Quantification of lectin fluorescence in GNE myopathy muscle biopsies

Leoyklang, Petcharat; Class, Bradley; Noguchi, S.; Gahl, William A.; Carrillo-Carrasco, Nuria; Nishino, Ichizo; Huizing, Marjan; Malicdan, May Christine V.

doi:10.1002/mus.26135

Cited by 15 publications

(10 citation statements)

References 32 publications

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“…There is supporting evidence suggesting that hyposialylation of muscle cell surface glycans play a significant role in GNE myopathy. Although overall sialylation in GNE myopathy serum glycans and myoblasts appears normal [58,59], organ-specific membrane hyposialylation was found in GNE-deficient mice [56], and specific skeletal muscle glycans including alpha-dystroglycan, NCAM, neprilysin, GM3 ganglioside, and O-linked glycans have been reported to be hyposialylated in GNE myopathy [58,[60][61][62][63][64][65][66]. Additional evidence comes from murine models of GNE myopathy; in one model, muscle atrophy and weakness could be prevented by treatment with oral sialic acid metabolites [67] and in another model, impaired muscle sialylation was restored with the administration of oral N-acetylmannosamine (ManNAc) [68].…”

Section: Sialylation Of Muscle Glycansmentioning

confidence: 99%

“…Images in (c): adapted with permission from Niethamer et al [68] glycoproteins (Fig. 4b, c) [11,64,66]. Since SNA predominantly recognizes terminal sialic acid, muscle histochemistry could be further developed, including testing sensitivity and specificity, to assist in the diagnosis and evaluation of patients with GNE myopathy [64][65][66]68].…”

Section: Muscle Histologymentioning

confidence: 99%

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GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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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.

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Section: Sialylation Of Muscle Glycansmentioning

confidence: 99%

Section: Muscle Histologymentioning

confidence: 99%

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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“…The human GNE gene (NM_001128227.2), localized on chromosome 9p13.3, consists of 14 exons and encodes 724 amino acids [ 3 , 5 , 6 , 11 ] The protein encoded by this gene is a bifunctional enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc), which is a precursor of sialic acid [ 12 ] .…”

Section: Discussionmentioning

confidence: 99%

Congenital thrombocytopenia associated with GNE mutations in twin sisters: a case report and literature review

Liu

Lei

et al. 2020

BMC Med Genet

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Background Neonatal thrombocytopenia is common in preterm and term neonates admitted to neonatal intensive care units. The etiology behind neonatal thrombocytopenia is complex. Inherited thrombocytopenia is rare and usually results from genetic mutations. Case presentation Here we report a case of twins with severe inherited thrombocytopenia presented in the neonatal period who were shown to be compound heterozygotes for 2 UDP-N-acetylglucosamine 2-epimerase (GNE) gene mutations, c.1351C > T and c.1330G > T, of which c.1330G > T is a novel mutation. Conclusion These two GNE mutations may help in the diagnosis and management of thrombocytopenia diagnosed in neonates.

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“…Intracellular concentrations of CMP-Neu5Ac were measured on white blood cell (WBC) pellets by LC/MS-MS, as previously reported [ 22 ]. Change in sarcolemmal sialylation from baseline to day 90 was evaluated by a blinded evaluator on muscle biopsies using a quantitative lectin fluorescence method to determine the Sambucus nigra agglutinin (SNA), a lectin that predominantly recognizes terminal α2,6-linked Neu5Ac (Neu5Acα2,6 Galβ), colocalized with the sarcolemmal protein Caveolin-3 (Cav-3), as previously described [ 23 ]. Muscle biopsies were obtained from biceps brachii and a lower extremity muscle at baseline and at day 90 for a total of up to four specimens (two pairs) per patient.…”

Section: Methodsmentioning

confidence: 99%

Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

Carrillo

Malicdan

Leoyklang

et al. 2021

Genetics in Medicine

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Purpose To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. Methods We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. Results Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. Conclusion ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.

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Quantification of lectin fluorescence in GNE myopathy muscle biopsies

Cited by 15 publications

References 32 publications

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

Congenital thrombocytopenia associated with GNE mutations in twin sisters: a case report and literature review

Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study

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