Recent advances in establishing a cure for GNE myopathy

Yoshioka, Wakako; Nishino, Ichizo; Noguchi, S.

doi:10.1097/wco.0000000000001090

Cited by 8 publications

(4 citation statements)

References 46 publications

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“…Although there are no significant therapeutic drugs approved for Nonaka myopathy, trials for several potential therapeutic tools, including sialic acid supplementation and gene therapy, are currently in progress [6,50]. Long-term safety was assessed for ManNAc, which may provide preliminary evidence for clinical efficacy [51].…”

Section: Discussionmentioning

confidence: 99%

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

Tamanna,

Pi,

Lee

et al. 2024

Genes

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Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of sialic acid biosynthesis (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This study was performed to find GNE mutations in six independent distal myopathy patients with or without peripheral neuropathy using whole-exome sequencing (WES). In silico pathogenic prediction and simulation of 3D structural changes were performed for the mutant GNE proteins. As a result, we identified five pathogenic or likely pathogenic missense variants: c.86T>C (p.Met29Thr), c.527A>T (p.Asp176Val), c.782T>C (p.Met261Thr), c.1714G>C (p.Val572Leu), and c.1771G>A (p.Ala591Thr). Five affected individuals showed compound heterozygous mutations, while only one patient revealed a homozygous mutation. Two patients revealed unreported combinations of combined heterozygous mutations. We observed some specific clinical features, such as complex phenotypes of distal myopathy with distal hereditary peripheral neuropathy, an earlier onset of weakness in legs than that of hands, and clinical heterogeneity between two patients with the same set of compound heterozygous mutations. Our findings on these genetic causes expand the clinical spectrum associated with the GNE mutations and can help prepare therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

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

Tamanna,

Pi,

Lee

et al. 2024

Genes

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“…Moreover, Neu5Ac extended-release formulation therapies helped GNE myopathy patients ameliorate the decline in upper extremity muscle strength [ 65 ]. GNE myopathy, arising from variants in gene GNE , is a kind of neuromuscular disease.…”

Section: Applications Of Neu5acmentioning

confidence: 99%

Recent advances on N-acetylneuraminic acid: Physiological roles, applications, and biosynthesis

Zhao

Zhu

Wang³

et al. 2023

Synthetic and Systems Biotechnology

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“…2017 ). A current review of clinical trials to treat GNEM patients can be found here ( Yoshioka et al. 2022 ).…”

Section: Introductionmentioning

confidence: 99%

GNE deficiency impairs Myogenesis in C2C12 cells and cannot be rescued by ManNAc supplementation

Neu,

Weilepp,

Bork

et al. 2024

Glycobiology

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GNE myopathy (GNEM) is a late-onset muscle atrophy, caused by mutations in the gene for the key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). With an incidence of one to nine cases per million it is an ultra-rare, so far untreatable, autosomal recessive disease. Several attempts have been made to treat GNEM patients by oral supplementation with sialic acid precursors (e.g. N-acetylmannosamine, ManNAc) to restore sarcolemmal sialylation and muscle strength. In most studies, however, no significant improvement was observed. The lack of a suitable mouse model makes it difficult to understand the exact pathomechanism of GNEM and many years of research have failed to identify the role of GNE in skeletal muscle due to the lack of appropriate tools. We established a CRISPR/Cas9-mediated Gne-knockout cell line using murine C2C12 cells to gain insight into the actual role of the GNE enzyme and sialylation in a muscular context. The main aspect of this study was to evaluate the therapeutic potential of ManNAc and N-acetylneuraminic acid (Neu5Ac). Treatment of Gne-deficient C2C12 cells with Neu5Ac, but not with ManNAc, showed a restoration of the sialylation level back to wild type levels–albeit only with long-term treatment, which could explain the rather low therapeutic potential. We furthermore highlight the importance of sialic acids on myogenesis, for C2C12 Gne-knockout myoblasts lack the ability to differentiate into mature myotubes.

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Recent advances in establishing a cure for GNE myopathy

Cited by 8 publications

References 46 publications

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

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

Recent advances on N-acetylneuraminic acid: Physiological roles, applications, and biosynthesis

GNE deficiency impairs Myogenesis in C2C12 cells and cannot be rescued by ManNAc supplementation

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