GNE myopathy: current update and future therapy

Background GNE myopathy is a rare genetic disease characterized by progressive muscle atrophy and weakness. It is caused by biallelic mutations in the GNE gene that encodes for the bifunctional enzyme, uridine diphosphate (UDP)‐N‐acetylglucosamine (GlcNAc) 2‐epimerase/N‐acetylmannosamine (ManNAc) kinase. Typical characteristics of GNE myopathy include progressive myopathy, first involving anterior tibialis muscle and sparing the quadriceps, and rimmed vacuoles on muscle biopsy. Identifying biallelic mutations by sequencing of the GNE gene confirms the diagnosis of GNE myopathy. In a subset of patients, diagnostic confirmation is challenged by the identification of mutations in only one allele, suggesting mutations in deep intronic regions or regulatory regions.MethodsWe performed targeted sequencing and copy number variant (CNV) analysis of GNE in two siblings who clinically presented with GNE myopathy. Further molecular and biochemical studies were done to characterize the effect of a previously uncharacterized GNE mutation.ResultsWe report two siblings of Indian descent with characteristic features of GNE myopathy, including progressive skeletal muscle weakness initially involving the anterior tibialis, and rimmed vacuoles on muscle biopsy, in which a heterozygous mutation, p.Val727Met, was identified in both affected siblings, but no other deleterious variants in either coding region or exon–intron boundaries of the gene. Subsequent insertion/deletion analysis identified a novel 11.3‐kb deletion (Chr9 [GRCh37]: g.36257583_36268910del) encompassing the GNE promoter region, with breakpoints residing in Alu repeats. Gene expression analysis revealed reduced GNE mRNA and protein levels, confirming decreased expression of the deleted allele harboring the deletion.ConclusionsWe have identified GNE as one of the genes susceptible to Alu‐mediated recombination. Our findings suggest that the deletion may encompass the promoter or another region necessary for GNE expression. In patients with typical manifestations of GNE myopathy and a single GNE variant identified, copy number variant (CNV) analysis may be useful in arriving at the diagnosis.

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“…2014; Nishino et al. 2015). The anterior tibialis is typically the first affected muscle, resulting in foot drop and tripping.…”

Section: Introductionmentioning

confidence: 99%

Identification of an Alu element‐mediated deletion in the promoter region of GNE in siblings with GNE myopathy

Garland

Stephen

Class

et al. 2017

Molec Gen & Gen Med

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“…GNE myopathy is an autosomal recessive muscular disorder characterized by progressive muscle weakness and atrophy with onset in early adulthood [4,5]. GNE myopathy is caused by biallelic mutations in the GNE gene, which encodes the bifunctional enzyme uridine diphospho-N-acetylglucosamine 2-epimerase (UDP-GlcNAc epimerase) and N-acetylmannosamine kinase (ManNAc kinase).…”

Section: Introductionmentioning

confidence: 99%

Quantitative hydrophilic interaction chromatography–mass spectrometry analysis of N-acetylneuraminic acid and N-acetylmannosamine in human plasma

Shi

Meng

et al. 2015

Journal of Chromatography B

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N-Acetylneuraminic acid (Neu5Ac or NANA) is the most predominant sialic acid in mammals. As a terminal component in many glycoproteins and glycolipids, sialic acid is believed to be an important biomarker related to various diseases. Its precursor, N-acetylmannosamine (ManNAc), is being investigated as a potential treatment for GNE myopathy. In this work, we developed two highly sensitive and selective liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods for the quantitation of ManNAc and free Neu5Ac in human plasma. A fit-for-purpose approach was adopted during method validation and sample analysis. To measure the endogenous compounds and overcome the interference from plasma samples, a surrogate matrix that contained 5% bovine serum albumin (BSA) was used for the preparation of calibration standards and certain levels of quality control (QC) samples. QC samples at higher concentrations were prepared in the authentic matrix (human plasma) to best mimic incurred samples. For both methods, an Ostro 96-well phospholipid removal plate was used for sample extraction, which efficiently removed the phospholipids from the plasma samples prior to LC injection, eliminated matrix effect, and improved sensitivity. Chromatographic separation was achieved using hydrophilic interaction chromatography (HILIC) and gradient elution in order to retain the two polar compounds. The lower limit of quantitation (LLOQ) for ManNAc and Neu5Ac was 10.0 and 25.0 ng/mL, respectively. The overall accuracy of the two assays was no less than 91.7% based on three levels of QC samples. Inter- and intra-run precision (coefficient of variation [%CV]) across three analytical runs was less than 6.7% for ManNAc and less than 10.8% for Neu5Ac. These methods have been validated to support clinical studies.

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“…GNE myopathy (MIM#605820) is a rare autosomal recessive disorder with a higher prevalence in individuals with Middle Eastern or Japanese ancestries 1 . We present a 23-year-old Brazilian female, without such ancestries, with slowly progressive distal and proximal weakness in her lower limbs since the age of 18.…”

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confidence: 99%

Muscle biopsy with dystrophic pattern and rimmed vacuoles: GNE myopathy in a Brazilian patient

Estephan

Moreno

Silva

et al. 2017

Arq. Neuro-Psiquiatr.

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GNE myopathy: current update and future therapy

Abstract: GNE myopathy is an

Cited by 142 publications

References 50 publications

Identification of an Alu element‐mediated deletion in the promoter region of GNE in siblings with GNE myopathy

Identification of an Alu element‐mediated deletion in the promoter region of GNE in siblings with GNE myopathy

Quantitative hydrophilic interaction chromatography–mass spectrometry analysis of N-acetylneuraminic acid and N-acetylmannosamine in human plasma

Muscle biopsy with dystrophic pattern and rimmed vacuoles: GNE myopathy in a Brazilian patient

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