GNE myopathy, also known as hereditary inclusion body myopathy (HIBM), is a rare genetic muscle disorder marked by a gradual onset of muscle weakness in young adults. GNE myopathy (GNEM) is caused by bi-allelic variants in the UDP-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase)/N-acetylmannosamine kinase (ManNAc kinase) gene (GNE), clinically resulting in the loss of ambulation within 10–20 years from the onset of the initial symptoms. The disease’s mechanism is poorly understood and non-invasive biomarkers are lacking, hindering effective therapy development. Based on the available evidence, we employed a lipidomic approach to study the serum lipid profile of GNE patients. The multivariate statistical analysis revealed a downregulation of carnitines, as well as of lysophosphatidylcholines, in sera samples derived from GNEM patients. Furthermore, we identified lower levels of sphingomyelins and, concomitantly, high levels of ceramides in serum samples from GNEM patients when compared to control samples derived from healthy donors. Moreover, the GNEM serum samples showed the upregulation of Krebs cycle intermediates, in addition to a decrease in oxaloacetic acid. The correlated data gathered in this study can offer a promising diagnostic panel of complex lipids and polar metabolites that can be used in clinic for GNEM in terms of a metabolic fingerprint measurable in a minimally invasive manner.
GNE myopathy is a rare recessive myopathy associated with inclusion bodies on muscle biopsy. The clinical phenotype is associated with distal muscle weakness with quadriceps sparing. Most of the current information on GNE myopathy has been obtained through studies of Jewish and Japanese patient cohorts carrying founder mutations in the GNE gene. However, little is known about GNE myopathy in Europe where the prevalence is thought to be very low.
Methods
Patients were referred through the National Specialist Commissioning Team service for limb-girdle muscular dystrophies at Newcastle (UK). All patients harbouring mutations in the GNE gene were recruited for our study. Detailed clinical and genetic data as well as muscle MRIs and muscle biopsies were reviewed.
Results
We identified 26 patients harbouring mutations in the GNE gene. Two previously reported mutations (c.1985C>T, p.Ala662Val and c.1225G>T, p.Asp409Tyr) were prevalent in the Scottish, Northern Irish and Northern English populations; with 90% of these patients carrying at least one of the two mutations. Clinically, we confirmed the homogenous pattern of selective quadriceps sparing but noted additional features like asymmetry of weakness at disease onset.
Conclusions
GNE myopathy is an important diagnosis to consider in patients presenting with distal leg muscle weakness. We report, for the first time, two common mutations in the north of Britain and highlight the broader spectrum of clinical phenotypes. We also propose that the prevalence of GNE myopathy may be underestimated due to the frequent absence of rimmed vacuoles in the muscle biopsy.
To test the hypothesis that common GNE mutations influence disease severity; using statistical analysis of patient cohorts from different countries.
Methods
Systematic literature review identified 11 articles reporting 759 patients. GNE registry data were used as a second data set. The relative contributions of the GNE mutations, homozygosity, and country to the age at onset were explored using linear modeling, and relative importance measures were calculated. The rate of ambulation loss for GNE mutations, homozygosity, country, and age at onset was analyzed using Cox proportional hazards models.
Results
A spectrum of symptoms and large variability of age at onset and nonambulatory status was observed within families and cohorts. We estimated that 20% of variability is explained by GNE mutations. Individuals harboring p.Asp207Val have an expected age at onset 8.0 (s.e1.0) years later than those without and probability of continued ambulation at age 40 of 0.98 (95% confidence interval [CI] 0.96–1). In contrast, p.Leu539Ser results in onset on average 7.2 (s.e.2.7) years earlier than those without this mutation, and p.Val603Leu has a probability of continued ambulance of 0.61 (95% CI 0.50–0.74) at age 40, but has a nonsignificant effect on age at onset.
Conclusions
GNE myopathy severity significantly varies in all cohorts, with 20% of variability explained by the GNE mutation. Atypical symptoms and clinical presentation suggest that physical and instrumental examination should include additional clinical tests. Proven and measurable effect of GNE mutations on the disease severity should be factored in patient management and clinical research study for a better data interpretation.
To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy.UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results.Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs placebo -2.99 kg; LSM difference confidence interval [CI] 0.74 [-1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs.Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy.This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.
Identifying translatable, non-invasive biomarkers of muscular dystrophy that better reflect the disease pathology than those currently available would aid the development of new therapies, the monitoring of disease progression and the response to therapy.The goal of this study was to evaluate a panel of serum protein biomarkers with the potential to specifically detect skeletal muscle injury.Serum concentrations of skeletal troponin I (sTnI), myosin light chain 3 (Myl3), fatty acid binding protein 3 (FABP3) and muscle-type creatine kinase (CKM) proteins were measured in 74 Duchenne muscular dystrophy (DMD), 38 Becker muscular dystrophy (BMD) and 49 Limb-girdle muscular dystrophy type 2B (LGMD2B) patients and 32 healthy controls.All four proteins were significantly elevated in the serum of these three muscular dystrophy patient populations when compared to healthy controls, but, interestingly, displayed different profiles depending on the type of muscular dystrophy. Additionally, the effects of patient age, ambulatory status, cardiac function and treatment status on the serum concentrations of the proteins were investigated. Statistical analysis revealed correlations between the serum concentrations and certain clinical endpoints including forced vital capacity in DMD patients and the time to walk ten meters in LGMD2B patients. Serum concentrations of these proteins were also elevated in two preclinical models of muscular dystrophy, the mdx mouse and the golden-retriever muscular dystrophy dog.These proteins, therefore, are potential muscular dystrophy biomarkers for monitoring disease progression and therapeutic response in both preclinical and clinical studies.
To quantify any risk of atrial fibrillation (AF) associated with ivabradine treatment by meta-analysis of clinical trial data.
Methods
Medline, Embase, Web of Knowledge and the Cochrane central register of controlled trials were searched for double-blinded randomised controlled trials of ivabradine with a minimum follow-up period of 4 weeks. For studies where AF data were unpublished, safety data were obtained from the European Medicines Agency (EMeA) website and personal communications. Studies were appraised for risk of bias using components recommended by the Cochrane Collaboration. Meta-analyses were performed of relative risk of AF and absolute risk difference of AF per year of treatment. The main outcome measure was incident AF during the follow-up period.
Results
AF data were available from 11 studies: one from the published report, six from the EMeA and four from personal communications. Ivabradine treatment was associated with a relative risk of AF of 1.15 (95% CI 1.07 to 1.24, p=0.0027) among 21 571 patients in the meta-analysis. From this we estimated that the number needed to harm for ivabradine would be 208 (95% CI 122 to 667) per year of treatment.
Conclusions
AF is a substantially more common side effect of ivabradine treatment than one patient in 10 000, the risk presently reported in the product literature. The incidence of AF has not routinely been reported in clinical trials of ivabradine.
ABSTRACT Introduction : GNE myopathy is a rare recessive myopathy caused by mutations in the GNE gene. It is mainly a distal myopathy with relative sparing of the quadriceps muscle. Methods : Patients with distal myopathies from Kuwait were examined and tested for the Middle Eastern GNE gene founder mutation, p.M743T. Patients were further studied for disease‐associated features. Results : GNE myopathy was confirmed in 14 of the 37 patients (37.8%) screened. All cases were caused by the p.M743T mutation. Age of onset and time from disease onset to loss of ambulation were variable. Both wasted and hypertrophied calf muscles were noted. Severely affected quadriceps were present in 1 patient, and ptosis, ophthalmoplegia, and tongue wasting in another. Discussion : The scope of the p.M743T mutation now includes the Arabian Peninsula. Variations in age of onset, disease progression, and distribution in patients harboring the same mutation suggest the role of other genetic‐ and environment‐modifying factors. Muscle Nerve 58 : 700–707, 2018
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