GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

Abstract

GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic Brimmed^vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.

Genetic and phenotypic characterisation of inherited myopathies in a tertiary neuromuscular centre

“…The candidate gene approach failed to identify the diagnosis as muscle biopsy did not show rimmed vacuoles and consequently GNE specific testing was not requested. This is an increasingly recognized pitfall in GNE-related myopathy [19] and muscle MRI has been suggested as a useful diagnostic tool both for targeting the biopsy and for pattern analysis in distal myopathies [20]. Of note muscle MRI showed an involvement of proximal muscles in 24 of 27 (89%) cases with MRI available further highlighting the importance of including thigh muscles scanning in distal myopathies.…”

A Three-Gene Classifier Associated With MicroRNA-Mediated Regulation Predicts Prostate Cancer Recurrence After Radical Prostatectomy

“…Notably, FAM72 has been reported as a novel neural progenitor cell (NPC) self-renewal supporting protein expressed under physiological conditions at low levels in other tissues and accumulating data indicate the potential pivotal tumorigenic effects of FAM72 (Kutzner et al, 2015). GNE is well known for its role in GNE myopathy, which is a rare muscle disease characterized by slowly progressive weakness and atrophy of skeletal muscles (Carrillo et al, 2018). A recent study demonstrated that GNE contributed to a strategy to provide novel insights into breast cancer subtypes and provide a foundation for new methods of diagnosis of breast cancer (Saeui et al, 2018).…”

Generation and Characterization of Skeletal Muscle Cell based Model for GNE Myopathy: Implications in Actin Dynamics

“…More than 200 mutations have been identi ed to cause the disease with 20% phenotypic variability associated to genotype 3,4 . Both homozygous and compound heterozygous mutations have been reported in patients with predominantly M743T in Persian Jews, A207V in Japanese, I618T in Roma Gypsies and V727M in Indian subcontinent [1][2][3][4][5] . A patient with deletion in promoter region of one allele and single mutation in other allele has also been reported with GNE Myopathy 6 .…”

“…Though it is a slowly progressive disease, progressivity also depends on the nature of biallelic mutation 7 . There are limited therapeutic options, majorly depending on supplementation of sialic acid and its different derivatives-sialyllactose, aceneuramic acid, ManNAc 2,8,9 (NCT01634750). However, supplementation of sialic acid and administration of aceneuramic acid extended release (Ace-ER) to the patients did not show statistically signi cant results 10 .…”