients with or without Peripheral Neuropathy

“…The patients from the Myo-6 and Myo-8 families showed the same compound heterozygous mutations; thus, four different combinations of heterozygous mutations were observed in this study. Compared to some countries, this study showed that the frequency of patients with compound heterozygous mutations was relatively higher (83%) than that of patients with homozygous mutations [39,[41][42][43]. This result is consistent with the studies of other recessive genetic diseases in Koreans [44,45].…”

“…Although this difference in severity was thought to be partly due to the duration of the disease, it suggests the presence of modifying factors that can influence the clinical phenotypes. Phenotypic heterogeneity has frequently been reported in patients with Nonaka myopathy [25,40,43].…”

Novel GNE missense variants impair de novo sialylation and cause defective angiogenesis in the developing brain in mice

“…Since the first genomic mutation in GNE was discovered in a patient with sialuria in 1989, 13 several GNE variants have been reported to be relevant to sialuria and HIBM. 7 , 9 , 14 Sialuria is caused by GNE mutation–mediated impairment of the inhibitory feedback in the sialic acid production pathway and is inherited as an autosomal dominant trait, whereas loss-of-function GNE mutations cause HIBM as an autosomal recessive disease. Interestingly, several recent reports have shown that GNE pathogenic variants are associated with congenital macrothrombocytopenia and, in some cases, with concomitant myopathy.…”