RARE DISEASE
GNE myopathy
GNE myopathy
GNE myopathy
Synonyms: DMRV, Distal myopathy with rimmed vacuoles, Distal myopathy, Nonaka type, HIBM2, Hereditary inclusion body myopathy type 2, IBM2, Inclusion body myopathy type 2, Nonaka myopathy, Quadriceps-sparing myopathy
Synonyms: DMRV, Distal myopathy with rimmed vacuoles, Distal myopathy, Nonaka type, HIBM2, Hereditary inclusion body myopathy type 2, IBM2, Inclusion body myopathy type 2, Nonaka myopathy, Quadriceps-sparing myopathy
Synonyms: DMRV, Distal myopathy with rimmed vacuoles, Distal myopathy, Nonaka type, HIBM2, Hereditary inclusion body myopathy type 2, IBM2, Inclusion body myopathy type 2, Nonaka myopathy, Quadriceps-sparing myopathy
Drug discovery
7
drugs
With orphan designations
Overview
GNE myopathy is an autosomal recessive distal myopathy caused by biallelic GNE mutations, disrupting sialic acid biosynthesis. It presents in early adulthood (typically 20s–40s) with progressive distal weakness (e.g., foot drop), sparing quadriceps until late stages. Diagnosis relies on genetic testing, muscle biopsy (rimmed vacuoles), and characteristic MRI patterns. Serum CK is normal/mildly elevated. No approved disease-modifying therapies exist globally, though supportive care improves quality of life [1][4][5][9].
Categories: rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
146 drug discovery papers about GNE myopathy, with 1 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
146 drug discovery papers about GNE myopathy, with 1 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2022-07-07 | Targeting Immune-Mediated Responses to Tackle GNE Myopathy
GNE myopathy (GNEM) is a rare disease clinically characterized by progressive muscle atrophy and weakness. Besides the rare incidence of the disease, the limited preclinical models are among the major bottlenecks for a better pathophysiological understanding of GNEM. This work aimed then at exploring the immunological context of GNEM in a recently established cell model. Our main findings suggest the involvement of an immune adaptive response, pointing to new alternative biological targets behind GNEM pathomechanisms.
2017-09-12 | Muscle growth by activin type II receptor blocking ameliorates weakness in GNE myopathy mice
GNE myopathy is a debilitating autosomal recessive myopathy due to mutations in the GNE gene, UDP-N-acetylglucosamine-2-epimerase/ N-Acetylmannosamine kinase, which encodes critical enzymes for sialic acid biosynthesis. Clinically, it is characterized by atrophy and weakness in distal skeletal muscle. We have established that a key factor in the mechanism of disease is sialic acid deficiency, a target for recent and ongoing clinical trials. In GNE myopathy patients with existing severe muscle atrophy and degeneration, however, exploring additional therapeutic options may prove beneficial. In this study, we demonstrated the efficacy of myostatin pathway blockade, which promotes muscle growth, on GNE myopathy model mice. CDD866, a murinized anti-activin type II receptor antibody, not only promoted body weight gain and increase in muscle size, but also led to the recovery of specific tetanic force, which is a functional indicator of muscle contractile devices. In addition, we demonstrated that increased S-nitrosylation of contractile and metabolic proteins leads to muscle weakness in GNE myopathy mice. More importantly, CDD866 treatment in mice reversed S-nitrosylation of the muscle proteins along with the recovery of muscle function. Our results suggest that protein synthesis via myostatin pathway blockade has a beneficial effect by providing newly-synthesized fresh muscle proteins to chronic myopathic muscles in addition to muscle size increment. Myostatin pathway blockade may be a promising therapy on GNE myopathy in addition to sialic acid supplementation.
2014-06-01 | Sialylation of Thomsen–Friedenreich antigen is a noninvasive blood-based biomarker for GNE myopathy
Aim: The exact pathomechanism of GNE myopathy remains elusive, but likely involves aberrant sialylation. We explored sialylation status of blood-based glycans as potential disease markers. Methods: We employed immunoblotting, lectin histochemistry and mass spectrometry. Results: GNE myopathy muscle showed hyposialylation of predominantly O-linked glycans. The O-linked glycome of patients' plasma compared with controls showed increased amounts of desialylated Thomsen–Friedenreich (T)-antigen, and/or decreased amounts of its sialylated form, ST-antigen. Importantly, all patients had increased T/ST ratios compared with controls. These ratios were normalized in a patient treated with intravenous immunoglobulins as a source of sialic acid. Discussion: GNE myopathy clinical trial data will reveal whether T/ST ratios correlate to muscle function. Conclusion: Plasma T/ST ratios are a robust blood-based biomarker for GNE myopathy, and may also help explain the pathology and course of the disease.
2007-01-29 | Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study
Abstract Background Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE , codes for UDP- N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as α-dystroglycan and neural cell adhesion molecule (NCAM), has been reported in HIBM. Methods We treated 4 HIBM patients with intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 μmol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals. Results For all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for α-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting. Conclusion The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM.
proteins
2022-03-14 | Elucidation of ER stress and UPR pathway in sialic acid-deficient cells: Pathological relevance to GNEM.
Accumulation of misfolded proteins in endoplasmic reticulum (ER) generates a stress condition in the cell. The cell combats ER stress by activating unfolded protein response (UPR) and ERAD (ER stress-associated degradation) pathway. Failure to restore favorable folding environment results in cell dysfunction and apoptosis. Various neurodegenerative disorders are characterized by the accumulation of misfolded protein, protein aggregates, and ER stress. GNE myopathy (GNEM) is a neuromuscular disorder pathologically characterized by rimmed vacuole formation due to the accumulation of protein aggregates. More than 200 mutations in key sialic acid biosynthetic enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) have been identified worldwide in the muscle biopsies of GNE myopathy patients. However, the cellular and molecular pathomechanism leading to the disease ar poorly understood. In the present study, the phenomenon of ER stress has been elucidated in GNE mutant cells overexpressing GNE mutations of Indian origin. The effect of GNE mutations on activation of UPR signaling via inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE-1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6) were deciphered to understand the effect of GNE mutations on these proteins. GRP78 was upregulated with increased X-box-binding protein-1 (XBP-1) splicing and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) upregulation leading to increased apoptosis of GNE mutant cells. Insulin-like growth factor 1 (IGF-1) ligand rescued the cells from apoptotic phenotype by supporting cell survival mechanism. Our study indicates a balance of cell death and survival that decides cell fate and offers potential therapeutic targets to combat ER stress in diseases associated with dysfunctional UPR pathway.
2018-05-03 | Role of IGF-1R in ameliorating apoptosis of GNE deficient cells
Sialic acids (SAs) are nine carbon acidic amino sugars, found at the outermost termini of glycoconjugates performing various physiological and pathological functions. SA synthesis is regulated by UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) that catalyzes rate limiting steps. Mutations in GNE result in rare genetic disorders, GNE myopathy and Sialuria. Recent studies indicate an alternate role of GNE in cell apoptosis and adhesion, besides SA biosynthesis. In the present study, using a HEK cell-based model for GNE myopathy, the role of Insulin-like Growth Factor Receptor (IGF-1R) as cell survival receptor protein was studied to counter the apoptotic effect of non-functional GNE. In the absence of functional GNE, IGF-1R was hyposialylated and transduced a downstream signal upon IGF-1 (IGF-1R ligand) treatment. IGF-1 induced activation of IGF-1R led to AKT (Protein Kinase B) phosphorylation that may phosphorylate BAD (BCL2 Associated Death Promoter) and its dissociation from BCL2 to prevent apoptosis. However, reduced ERK (Extracellular signal-regulated kinases) phosphorylation in GNE deficient cells after IGF-1 treatment suggests downregulation of the ERK pathway. A balance between the ERK and AKT pathways may determine the cell fate towards survival or apoptosis. Our study suggests that IGF-1R activation may rescue apoptotic cell death of GNE deficient cell lines and has potential as therapeutic target.
2016-04-02 | Aberrant O‐GlcNAcylation disrupts GNE enzyme activity in GNE myopathy
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is the key enzyme for the biosynthesis of sialic acids. Sialic acids are terminal monosaccharides of glycoconjugates and gangliosides, which have an essential influence on various cell interactions. The sialylation of proteins varies during development, aging, and pathogenesis of degenerative diseases such as Morbus Alzheimer, diabetes mellitus type II, or myopathies. Mutation of methionine 743 in the GNE leads to a 30% reduction of the enzyme activity and is responsible for an aggressive form of GNE myopathy. GNE myopathy or hereditary inclusion body myopathy (HIBM) is an age-dependent muscular dystrophy. Here, we analyzed the impact of the exchange of methionine to threonine at position 743 which introduces an additional potential phosphorylation/O-GlcNAcylation site. We found increased O-GlcNAcylation of the M743T variant compared to the wild-type GNE. In addition, removal of the O-GlcNAc of the M743T variant resulted in an increased activity comparable to activity of the wild-type GNE. Furthermore, the half-life of the M743T variant is two times longer than for the wild-type GNE protein. This study provides that the balance of phosphorylation and O-GlcNAcylation is decisive involved in efficiency and regulation of GNE.
small molecules
2026-07-22 | Nutritional interventions and dietary supplements in muscle diseases: a systematic review.
Medical nutrition therapy significantly impacts cardiovascular risk and overall health, but effects on muscle diseases remain unclear. This systematic review evaluates the safety and efficacy of dietary interventions and supplements on muscle disease outcomes. A multidisciplinary team conducted a PRISMA-guided systematic review registered on PROSPERO. Searches were conducted across multiple databases and screened against pre-specified inclusion criteria. Of 107 full-text articles screened, 51 met inclusion criteria. Most identified interventions used dietary supplements rather than whole dietary approaches. In inflammatory myopathies, creatine (loading dose 20 g/day, maintenance 3 g/day) combined with exercise improved high-intensity functional performance in PM and DM over 6 months. In Duchenne muscular dystrophy, creatine (2-10 g/day for 8-16 weeks) improved maximal voluntary contraction and fatigue resistance. Carbohydrate-rich diets (65% CHO) reduced exercise-related symptoms in McArdle disease, while high-dose creatine (150 mg/kg/day) paradoxically worsened symptoms. Four trials of aceneuramic acid (6 g/day for 48 weeks) in GNE myopathy demonstrated dose-dependent strength improvements, leading to regulatory approval in Japan. High-protein supplementation showed positive trends for muscle preservation in critical illness myopathy. Quality assessment revealed 31% at low risk of bias, 49% with some concerns and 20% at high risk. Evidence for nutritional interventions in muscle diseases remains limited, especially for inflammatory myopathies. The strongest support emerged for mechanistically targeted approaches: creatine with exercise, carbohydrate-rich and ketogenic diets in McArdle disease and sialic acid in GNE myopathy. Future research requires adequately powered multicentre trials with standardized outcomes, with focus on inflammatory myopathies.
2026-07-06 | Are there any upcoming clinical trials for humans with GNE myopathy?
Upcoming clinical trials for GNE myopathy include a study on UX016 to evaluate its safety and efficacy, as well as potential future studies on ManNAc dosing and aceneuramic formulations.
2026-04-11 | Defective autophagy in GNE myopathy is rescued by inhibition of noncanonical Akt-mTORC1 activation across multiple isogenic models.
GNE myopathy is a recessive autosomal disease caused by mutations in glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE), characterized by impaired sialic acid biosynthesis and the formation of rimmed vacuoles. Similar to other autophagic vacuolar myopathies, defective autophagy has been implicated in disease pathogenesis; however, the underlying molecular mechanisms remain poorly understood. By performing transcriptome analysis on two independent GNE myoblast models derived from human pluripotent stem cells, we identified multiple autophagy-related gene sets as pathogenic signatures of GNE myopathy. These predictions were biochemically validated using Gne-knockout C2C12 myoblasts. Mechanistically, our data reveal that aberrant activation of the noncanonical AKT-mTORC1 pathway-driven by excessive extracellular matrix production-induces inhibitory phosphorylation of ULK1, thereby suppressing autophagy initiation. To identify therapeutic targets, we performed a transcriptome-based drug screen using gene signature reversal, which nominated copanlisib, an FDA-approved Pi3k inhibitor, as a promising candidate. Functional validation in human pluripotent stem cell-derived neuromuscular organoids demonstrated that copanlisib reactivates autophagy via restoration of ULK1 activity. Together, our findings uncover a mechanistic link between extracellular matrix dysregulation and impaired autophagy in GNE myopathy and highlight copanlisib as a potential therapeutic strategy.
2025-12-15 | Towards a Cure: Emerging Therapeutic Advances for DMD, LGMD, and GNEM- Insights from Pre-Clinical and Clinical Research
Duchenne muscular dystrophy (DMD), Limb-girdle muscular dystrophies (LGMD), and GNE myopathy (GNEM) are progressive neuromuscular rare genetic diseases with differing etiologies either due to defects in structural muscle proteins or impaired metabolism and manifests through progressive weakening and deterioration of skeletal muscle tissues. This review summarizes current and recent clinical trials worldwide, highlighting curative approaches for neuromuscular diseases such as DMD, LGMD, and GNEM. We compiled and summarized latest and most promising outcomes from ongoing global clinical trials, using information from official websites, news sources, trial registries, databases and literature across four key therapeutic modalities: 1) palliative therapies: steroidal and non-steroidal 2) gene therapy and gene-targeted interventions, 3) cell-based regenerative strategies and 4) universal treatments (therapies not limited to the mutation type). We also highlighted the risks associated with gene therapy and discussed key regulatory considerations.Several current clinical trials show promise for muscular dystrophy treatments. RGX-202 gene therapy demonstrates early muscle strength improvement in DMD children. MyoPAXon, a stem cell therapy for DMD muscle regeneration, has FDA clearance to begin trials. Sevasemten (EDG-5506) trials report slowed DMD/BMD progression. SRP-9003 gene therapy targets protein restoration in LGMD. ACENOBEL, approved in Japan for GNEM, may delay disease progression if started early. These trials offer high potential to become widely available treatments improving quality of life and provide life-saving therapeutic options. Additionally, Indian specific founder mutations for the mentioned muscular dystrophies are highlighted to understand the disease etiology in Indian populations for precise diagnostics and therapeutics.
2025-12-04 | Hydroxyethylamine & phthalimide analogs restoring defects due to GNE dysfunction: rare disease therapeutic significance.
Rare diseases refer to a group of neglected diseases with low prevalence that face challenges in diagnostics as well as therapeutics due to phenotypic heterogeneity and ineffective clinical trials. In this study, we evaluated two novel analogs of hydroxyethylamine & phthalimide (LTC-181 and LTC-1717) for their potential effect on the epimerase activity of mutant GNE proteins associated with GNE myopathy. GNE gene encodes a key bifunctional sialic acid biosynthetic enzyme, UDP-N-acetyl Glucosamine 2-epimerase/N-acetyl Mannosamine Kinase; GNE). The compounds have significantly increased the epimerase activity of r-F307C-GNE and r-A555V-GNE mutant proteins in vitro. Reduced GNE epimerase activity and sialic acid content in muscle cell-based model for GNE function (SKM-GNEHz) was increased by 2-fold after addition of these compounds. The proteomic study showed that the compounds affected cytoskeletal organization, autophagy and muscle atrophy. Also, treatment with analogs enhanced the cell viability of SKM-GNEHz cells with increased F-actin polymerization and cell migration, thereby, restoring GNE deficient function. Additionally, effect of these compounds was observed with enhanced autophagy and reduced muscle atrophy function in GNE deficient muscle cell. Docking and interaction studies showed that LTC-1717 stabilize GNE better than LTC-181, indicating better therapeutic potential. Overall, this study indicates that HEA-phthalimide analog could be promising leads for treating GNE myopathy.
gene therapies
2026-05-26 | In Vivo Assessment of dbDNA GNEwt/bi-shRNA-GNEM743T Lipoplex for GNE Myopathy: Improved Potency and Safety.
GNE myopathy is an autosomal recessive disease, associated with skeletal muscle deterioration, which afflicts young adults. GNE plays a pivotal role in sialic acid production. Sialic acid acts as a buffer against reactive oxygen species generated during muscle contraction. Increased oxidative stress may relate to muscle atrophy involving patients with GNE myopathy. GNEM743T is the most common mutation leading to GNE myopathy. In our previous work, we demonstrated that a bifunctional plasmid that expresses wild type (wt) GNE and knocks down the GNEM743T mutant improves sialic acid production in vitro. Now, we expand evidence of in vivo activity of the bifunctional plasmid using a DOTAP-Cholesterol delivery vehicle and reduced toxic plasmid components using dbDNA conversion. We demonstrate that IV delivery of dbDNA lipoplex (LPX) in murine and rat models shows safety, increased DNA delivery, and improved RNA expression per LPX in skeletal muscle over non db plasmid at equal dose. Sialic acid protein expression was also shown increased in mouse muscle following IV treatment with dbDNA plasmid (pDNA) GNEwt/bi-shRNA-GNEM743T LPX. These results support further preclinical investigation to justify product IND development towards Phase 1 trial involving patients with GNE myopathy.
2026-04-15 | Profile of Inherited Neuromuscular and Movement Disorders Among Filipinos: A Referral Single-Center Retrospective Study
Background: Neuromuscular and movement disorders comprise a heterogeneous group of acquired and inherited conditions affecting the motor unit and central movement pathways. Genetic data from underserved populations, including Filipinos, remain limited, highlighting the need for population-specific characterization. Objective: To characterize inherited neuromuscular and movement disorders among Filipinos and determine the diagnostic yield and genetic spectrum using next-generation sequencing (NGS). Methods: This referral single-center retrospective study reviewed Filipino patients who underwent genetic testing for suspected inherited neuromuscular and movement disorders. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results: Among 85 patients, 24 (28.2%) had pathogenic/likely pathogenic variants, 33 (38.8%) had variants of uncertain significance (VUS) and 28 (32.9%) were negative. Confirmed diagnoses included pediatric cases of limb-girdle muscular dystrophy, Duchenne muscular dystrophy, spinal muscular atrophy and GNE-related myopathy, and adult cases with myofibrillar myopathy, spinocerebellar ataxia and amyotrophic lateral sclerosis. Pathogenic variants involved 26 genes, most commonly SMN1. Conclusion: This NGS-based characterization of inherited neuromuscular and movement disorders in Filipinos showed 28% diagnostic yield and a spectrum comparable to other Asian cohorts. The high rate of VUS underscores the need for family segregation studies and careful genotype–phenotype correlation. This study highlights the critical role of genetic testing in accurate diagnosis and targeted management to improve outcomes for patients with these rare disorders.
2026-04-06 | Overlapping phenotype of GNE myopathy and dystrophinopathy: a rare case with dual variants from India
Distal myopathies are rare neuromuscular disorders, among which GNE myopathay (also known as Nonaka myopathy) results from autosomal recessive mutations in the GNE [glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase] gene, while Duchenne muscular dystrophy (DMD), the most common form, is caused by X-linked recessive mutations in the DMD gene. We describe a rare case of overlapping pathogenic variants in both genes, leading to an atypical phenotype. A 24-year-old Indian male with a history of progressive muscle weakness since childhood was evaluated. Clinical assessment, serum creatine phosphokinase (CK) testing, multiplex ligation-dependent probe amplification (MLPA) for DMD, whole exome sequencing (WES), Sanger sequencing, and genomic DNA–based real-time PCR were performed. Family segregation analysis was also undertaken. The patient presented with progressive quadriparesis, myalgia, hypotonia, and bent fingers (camptodactyly), and had been wheelchair-bound for 12 years. CK was moderately elevated (285 U/L) when measured at 22 years of age. MLPA analysis did not detect any exonic deletions or duplications in DMD. WES revealed a hemizygous novel pathogenic variant in DMD (c.3163 A > T; p.Asn1055Tyr), a heterozygous missense variant in GNE (c.2086G > A; p.Val696Met), and a heterozygous deletion in exon 11 of GNE (9p13.3). SNVs were validated by Sanger sequencing and the CNV by genomic DNA based real-time PCR. Segregation analysis demonstrated maternal inheritance of the DMD variant, paternal inheritance of the GNE missense variant, and a proband-specific GNE deletion. This case represents a rare example of early onset distal myopathy with concurrent pathogenic variations in both DMD and GNE. The coexistence of multiple variants highlights a possible synergistic effect contributing to the unique clinical phenotype observed.
2026-03-02 | Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy
GNE myopathy is a heredity disease of unmet medical need associated with progressive skeletal muscle wasting, atrophy and weakness caused by mutations in the GNE gene. GNE plays a pivotal role in sialic acid production. Sialic acid is a critical part of glycoprotein, ganglioside and glycolipid cell-cell interaction which is necessary for normal skeletal muscle function. Previously we demonstrated safety and efficacy of the GNEwt gene lipoplex in one patient. We engineered GNEM743T and dual function GNEwt/bi-shRNA plasmids to evaluate GNEM743T specific knockdown and GNEwt expression. Knockdown efficiency, protein expression, and functional rescue were assessed. A dose range study in mice quantified plasmid delivery and human GNE expression in muscle. We demonstrate effective plasmid function via knockdown of the GNEM743T gene mutation and concurrent expression of GNEwt gene in a dose dependent manner. Similar in vitro increase in sialic acid production is shown between prior single function plasmid and GNEwt/bi-shRNA-GNEM743T dual function plasmid. Moreover, we demonstrate murine in vivo muscle delivery and expression of GNEwt mRNA from the GNEwt/bi-shRNA-GNEM743T plasmid delivered via DOTAP-Cholesterol lipoplex following intravenous injection. These results encourage future studies, potentially leading toward clinical testing of GNEwt/bi-shRNA-GNEM743T lipoplex for GNE myopathy. GNEwt/bi-shRNA-GNEM743T dual function plasmid expresses GNE protein and knocks down GNEM743T.Transfection with GNEwt/bi-shRNA-GNEM743T results in increased sialic acid expression in vitro.GNEwt/bi-shRNA-GNEM743T plasmid demonstrates delivery and expression in murine model. GNEwt/bi-shRNA-GNEM743T dual function plasmid expresses GNE protein and knocks down GNEM743T. Transfection with GNEwt/bi-shRNA-GNEM743T results in increased sialic acid expression in vitro. GNEwt/bi-shRNA-GNEM743T plasmid demonstrates delivery and expression in murine model.
2025-11-26 | 74 An approach to GNE myopathy: a tale of two sisters presenting with bilateral foot drop
a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1329:" GNE myopathy is an autosomal recessive distal myopathy caused by a mutation in the GNE gene which encodes the rate limiting enzyme in sialic acid biosynthesis. It is a rare condition affecting about 1 in 1 million people and is more common in people of Japanese and Middle Eastern descent. GNE myopathy presents in adolescence to early adulthood, typically with bilateral foot drop due to anterior tibialis weakness and progresses over decades to involve skeletal muscles throughout the body, characteristically sparring the quadriceps. We report cases of 2 sisters of Southeast Asian ancestry, presenting with difficulty in walking and bilateral foot drop at the age 17 and 26 respectively. Initially investigated for more common hereditary and acquired causes of distal muscle weakness, they were eventually diagnosed with distal myopathy based on symptom progression, MRI, neurophysiology, and muscle biopsy. Subsequently, genetic testing in 2024 confirmed GNE Myopathy. Whilst GNE myopathy is currently an untreatable condition, there are several avenues for promising treatment in preclinical and clinical studies from substrate substitution to gene therapy options. Therefore, the increasing recognition and awareness of this myopathy is of clinical importance. rebecca.johnson131{at}nhs.net ";}
other
2026-07-16 | Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery–Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.
2026-03-02 | Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy.
GNE myopathy is a heredity disease of unmet medical need associated with progressive skeletal muscle wasting, atrophy and weakness caused by mutations in the GNE gene. GNE plays a pivotal role in sialic acid production. Sialic acid is a critical part of glycoprotein, ganglioside and glycolipid cell-cell interaction which is necessary for normal skeletal muscle function. Previously we demonstrated safety and efficacy of the GNEwt gene lipoplex in one patient. We engineered GNEM743T and dual function GNEwt/bi-shRNA plasmids to evaluate GNEM743T specific knockdown and GNEwt expression. Knockdown efficiency, protein expression, and functional rescue were assessed. A dose range study in mice quantified plasmid delivery and human GNE expression in muscle. We demonstrate effective plasmid function via knockdown of the GNEM743T gene mutation and concurrent expression of GNEwt gene in a dose dependent manner. Similar in vitro increase in sialic acid production is shown between prior single function plasmid and GNEwt/bi-shRNA-GNEM743T dual function plasmid. Moreover, we demonstrate murine in vivo muscle delivery and expression of GNEwt mRNA from the GNEwt/bi-shRNA-GNEM743T plasmid delivered via DOTAP-Cholesterol lipoplex following intravenous injection. These results encourage future studies, potentially leading toward clinical testing of GNEwt/bi-shRNA-GNEM743T lipoplex for GNE myopathy.
2022-08-19 | Novel GNE Gene Variants Associated with Severe Congenital Thrombocytopenia and Platelet Sialylation Defect.
The GNE gene encodes an enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically associated with Nonaka myopathy and sialuria, following an autosomal recessive and autosomal dominant inheritance pattern. Reports show that single GNE variants cause severe thrombocytopenia without muscle weakness. Using panel sequencing, we identified two novel compound heterozygous variants in GNE in a young girl with life-threatening bleedings, severe congenital thrombocytopenia, and a platelet secretion defect. Both variants are located in the nucleotide-binding site of the N-acetylmannosamin kinase domain of GNE. Lectin array showed decreased α-2,3-sialylation on platelets, consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. Hematopoietic stem cell transplantation (HSCT) normalized platelet counts. This is the first report of an HSCT in a patient with an inherited GNE defect leading to normal platelet counts.
2021-11-16 | Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
GNE gene-specific c.2179G>A(p.V727M) is a key alteration reported in patients with hereditary inclusion body myopathy (HIBM) and represents an ethnic founder mutation in the Indian cohort. However, the underlying role of this mutation in pathogenesis remains largely unknown. Thus, in this study, we aimed to access possible mechanisms of V727M mutation that could be leading to myopathy. We evaluated various in silico tools to predict the effect of this mutation on pathogenicity, structural or possible interactions, that could induce myopathy. Our results propose that V727M mutation could induce deleterious effects or pathogenicity and affect the stability of GNE protein. Analysis of differential genes reported in the V727 mutant case suggests that it can affect GNE protein interaction with Myc-proto-oncogene (MYC) transcription factor. Our in silico analysis also suggests a possible interaction between GNE ManNac-kinase domain with MYC protein at the C-terminal DNA-binding domain. MYC targets reported in skeletal muscles via ChIP-seq suggest that it plays a key role in regulating the expression of many genes reported differentially expressed in V727M-mutated HIBMs. We conclude that V727M mutation could alter the interaction of GNE with MYC thereby altering transcription of sialyltransferase and neuromuscular genes, thus understanding these effects could pave the way for developing effective therapies against HIBM.
2016-09-09 | Development of a zebrafish model for GNE myopathy
GNE Myopathy is caused by recessive mutations in the GNE gene. The process by which the mutations lead to myopathy is not well understood, and there is a lack of reliable animal models for the disease. Zebrafish (Danio rerio) was previously shown in our laboratory to have the potential to be used as a genetic model system for GNE myopathy. Now we are developing a transgenic zebrafish knocked out for the endogenic gne gene, expressing the human GNEM743T gene under the control of the zebrafish gne promoter. In order to create this model fish we used the Tol2 transposon system for the integration of the mutated human GNE gene (M743T) as well as the CRISPR RNA-guided Cas9 nuclease (RGN) system to efficiently introduce somatic indel mutations in the endogenous zebrafish gne gene in order to knock it out. This zebrafish model will allow continuous research for the biochemical and molecular pathways by which the mutation leads to the development of the myopathy. In addition, a reliable model will allow the evaluation of therapy approaches and eventually future large scale screening for potential molecules with the ability to rescue the myopathic muscle phenotype.
antibodies
2022-07-07 | Targeting Immune-Mediated Responses to Tackle GNE Myopathy
GNE myopathy (GNEM) is a rare disease clinically characterized by progressive muscle atrophy and weakness. Besides the rare incidence of the disease, the limited preclinical models are among the major bottlenecks for a better pathophysiological understanding of GNEM. This work aimed then at exploring the immunological context of GNEM in a recently established cell model. Our main findings suggest the involvement of an immune adaptive response, pointing to new alternative biological targets behind GNEM pathomechanisms.
2017-09-12 | Muscle growth by activin type II receptor blocking ameliorates weakness in GNE myopathy mice
GNE myopathy is a debilitating autosomal recessive myopathy due to mutations in the GNE gene, UDP-N-acetylglucosamine-2-epimerase/ N-Acetylmannosamine kinase, which encodes critical enzymes for sialic acid biosynthesis. Clinically, it is characterized by atrophy and weakness in distal skeletal muscle. We have established that a key factor in the mechanism of disease is sialic acid deficiency, a target for recent and ongoing clinical trials. In GNE myopathy patients with existing severe muscle atrophy and degeneration, however, exploring additional therapeutic options may prove beneficial. In this study, we demonstrated the efficacy of myostatin pathway blockade, which promotes muscle growth, on GNE myopathy model mice. CDD866, a murinized anti-activin type II receptor antibody, not only promoted body weight gain and increase in muscle size, but also led to the recovery of specific tetanic force, which is a functional indicator of muscle contractile devices. In addition, we demonstrated that increased S-nitrosylation of contractile and metabolic proteins leads to muscle weakness in GNE myopathy mice. More importantly, CDD866 treatment in mice reversed S-nitrosylation of the muscle proteins along with the recovery of muscle function. Our results suggest that protein synthesis via myostatin pathway blockade has a beneficial effect by providing newly-synthesized fresh muscle proteins to chronic myopathic muscles in addition to muscle size increment. Myostatin pathway blockade may be a promising therapy on GNE myopathy in addition to sialic acid supplementation.
2014-06-01 | Sialylation of Thomsen–Friedenreich antigen is a noninvasive blood-based biomarker for GNE myopathy
Aim: The exact pathomechanism of GNE myopathy remains elusive, but likely involves aberrant sialylation. We explored sialylation status of blood-based glycans as potential disease markers. Methods: We employed immunoblotting, lectin histochemistry and mass spectrometry. Results: GNE myopathy muscle showed hyposialylation of predominantly O-linked glycans. The O-linked glycome of patients' plasma compared with controls showed increased amounts of desialylated Thomsen–Friedenreich (T)-antigen, and/or decreased amounts of its sialylated form, ST-antigen. Importantly, all patients had increased T/ST ratios compared with controls. These ratios were normalized in a patient treated with intravenous immunoglobulins as a source of sialic acid. Discussion: GNE myopathy clinical trial data will reveal whether T/ST ratios correlate to muscle function. Conclusion: Plasma T/ST ratios are a robust blood-based biomarker for GNE myopathy, and may also help explain the pathology and course of the disease.
2007-01-29 | Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study
Abstract Background Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, non-inflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE , codes for UDP- N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase, which catalyzes the first two reactions in the synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as α-dystroglycan and neural cell adhesion molecule (NCAM), has been reported in HIBM. Methods We treated 4 HIBM patients with intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 μmol of sialic acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg at weekly intervals. Results For all four patients, mean quadriceps strength improved from 19.0 kg at baseline to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows. Objective measures of functional improvement gave variable results, but the patients experienced improvements in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of muscle biopsies for α-dystroglycan and NCAM did not provide consistent evidence for increased sialylation after IVIG treatment. Side effects were limited to transient headaches and vomiting. Conclusion The mild benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM.
proteins
2022-03-14 | Elucidation of ER stress and UPR pathway in sialic acid-deficient cells: Pathological relevance to GNEM.
Accumulation of misfolded proteins in endoplasmic reticulum (ER) generates a stress condition in the cell. The cell combats ER stress by activating unfolded protein response (UPR) and ERAD (ER stress-associated degradation) pathway. Failure to restore favorable folding environment results in cell dysfunction and apoptosis. Various neurodegenerative disorders are characterized by the accumulation of misfolded protein, protein aggregates, and ER stress. GNE myopathy (GNEM) is a neuromuscular disorder pathologically characterized by rimmed vacuole formation due to the accumulation of protein aggregates. More than 200 mutations in key sialic acid biosynthetic enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) have been identified worldwide in the muscle biopsies of GNE myopathy patients. However, the cellular and molecular pathomechanism leading to the disease ar poorly understood. In the present study, the phenomenon of ER stress has been elucidated in GNE mutant cells overexpressing GNE mutations of Indian origin. The effect of GNE mutations on activation of UPR signaling via inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE-1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor-6 (ATF6) were deciphered to understand the effect of GNE mutations on these proteins. GRP78 was upregulated with increased X-box-binding protein-1 (XBP-1) splicing and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) upregulation leading to increased apoptosis of GNE mutant cells. Insulin-like growth factor 1 (IGF-1) ligand rescued the cells from apoptotic phenotype by supporting cell survival mechanism. Our study indicates a balance of cell death and survival that decides cell fate and offers potential therapeutic targets to combat ER stress in diseases associated with dysfunctional UPR pathway.
2018-05-03 | Role of IGF-1R in ameliorating apoptosis of GNE deficient cells
Sialic acids (SAs) are nine carbon acidic amino sugars, found at the outermost termini of glycoconjugates performing various physiological and pathological functions. SA synthesis is regulated by UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) that catalyzes rate limiting steps. Mutations in GNE result in rare genetic disorders, GNE myopathy and Sialuria. Recent studies indicate an alternate role of GNE in cell apoptosis and adhesion, besides SA biosynthesis. In the present study, using a HEK cell-based model for GNE myopathy, the role of Insulin-like Growth Factor Receptor (IGF-1R) as cell survival receptor protein was studied to counter the apoptotic effect of non-functional GNE. In the absence of functional GNE, IGF-1R was hyposialylated and transduced a downstream signal upon IGF-1 (IGF-1R ligand) treatment. IGF-1 induced activation of IGF-1R led to AKT (Protein Kinase B) phosphorylation that may phosphorylate BAD (BCL2 Associated Death Promoter) and its dissociation from BCL2 to prevent apoptosis. However, reduced ERK (Extracellular signal-regulated kinases) phosphorylation in GNE deficient cells after IGF-1 treatment suggests downregulation of the ERK pathway. A balance between the ERK and AKT pathways may determine the cell fate towards survival or apoptosis. Our study suggests that IGF-1R activation may rescue apoptotic cell death of GNE deficient cell lines and has potential as therapeutic target.
2016-04-02 | Aberrant O‐GlcNAcylation disrupts GNE enzyme activity in GNE myopathy
UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is the key enzyme for the biosynthesis of sialic acids. Sialic acids are terminal monosaccharides of glycoconjugates and gangliosides, which have an essential influence on various cell interactions. The sialylation of proteins varies during development, aging, and pathogenesis of degenerative diseases such as Morbus Alzheimer, diabetes mellitus type II, or myopathies. Mutation of methionine 743 in the GNE leads to a 30% reduction of the enzyme activity and is responsible for an aggressive form of GNE myopathy. GNE myopathy or hereditary inclusion body myopathy (HIBM) is an age-dependent muscular dystrophy. Here, we analyzed the impact of the exchange of methionine to threonine at position 743 which introduces an additional potential phosphorylation/O-GlcNAcylation site. We found increased O-GlcNAcylation of the M743T variant compared to the wild-type GNE. In addition, removal of the O-GlcNAc of the M743T variant resulted in an increased activity comparable to activity of the wild-type GNE. Furthermore, the half-life of the M743T variant is two times longer than for the wild-type GNE protein. This study provides that the balance of phosphorylation and O-GlcNAcylation is decisive involved in efficiency and regulation of GNE.
small molecules
2026-07-22 | Nutritional interventions and dietary supplements in muscle diseases: a systematic review.
Medical nutrition therapy significantly impacts cardiovascular risk and overall health, but effects on muscle diseases remain unclear. This systematic review evaluates the safety and efficacy of dietary interventions and supplements on muscle disease outcomes. A multidisciplinary team conducted a PRISMA-guided systematic review registered on PROSPERO. Searches were conducted across multiple databases and screened against pre-specified inclusion criteria. Of 107 full-text articles screened, 51 met inclusion criteria. Most identified interventions used dietary supplements rather than whole dietary approaches. In inflammatory myopathies, creatine (loading dose 20 g/day, maintenance 3 g/day) combined with exercise improved high-intensity functional performance in PM and DM over 6 months. In Duchenne muscular dystrophy, creatine (2-10 g/day for 8-16 weeks) improved maximal voluntary contraction and fatigue resistance. Carbohydrate-rich diets (65% CHO) reduced exercise-related symptoms in McArdle disease, while high-dose creatine (150 mg/kg/day) paradoxically worsened symptoms. Four trials of aceneuramic acid (6 g/day for 48 weeks) in GNE myopathy demonstrated dose-dependent strength improvements, leading to regulatory approval in Japan. High-protein supplementation showed positive trends for muscle preservation in critical illness myopathy. Quality assessment revealed 31% at low risk of bias, 49% with some concerns and 20% at high risk. Evidence for nutritional interventions in muscle diseases remains limited, especially for inflammatory myopathies. The strongest support emerged for mechanistically targeted approaches: creatine with exercise, carbohydrate-rich and ketogenic diets in McArdle disease and sialic acid in GNE myopathy. Future research requires adequately powered multicentre trials with standardized outcomes, with focus on inflammatory myopathies.
2026-07-06 | Are there any upcoming clinical trials for humans with GNE myopathy?
Upcoming clinical trials for GNE myopathy include a study on UX016 to evaluate its safety and efficacy, as well as potential future studies on ManNAc dosing and aceneuramic formulations.
2026-04-11 | Defective autophagy in GNE myopathy is rescued by inhibition of noncanonical Akt-mTORC1 activation across multiple isogenic models.
GNE myopathy is a recessive autosomal disease caused by mutations in glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE), characterized by impaired sialic acid biosynthesis and the formation of rimmed vacuoles. Similar to other autophagic vacuolar myopathies, defective autophagy has been implicated in disease pathogenesis; however, the underlying molecular mechanisms remain poorly understood. By performing transcriptome analysis on two independent GNE myoblast models derived from human pluripotent stem cells, we identified multiple autophagy-related gene sets as pathogenic signatures of GNE myopathy. These predictions were biochemically validated using Gne-knockout C2C12 myoblasts. Mechanistically, our data reveal that aberrant activation of the noncanonical AKT-mTORC1 pathway-driven by excessive extracellular matrix production-induces inhibitory phosphorylation of ULK1, thereby suppressing autophagy initiation. To identify therapeutic targets, we performed a transcriptome-based drug screen using gene signature reversal, which nominated copanlisib, an FDA-approved Pi3k inhibitor, as a promising candidate. Functional validation in human pluripotent stem cell-derived neuromuscular organoids demonstrated that copanlisib reactivates autophagy via restoration of ULK1 activity. Together, our findings uncover a mechanistic link between extracellular matrix dysregulation and impaired autophagy in GNE myopathy and highlight copanlisib as a potential therapeutic strategy.
2025-12-15 | Towards a Cure: Emerging Therapeutic Advances for DMD, LGMD, and GNEM- Insights from Pre-Clinical and Clinical Research
Duchenne muscular dystrophy (DMD), Limb-girdle muscular dystrophies (LGMD), and GNE myopathy (GNEM) are progressive neuromuscular rare genetic diseases with differing etiologies either due to defects in structural muscle proteins or impaired metabolism and manifests through progressive weakening and deterioration of skeletal muscle tissues. This review summarizes current and recent clinical trials worldwide, highlighting curative approaches for neuromuscular diseases such as DMD, LGMD, and GNEM. We compiled and summarized latest and most promising outcomes from ongoing global clinical trials, using information from official websites, news sources, trial registries, databases and literature across four key therapeutic modalities: 1) palliative therapies: steroidal and non-steroidal 2) gene therapy and gene-targeted interventions, 3) cell-based regenerative strategies and 4) universal treatments (therapies not limited to the mutation type). We also highlighted the risks associated with gene therapy and discussed key regulatory considerations.Several current clinical trials show promise for muscular dystrophy treatments. RGX-202 gene therapy demonstrates early muscle strength improvement in DMD children. MyoPAXon, a stem cell therapy for DMD muscle regeneration, has FDA clearance to begin trials. Sevasemten (EDG-5506) trials report slowed DMD/BMD progression. SRP-9003 gene therapy targets protein restoration in LGMD. ACENOBEL, approved in Japan for GNEM, may delay disease progression if started early. These trials offer high potential to become widely available treatments improving quality of life and provide life-saving therapeutic options. Additionally, Indian specific founder mutations for the mentioned muscular dystrophies are highlighted to understand the disease etiology in Indian populations for precise diagnostics and therapeutics.
2025-12-04 | Hydroxyethylamine & phthalimide analogs restoring defects due to GNE dysfunction: rare disease therapeutic significance.
Rare diseases refer to a group of neglected diseases with low prevalence that face challenges in diagnostics as well as therapeutics due to phenotypic heterogeneity and ineffective clinical trials. In this study, we evaluated two novel analogs of hydroxyethylamine & phthalimide (LTC-181 and LTC-1717) for their potential effect on the epimerase activity of mutant GNE proteins associated with GNE myopathy. GNE gene encodes a key bifunctional sialic acid biosynthetic enzyme, UDP-N-acetyl Glucosamine 2-epimerase/N-acetyl Mannosamine Kinase; GNE). The compounds have significantly increased the epimerase activity of r-F307C-GNE and r-A555V-GNE mutant proteins in vitro. Reduced GNE epimerase activity and sialic acid content in muscle cell-based model for GNE function (SKM-GNEHz) was increased by 2-fold after addition of these compounds. The proteomic study showed that the compounds affected cytoskeletal organization, autophagy and muscle atrophy. Also, treatment with analogs enhanced the cell viability of SKM-GNEHz cells with increased F-actin polymerization and cell migration, thereby, restoring GNE deficient function. Additionally, effect of these compounds was observed with enhanced autophagy and reduced muscle atrophy function in GNE deficient muscle cell. Docking and interaction studies showed that LTC-1717 stabilize GNE better than LTC-181, indicating better therapeutic potential. Overall, this study indicates that HEA-phthalimide analog could be promising leads for treating GNE myopathy.
gene therapies
2026-05-26 | In Vivo Assessment of dbDNA GNEwt/bi-shRNA-GNEM743T Lipoplex for GNE Myopathy: Improved Potency and Safety.
GNE myopathy is an autosomal recessive disease, associated with skeletal muscle deterioration, which afflicts young adults. GNE plays a pivotal role in sialic acid production. Sialic acid acts as a buffer against reactive oxygen species generated during muscle contraction. Increased oxidative stress may relate to muscle atrophy involving patients with GNE myopathy. GNEM743T is the most common mutation leading to GNE myopathy. In our previous work, we demonstrated that a bifunctional plasmid that expresses wild type (wt) GNE and knocks down the GNEM743T mutant improves sialic acid production in vitro. Now, we expand evidence of in vivo activity of the bifunctional plasmid using a DOTAP-Cholesterol delivery vehicle and reduced toxic plasmid components using dbDNA conversion. We demonstrate that IV delivery of dbDNA lipoplex (LPX) in murine and rat models shows safety, increased DNA delivery, and improved RNA expression per LPX in skeletal muscle over non db plasmid at equal dose. Sialic acid protein expression was also shown increased in mouse muscle following IV treatment with dbDNA plasmid (pDNA) GNEwt/bi-shRNA-GNEM743T LPX. These results support further preclinical investigation to justify product IND development towards Phase 1 trial involving patients with GNE myopathy.
2026-04-15 | Profile of Inherited Neuromuscular and Movement Disorders Among Filipinos: A Referral Single-Center Retrospective Study
Background: Neuromuscular and movement disorders comprise a heterogeneous group of acquired and inherited conditions affecting the motor unit and central movement pathways. Genetic data from underserved populations, including Filipinos, remain limited, highlighting the need for population-specific characterization. Objective: To characterize inherited neuromuscular and movement disorders among Filipinos and determine the diagnostic yield and genetic spectrum using next-generation sequencing (NGS). Methods: This referral single-center retrospective study reviewed Filipino patients who underwent genetic testing for suspected inherited neuromuscular and movement disorders. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Results: Among 85 patients, 24 (28.2%) had pathogenic/likely pathogenic variants, 33 (38.8%) had variants of uncertain significance (VUS) and 28 (32.9%) were negative. Confirmed diagnoses included pediatric cases of limb-girdle muscular dystrophy, Duchenne muscular dystrophy, spinal muscular atrophy and GNE-related myopathy, and adult cases with myofibrillar myopathy, spinocerebellar ataxia and amyotrophic lateral sclerosis. Pathogenic variants involved 26 genes, most commonly SMN1. Conclusion: This NGS-based characterization of inherited neuromuscular and movement disorders in Filipinos showed 28% diagnostic yield and a spectrum comparable to other Asian cohorts. The high rate of VUS underscores the need for family segregation studies and careful genotype–phenotype correlation. This study highlights the critical role of genetic testing in accurate diagnosis and targeted management to improve outcomes for patients with these rare disorders.
2026-04-06 | Overlapping phenotype of GNE myopathy and dystrophinopathy: a rare case with dual variants from India
Distal myopathies are rare neuromuscular disorders, among which GNE myopathay (also known as Nonaka myopathy) results from autosomal recessive mutations in the GNE [glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase] gene, while Duchenne muscular dystrophy (DMD), the most common form, is caused by X-linked recessive mutations in the DMD gene. We describe a rare case of overlapping pathogenic variants in both genes, leading to an atypical phenotype. A 24-year-old Indian male with a history of progressive muscle weakness since childhood was evaluated. Clinical assessment, serum creatine phosphokinase (CK) testing, multiplex ligation-dependent probe amplification (MLPA) for DMD, whole exome sequencing (WES), Sanger sequencing, and genomic DNA–based real-time PCR were performed. Family segregation analysis was also undertaken. The patient presented with progressive quadriparesis, myalgia, hypotonia, and bent fingers (camptodactyly), and had been wheelchair-bound for 12 years. CK was moderately elevated (285 U/L) when measured at 22 years of age. MLPA analysis did not detect any exonic deletions or duplications in DMD. WES revealed a hemizygous novel pathogenic variant in DMD (c.3163 A > T; p.Asn1055Tyr), a heterozygous missense variant in GNE (c.2086G > A; p.Val696Met), and a heterozygous deletion in exon 11 of GNE (9p13.3). SNVs were validated by Sanger sequencing and the CNV by genomic DNA based real-time PCR. Segregation analysis demonstrated maternal inheritance of the DMD variant, paternal inheritance of the GNE missense variant, and a proband-specific GNE deletion. This case represents a rare example of early onset distal myopathy with concurrent pathogenic variations in both DMD and GNE. The coexistence of multiple variants highlights a possible synergistic effect contributing to the unique clinical phenotype observed.
2026-03-02 | Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy
GNE myopathy is a heredity disease of unmet medical need associated with progressive skeletal muscle wasting, atrophy and weakness caused by mutations in the GNE gene. GNE plays a pivotal role in sialic acid production. Sialic acid is a critical part of glycoprotein, ganglioside and glycolipid cell-cell interaction which is necessary for normal skeletal muscle function. Previously we demonstrated safety and efficacy of the GNEwt gene lipoplex in one patient. We engineered GNEM743T and dual function GNEwt/bi-shRNA plasmids to evaluate GNEM743T specific knockdown and GNEwt expression. Knockdown efficiency, protein expression, and functional rescue were assessed. A dose range study in mice quantified plasmid delivery and human GNE expression in muscle. We demonstrate effective plasmid function via knockdown of the GNEM743T gene mutation and concurrent expression of GNEwt gene in a dose dependent manner. Similar in vitro increase in sialic acid production is shown between prior single function plasmid and GNEwt/bi-shRNA-GNEM743T dual function plasmid. Moreover, we demonstrate murine in vivo muscle delivery and expression of GNEwt mRNA from the GNEwt/bi-shRNA-GNEM743T plasmid delivered via DOTAP-Cholesterol lipoplex following intravenous injection. These results encourage future studies, potentially leading toward clinical testing of GNEwt/bi-shRNA-GNEM743T lipoplex for GNE myopathy. GNEwt/bi-shRNA-GNEM743T dual function plasmid expresses GNE protein and knocks down GNEM743T.Transfection with GNEwt/bi-shRNA-GNEM743T results in increased sialic acid expression in vitro.GNEwt/bi-shRNA-GNEM743T plasmid demonstrates delivery and expression in murine model. GNEwt/bi-shRNA-GNEM743T dual function plasmid expresses GNE protein and knocks down GNEM743T. Transfection with GNEwt/bi-shRNA-GNEM743T results in increased sialic acid expression in vitro. GNEwt/bi-shRNA-GNEM743T plasmid demonstrates delivery and expression in murine model.
2025-11-26 | 74 An approach to GNE myopathy: a tale of two sisters presenting with bilateral foot drop
a:2:{s:4:"lang";s:2:"en";s:7:"content";s:1329:" GNE myopathy is an autosomal recessive distal myopathy caused by a mutation in the GNE gene which encodes the rate limiting enzyme in sialic acid biosynthesis. It is a rare condition affecting about 1 in 1 million people and is more common in people of Japanese and Middle Eastern descent. GNE myopathy presents in adolescence to early adulthood, typically with bilateral foot drop due to anterior tibialis weakness and progresses over decades to involve skeletal muscles throughout the body, characteristically sparring the quadriceps. We report cases of 2 sisters of Southeast Asian ancestry, presenting with difficulty in walking and bilateral foot drop at the age 17 and 26 respectively. Initially investigated for more common hereditary and acquired causes of distal muscle weakness, they were eventually diagnosed with distal myopathy based on symptom progression, MRI, neurophysiology, and muscle biopsy. Subsequently, genetic testing in 2024 confirmed GNE Myopathy. Whilst GNE myopathy is currently an untreatable condition, there are several avenues for promising treatment in preclinical and clinical studies from substrate substitution to gene therapy options. Therefore, the increasing recognition and awareness of this myopathy is of clinical importance. rebecca.johnson131{at}nhs.net ";}
other
2026-07-16 | Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery–Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.
2026-03-02 | Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy.
GNE myopathy is a heredity disease of unmet medical need associated with progressive skeletal muscle wasting, atrophy and weakness caused by mutations in the GNE gene. GNE plays a pivotal role in sialic acid production. Sialic acid is a critical part of glycoprotein, ganglioside and glycolipid cell-cell interaction which is necessary for normal skeletal muscle function. Previously we demonstrated safety and efficacy of the GNEwt gene lipoplex in one patient. We engineered GNEM743T and dual function GNEwt/bi-shRNA plasmids to evaluate GNEM743T specific knockdown and GNEwt expression. Knockdown efficiency, protein expression, and functional rescue were assessed. A dose range study in mice quantified plasmid delivery and human GNE expression in muscle. We demonstrate effective plasmid function via knockdown of the GNEM743T gene mutation and concurrent expression of GNEwt gene in a dose dependent manner. Similar in vitro increase in sialic acid production is shown between prior single function plasmid and GNEwt/bi-shRNA-GNEM743T dual function plasmid. Moreover, we demonstrate murine in vivo muscle delivery and expression of GNEwt mRNA from the GNEwt/bi-shRNA-GNEM743T plasmid delivered via DOTAP-Cholesterol lipoplex following intravenous injection. These results encourage future studies, potentially leading toward clinical testing of GNEwt/bi-shRNA-GNEM743T lipoplex for GNE myopathy.
2022-08-19 | Novel GNE Gene Variants Associated with Severe Congenital Thrombocytopenia and Platelet Sialylation Defect.
The GNE gene encodes an enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid, a precursor of sialic acids. GNE mutations are classically associated with Nonaka myopathy and sialuria, following an autosomal recessive and autosomal dominant inheritance pattern. Reports show that single GNE variants cause severe thrombocytopenia without muscle weakness. Using panel sequencing, we identified two novel compound heterozygous variants in GNE in a young girl with life-threatening bleedings, severe congenital thrombocytopenia, and a platelet secretion defect. Both variants are located in the nucleotide-binding site of the N-acetylmannosamin kinase domain of GNE. Lectin array showed decreased α-2,3-sialylation on platelets, consistent with loss of sialic acid synthesis and indicative of rapid platelet clearance. Hematopoietic stem cell transplantation (HSCT) normalized platelet counts. This is the first report of an HSCT in a patient with an inherited GNE defect leading to normal platelet counts.
2021-11-16 | Dissecting role of founder mutation p.V727M in GNE in Indian HIBM cohort
GNE gene-specific c.2179G>A(p.V727M) is a key alteration reported in patients with hereditary inclusion body myopathy (HIBM) and represents an ethnic founder mutation in the Indian cohort. However, the underlying role of this mutation in pathogenesis remains largely unknown. Thus, in this study, we aimed to access possible mechanisms of V727M mutation that could be leading to myopathy. We evaluated various in silico tools to predict the effect of this mutation on pathogenicity, structural or possible interactions, that could induce myopathy. Our results propose that V727M mutation could induce deleterious effects or pathogenicity and affect the stability of GNE protein. Analysis of differential genes reported in the V727 mutant case suggests that it can affect GNE protein interaction with Myc-proto-oncogene (MYC) transcription factor. Our in silico analysis also suggests a possible interaction between GNE ManNac-kinase domain with MYC protein at the C-terminal DNA-binding domain. MYC targets reported in skeletal muscles via ChIP-seq suggest that it plays a key role in regulating the expression of many genes reported differentially expressed in V727M-mutated HIBMs. We conclude that V727M mutation could alter the interaction of GNE with MYC thereby altering transcription of sialyltransferase and neuromuscular genes, thus understanding these effects could pave the way for developing effective therapies against HIBM.
2016-09-09 | Development of a zebrafish model for GNE myopathy
GNE Myopathy is caused by recessive mutations in the GNE gene. The process by which the mutations lead to myopathy is not well understood, and there is a lack of reliable animal models for the disease. Zebrafish (Danio rerio) was previously shown in our laboratory to have the potential to be used as a genetic model system for GNE myopathy. Now we are developing a transgenic zebrafish knocked out for the endogenic gne gene, expressing the human GNEM743T gene under the control of the zebrafish gne promoter. In order to create this model fish we used the Tol2 transposon system for the integration of the mutated human GNE gene (M743T) as well as the CRISPR RNA-guided Cas9 nuclease (RGN) system to efficiently introduce somatic indel mutations in the endogenous zebrafish gne gene in order to knock it out. This zebrafish model will allow continuous research for the biochemical and molecular pathways by which the mutation leads to the development of the myopathy. In addition, a reliable model will allow the evaluation of therapy approaches and eventually future large scale screening for potential molecules with the ability to rescue the myopathic muscle phenotype.
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Drug Discovery Landscape
7 orphan drug designations for GNE myopathy.
7 orphan drug designations for GNE myopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
aceneuramic acid | small molecules | FDA | 2025-07-03 | — | Nobelpharma Co., Ltd. |
6¿-Sialyllactose (SL) sodium salt | oligonucleotides | FDA | 2025-03-27 | — | NeuraGene, Inc. |
N-acetyl-D-mannosamine monohydrate | small molecules | EMA | 2016-03-21 | — | Leadiant GmbH |
Aceneuramic acid [Kepnetic] | small molecules | EMA | 2015-10-16 | — | Ultragenyx Germany GmbH |
N-Acetylmannosamine (ManNAc) | small molecules | FDA | 2010-04-05 | — | Leadiant Biosciences, Inc. |
GNE plasmid(H001) | gene therapies | FDA | 2010-03-26 | — | HIBM Research Group |
GNE Lipoplex | gene therapies | FDA | 2008-11-13 | — | Gradalis, Inc. |
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