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 » Disease Management
 » Future Perspectives
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REVIEW ARTICLE
Year : 2019  |  Volume : 67  |  Issue : 5  |  Page : 1213-1219

The Inherited Neuromuscular Disorder GNE Myopathy: Research to Patient Care


1 School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
2 School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
3 School of Life Sciences; World without GNE Myopathy, Jawaharlal Nehru University, New Delhi, India
4 World without GNE Myopathy, Jawaharlal Nehru University; School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, India

Date of Web Publication19-Nov-2019

Correspondence Address:
Dr. Sudha Bhattacharya
School of Environmental Sciences, Jawaharlal Nehru University, New Delhi -110 067
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.271259

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 » Abstract 


Inherited neuromuscular diseases are a heterogeneous group of rare diseases for which the low general awareness leads to frequent misdiagnosis. Advances in DNA sequencing technologies are changing this situation, and it is apparent that these diseases are not as rare as previously thought. Knowledge of the pathogenic variants in patients is helping in research efforts to develop new therapies. Here we present a review of current knowledge in GNE myopathy, a rare neuromuscular disorder caused by mutations in the GNE gene that catalyzes the biosynthesis of sialic acid. The most common initial symptom is foot drop caused by anterior tibialis muscle weakness. There is a progressive wasting of distal skeletal muscles in the lower and upper extremities as well. The quadriceps is relatively spared, which is a distinguishing feature of this disease. The characteristic histological features include autophagic rimmed vacuoles with inclusion bodies. GNE variant analysis of Indian patients has revealed a founder mutation (p.Val727Met) common within the normal Indian populations, especially in the state of Gujurat. We discuss therapeutic options, including metabolite supplementation, pharmacological chaperones, and gene therapy. Initiatives that bring together patients, researchers, and physicians are necessary to improve knowledge and treatment for these rare disorders.


Keywords: GNE myopathy, inherited neuromuscular disorders, rare diseases, gene therapy, genetic disorders
Key Message: GNE myopathy is a rare neuromuscular disorder which poses enigmatic questions pertaining to its etiology and effective treatment for patients. To address these issues it is critical to raise awareness for better diagnosis, research, patient care and treatment.


How to cite this article:
Awasthi K, Arya R, Bhattacharya A, Bhattacharya S. The Inherited Neuromuscular Disorder GNE Myopathy: Research to Patient Care. Neurol India 2019;67:1213-9

How to cite this URL:
Awasthi K, Arya R, Bhattacharya A, Bhattacharya S. The Inherited Neuromuscular Disorder GNE Myopathy: Research to Patient Care. Neurol India [serial online] 2019 [cited 2019 Dec 8];67:1213-9. Available from: http://www.neurologyindia.com/text.asp?2019/67/5/1213/271259




Inherited neuromuscular diseases are a heterogeneous group of rare diseases that affect a large number of people from early childhood to late adulthood. Unfortunately, our understanding of the pathophysiology of these diseases is limited, and the mechanistic basis of genotype to phenotype relations has not yet been worked out. Moreover, diagnosis of these diseases has been a problem with patients either spending decades before being correctly diagnosed or remaining undiagnosed. Recent advances in DNA sequencing technologies have revolutionized the diagnosis of genetic disorders with the result that many more patients are being identified. In addition, knowledge of pathogenic genetic variants is helping in the development of newer therapies for these diseases. It is therefore necessary to raise awareness about these rare diseases among all stakeholders so that benefits of these recent developments reach everyone.

GNE myopathy (GNEM) is one of many rare genetic disorders with a neuromuscular defect. Though the overall number is low, patients with GNEM are found all over the world. International efforts to understand the molecular basis of GNEM and develop treatment options for patients have been limited to a few laboratories. Within India, this effort has been miniscule. With a view to increase awareness about GNEM among all stakeholders to initiate research and clinical efforts translatable to patient care, a conference entitled “Perspectives in GNE myopathy: Research, Clinical Management And Patient Care” (February 16–17, 2018) was held at the Indian National Science Academy, New Delhi. Most of the leading GNEM research and clinical groups from around the world including India participated, and provided valuable insights into this rare disease. Here we present a review of GNEM, with inputs from the conference presentations, and discuss the challenges and possibilities for working toward a cure. Some of the issues raised are pertinent to other rare genetic disorders as well.


 » Overview of Gne Myopathy Top


The basic understanding of the disease and different milestones of progression in our knowledge was described by Dr. Zohar Argov (Hadassah Medical School, Israel). GNEM is an adult-onset disease that typically presents with foot drop. There is progressive distal skeletal muscle wasting leading to loss of ambulation. The distinguishing feature of GNEM is the relative sparing of quadriceps. Pathology of the affected muscles shows the presence of rimmed vacuoles, a diagnostic feature of this disease. During the past few decades, a number of different nomenclatures have been used to define this disease, namely, Nonaka's myopathy, distal myopathy with rimmed vacuoles, and hereditary inclusion body myopathy. Dr. Argov and Dr. Stella Mitrani-Rosenbaum originally linked GNEM to the GNE gene, which resulted in universal agreement of GNEM as the preferred nomenclature for the disease.[1],[2] GNEM is an autosomal recessive disorder caused by biallelic mutations in the GNE gene, located on the short arm of ninth chromosome, locus 9p13.3 [Figure 1]. The GNE gene encodes the bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine-kinase (GNE/MNK) that catalyzes the rate-limiting step of the 5-N-acetylneuraminic acid (sialic acid) biosynthetic pathway.[2],[3] Sialic acid (SA) is a modified sugar moiety that gets incorporated into a large variety of glycoproteins and glycolipids. It also mediates mediates important biological processes such as cell adhesion, migration, and signaling.[4] The consensus size of the GNE gene is 62538 bp (NG_008246.1), mRNA 5220 nucleotides (NM_001128227.3), and the corresponding protien sequence is 753 amino acids (NP_001121699.1) for the longest isoform.[5]
Figure 1: Missense mutations are spread across the GNE gene. Highlighted in red are the two most prevalent mutations in India

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 » Mutation Spectrum in Gne Myopathy Top


More than 160 GNE mutations in various sections of the gene have been recorded in patients with GNEM worldwide.[2],[6],[7],[8] Based on allele frequencies, the worldwide prevalence of GNEM is estimated to be ~4–21 people per million.[5] The mutations occur in both homozygous and compound heterozygous combinations. The latter are more commonly seen. Most mutations are missense [Figure 2]. Patients with biallelic null mutations have never been found, suggesting an essential role of GNE. Some founder mutations have been reported in specific populations, such as p. Met743Thr in Persian Jews,[2] p. Asp207Val in the Japanese,[3] p. Ile618Thr in Roma Gypsies,[8] and p. Val727Met in populations of the Indian subcontinent.[7] In Persian Jews, the common variant (p. Met743Thr) is found in the homozygous condition, and the prevalence of GNEM is estimated to be 1:1500.[2],[9] Dr. I. Nishino (National Institute of Psychiatry and Neuroscience, Japan) reported that the most common Japanese variant is p. Val603Leu, present as homozygous in 62% of patients. Another common variant, p. Asp207Val, is mostly found as compound heterozygous. In the homozygous condition, it is probably asymptomatic. The frequency of these alleles in the general Japanese population is 0.1% (p. Val603Leu) and 0.16% (p. Asp207Val). Dr. A. Nalini (NIMHANS, Bengaluru) described the GNEM variants in India, which they started observing in 2006.[10] So far, they have seen 82 genetically confirmed patients from different parts of the country. Thirty-five variants have been recorded in patients with GNEM in India, of which the most common is p. Val727Met, found in 71% of patients as compound heterozygous. This variant is found at high frequency in the normal pan-Indian population (1%–2%) and very high (14%) in the normal Gujarati population.[11] It is restricted to Indian subcontinent (and Thailand) and is not present in other populations. Dr. R.K. Singh (Bombay Hospital, Mumbai) described data with 58 genetically confirmed GNEM patients. They found p. Val727Met as the most common variant. They also reported the frequent occurrence of the p. Ile618Thr variant in Rajasthani patients, which may be linked to their historical connection with Roma gypsies.[12] The p. Val727Met variant could be used for routine testing of Indian patients with unexplained adult-onset neurological symptoms of the upper and lower extremities.
Figure 2: Missense mutations are spread across the GNE gene. Highlighted in red are the two most prevalent mutations in India

Click here to view



 » Clinical Aspects Top


Initial symptoms of the disease usually appear in the second or third decade, although Dr. Nalini has reported the onset of symptoms in a 12-year-old patient. Exceptional cases reported were 78-year-old (Israeli) and 61-year-old (Japanese) patients, both carrying homozygous mutations, who were asymptomatic. Severity and age of onset vary, even among siblings.[13],[14],[15],[16] These observations point toward incomplete penetrance and phenotype–genotype complexity.

The most common initial symptom is foot drop caused by anterior tibialis muscle weakness. There is progressive wasting of distal skeletal muscles in the lower and later upper extremities. Proximal muscles are also gradually involved, and there is marked disability within 10–20 years of initial symptoms, including wheelchair dependence. In a few cases, a faster progression has also been seen. Compared with Israeli patients, loss of ambulation is earlier in Japan and India.

The quadriceps is relatively spared which aids in walking even at late stages [Figure 3]a. Other muscles such as cardiac and respiratory muscles are rarely involved.[14],[17] The characteristic histological feature of GNEM includes autophagic rimmed vacuoles [Figure 3]b with inclusion bodies containing β-amyloid protein, α-synuclein, tau protein, and TDP-43.
Figure 3: (a and b) Muscle pathology in GNE myopathy. a) Quadriceps sparing in GNE Myopathy b) Rimmed vacuoles in GNE Myopathy (Courtesy Dr. I. Nishino)

Click here to view



 » Diagnosis Top


The correct diagnosis of GNEM depends on the typical pathological and clinical characteristics including distal muscle weakness of lower limbs (foot drop) and the sparing of the quadriceps. In GNEM, initially weakness of the anterior tibialis muscle is first present. The weakness spreads and in several years will involve the thigh and hand though the quadriceps are relatively spared. Quadriceps are relatively spared. Shoulder girdle muscles are weak, with relative sparing of the triceps. Neck flexors are commonly involved. Differential diagnosis is based on muscle biopsies and genetic evaluation. Tibialis anterior or biceps brachii muscles are normally chosen for for biopsy. They are stained with hematoxylin, eosin and modified Gomori Trichrome stains for histological evaluation including the detection of rimmed vacuoles, aggregation of proteins, and fiber size variation.[18],[19],[20] Genetic evaluation is playing an increasingly important role in diagnosis, as muscle biopsy is not always informative. Nerve conduction is normal. Magnetic resonance imaging can be used to show the sparing of quadriceps. Sometimes variants such as distal arm weakness, hamstring weakness and a lack of foot drop may present. Diagnosis may be confused with other distal myopathies as well (limb girdle muscular dystrophy, spinal muscular atrophy, and Charcot–Marie–Tooth disease). Rimmed vacuoles are not seen in all patients. It needs technical expertise and proper selection of biopsy site. Specialized lectin or antibody staining of affected muscle shows decreased sialylation.[21],[22],[23],[24] Next, recent observations from Dr. Nalini suggest the involvement of abdominal muscles, such as Beevor's sign in GNEM.[25] This can be a useful diagnostic feature. Dr. Nalini also described an advanced gait analysis system that can diagnose and measure the progression of the disease. This system can be useful in determining the efficacy of a new therapy in a clinical trial.

The detection of mutations in GNE remains the final, unambiguous diagnostic step for GNEM patients. Many clinicians are relying on DNA sequencing without going through muscle biopsy as it is an invasive process which also requires a competent pathologist. Genetic testing was elaborated by Dr. A. Mannan, Strand Life Sciences (Bengaluru). He dicusssed the extensive sequencing done for a large variety of rare genetic disorders including GNEM. Dr. Ravi Gupta (MedGenome, Kochi) described their large-scale genome analysis project (Genome Asia) of 100,000 Asian individuals to understand their population history and ethnic heritage.

Dr. Madhuri Hegde (Perkin Elmer, USA) addressed the important issue of other confounding factors that may determine disease severity. Her approach is to use whole genome sequencing along with metabolomics to identify other variants that may influence disease outcome.


 » Disease Pathophysiology Top


The exact molecular mechanism of disease progression or weakness of muscle fibers in GNEM is still unclear. It is posited that reduction in GNE enzyme activity causes hyposialylation of glycoproteins/glycolipids leading to muscle dysfunction. However, alternate mechanisms such as reduced interaction of mutant GNE protein with cytoskeletal proteins (such as α-actinin), aberrant mitochondrial function, and stimulation of apoptosis have been suggested. A discussion of the data follows.

Is GNEM a disease of hyposialylation?

Dr. Nishino's group strongly believes impaired sialylation to be the main cause of diseasepathology.[26] They have demonstrated hyposialylation of patient's myotubes and arrest of symptoms by SA supplementation in a mouse model.[23] However, the Israel group believes that SA deficiency may not account for the GNEM pathology, as overall SA levels are only slightly reduced in many patients.[27] It is suggested that the pathology may be due to hyposialylation of specific muscle glycoproteins/glycolipids rather than general hyposialylation.[28],[29],[30],[31],[32] Dr. Mitrani-Rosenbaum's group looked for a sialylation defect of specific glycoconjugate(s) but did not see significant changes in the sugar chain spectrum of glycoproteins and glycolipids in patients. This leads to the question below.

Is GNE involved in yet unrecognized function(s)?

A proteomic comparison between muscle cell/biopsy from patients and healthy controls revealed differential expression of three proteins that are involved in ubiquitination, stress response, and mitochondrial processes.[33] The loss of GNE induced the transcriptional activation of apoptosis pathway and unfolded protein response in pancreatic carcinoma cells.[34] Four molecular chaperones were also found to be highly expressed in GNEM.[35] These observations suggest that the pathology of GNEM could be due to defects in signal transduction mechanisms related to unfolded protein response, apoptosis, and cell survival through mitochondrial pathways.

Dr. Mitrani-Rosenbaum's group searched for GNE partner proteins and showed that they could directly bind α-actinin1 and α-actinin2. The Met743Thr mutant GNE protein showed 8-fold less affinity for α-actinin2 than the wild type.[36] They concluded that GNE and α-actinin 2 could be part of a broader complex, which could provide clues to GNE functions.

Dr. Ranjana Arya (JNU, New Delhi) has been studying GNEM pathology using HEK cell line system in which the mutant GNE is either overexpressed or knocked down using shRNA. They observed hyposialylation of cell surface receptor such as β-1 integrin that affected cell adhesion in GNE-deficient cells. They also observed differential apoptotic responses and mitochondrial membrane depolarizations with GNE mutations that could not be restored completely with SA supplementation, indicating alternate roles for GNE. The ER-resident chaperone Peroxiredoxin4 was downregulated in cells carrying the GNE mutation that affected ER redox state showing the activation of stress pathways in GNE mutant cells.[37] Dr. Arya proposed that this model system could be used to screen various drug molecules.

A major outcome of GNEM is the formation of inclusion bodies with protein aggregates. Dr. Kaushik Chakraborty (CSIR-IGIB, New Delhi) reasoned that GNEM may not be an enzyme activity disease, but a protein misfolding disease since mutations are at variable locations on the gene and not at an active site. It may be possible to activate the mutant proteins using small-molecule chaperones. Potentially these could modify the properties of the mutant protein and prevent inclusion body formation. Thus, they hold promise for therapeutics in GNEM.


 » Therapeutic Aspects Top


Metabolite supplementation

If GNEM is primarily a disease of low SA levels, then it stands to reason that supplementation with SA or its precursor N-acetyl D-mannosamine (ManNAc) could be a promising approach for therapy. Dr. Nishino's group has a transgenic mouse model (Gne-/-hGNE D207V-Tg) that could recapitulate some of the features of human GNEM. Using this mouse model, they demonstrated an arrest of symptoms upon feeding with SA or ManNAc.[23] Partly based on this study, a human clinical trial was conducted by Ultragenyx Corporation (USA) to study the efficacy of SA supplementation, which did not give encouraging results in phase 3 and the trial was recently stopped. A similar trial is being done by the National Institutes of Health (Maryland, USA) for ManNAc supplementation. Currently phase 3 is being initiated.

Dr. Argov and Dr. Mitrani-Rosenbaum believe that metabolite supplementation is unlikely to work as they find only modest hyposialylation in their patients with GNEM. Recent “failure” of Ultragenyx SA trial seems to endorse this view. However, Dr. Nishino commented that the Ultragenyx trial probably failed for technical reasons, such as the fact that the criteria in phase 3 for determining efficacy of SA were changed. In any case, alternate strategies need to be developed as treatment options.

Gene therapy

A quantum leap in the area of molecular biology and gene delivery has revolutionized the approach of gene therapy, and it is now conceivable that this approach will rapidly mature into a functional therapeutic option, particularly for genetic disorders. Of various options, the technology allows one to introduce a wild-type gene into patients to correct the mutation in target cells or express the wild-type protein. Since this is a platform, it would (in theory), work for many monogenic disorders. It does not require a clear knowledge of the mechanism of pathophysiology, and thus would be a promising option for GNEM.

Dr. Mitrani-Rosenbaum (along with Dr. J. Mendell's group in Ohio, USA). has been trying to develop an AAV-mediated gene vector for systemic introduction of normal GNE. She presented some of the preliminary preclinical data. The AAV vector is a robust gene delivery system with excellent safety and efficacy profiles, and evidence of long-term expression of donated gene in patients with hemophilia.[38],[39] Dr. Mitrani-Rosenbaum's group has shown proof of concept in the mouse model. A clinical trial for this is being planned after getting approval from Food and Drug Administration (USA).

Dr. Arkashubra Ghosh (GROW Labs, Narayan Nethralaya, Bengaluru) has a lot of experience with AAV vectors and is in the process of setting up AAV production facility. He proposed practical steps to bring gene therapy to India. He talked about suitable muscle-tropic vector system, AAV9, its production, and dosage. He also stressed on creating a clinical awareness toward vector handling and forming regulatory guidelines in India.

Other options

Drugs to block or modify degeneration processes, such as arimoclomol and N-acetylcysteine have been suggested.[40] This is based on the finding that S-nitrosylation may be the main biochemical trigger for the pathological damage in GNEM. Other approaches suggested by Dr. Kaushik Chakraborty include drugs that stimulate autophagy, pharmacological chaperones, and allosteric activators that could help correctly fold or enhance the activity of mutant GNE.

Dr. Sujata Mohanty (AIIMS, New Delhi) also described the possibilities of developing stem-cell-based therapies for GNEM, as it has been successfully tested in the mouse model of Duchenne muscular dystrophy and in many other genetic disorders. Aging muscle satellite cells undergo an irreversible transition from quiescence to senescence leading to impaired muscle fiber regeneration. The introduction of stem cells could aid in the regenerative process. Dr. Sujata's group have set up a sophisticated stem cell facility for creation, storage, and use of induced pluripotent stem cells that have an immense potential for providing stem cells for therapy. [Figure 4] shows a schematic of various therapeutic options.
Figure 4: Possible therapeutic approaches

Click here to view



 » Disease Management Top


Dr. T. Umapathi (National Institute of Neuroscience, Singapore) gave a motivational talk about overcoming the psychological burden of disability to improve one's quality of life. Dr. Harpreet Singh (AIIMS, New Delhi) advised general aerobic exercise, walking, static pedaling, and aquatic exercises as good options for patients with GNEM. He emphasized the need for early referral of patients before too much muscle damage occurs and expressed the need for specialty centers for patients with myopathies. The benefit of yoga and meditation in managing the disease condition was demonstrated through a live session by Dr. Vishnupriya (Yoga instructor). Dr. Bhavana Prasher (CSIR-IGIB, New Delhi) and Dr. Ramniwas Prasher highlighted the role of Ayurveda in nullifying some negative effect of the mutations.


 » Future Perspectives Top


Research in GNEM has raised important unanswered questions. There is no adequate explanation for late onset of disease. Is it due to the accumulation of inhibitory metabolites or depletion of essential ones due to age? What determines the variable degree of disease severity in patients and even among siblings? In looking to the future, whole genome screening for modifiers could help explain the difference in phenotypes among patients. Furthermore, the absence of a consistent animal model that mimics human disease is hindering studies on pathogenesis of GNEM, drug testing, and in gene therapy development. The conference highlighted the important aspects of GNEM in the Indian context. Misdiagnosis of GNEM seems to be high in India since neurologists lack familiarity with the disease. This is also the case with many other inherited neuromuscular disorders. More initiatives that bring together patients, researchers, and physicians will help get a necessary spotlight on these rare disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Huizing M, Carrillo-Carrasco N, Malicdan MC, Noguchi S, Gahl WA, Mitrani-Rosenbaum, S, et al. GNE myopathy: New name and new mutation nomenclature. Neuromuscul Disord 2014;24:387-9.  Back to cited text no. 1
    
2.
Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, et al. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 2001;29:83-7.  Back to cited text no. 2
    
3.
Nishino I, Noguchi S, Murayama K, Driss A, Sugie K, Oya Y, et al. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 2002;59:1689-93.  Back to cited text no. 3
    
4.
Schauer R. Sialic acids as regulators of molecular and cellular interactions. Curr Opin Struct Biol 2009;19:507-14.  Back to cited text no. 4
    
5.
Celeste FV, Vilboux T, Ciccone C, de Dios JK, Malicdan MC, Leoyklang P, et al. Mutation update for GNE gene variants associated with GNE myopathy. Hum Mutat 2014;35:915-26.  Back to cited text no. 5
    
6.
Saechao C, Valles-Ayoub Y, Esfandiarifard S, Haghighatgoo A, No D, Shook S, et al. Novel GNE mutations in hereditary inclusion body myopathy patients of non-Middle Eastern descent. Genet Test Mol Biomarkers 2010;14:157-62.  Back to cited text no. 6
    
7.
Nalini A, Gayathri N, Nishino I, Hayashi YK. GNE myopathy in India. Neurol India 2013;61:371-4.  Back to cited text no. 7
[PUBMED]  [Full text]  
8.
Kalaydjieva L, Lochmuller H, Tournev I, Baas F, Beres J, Colomer J, et al. 125th ENMC International Workshop: Neuromuscular disorders in the Roma (Gypsy) population, 23-25 April 2004, Naarden, The Netherlands. Neuromuscular Disord 2005;15:65-71.  Back to cited text no. 8
    
9.
Argov Z, Eisenberg I, Mitrani-Rosenbaum S. Genetics of inclusion body myopathies. Curr Opin Rheumatol 1998;10:543-7.  Back to cited text no. 9
    
10.
Nalini A, Gayathri N, Dawn R. Distal myopathy with rimmed vacuoles: Report on clinical characteristics in 23 cases. Neurol India 2010;58:235-41.  Back to cited text no. 10
[PUBMED]  [Full text]  
11.
Bhattacharya S, Khadilkar SV, Nalini A, Ganapathy A, Mannan AU, Majumder PP, et al. Mutation spectrum of GNE myopathy in the Indian sub-continent. J Neuromuscul Dis 2018;5:85-92.  Back to cited text no. 11
    
12.
Khadilkar SV, Nallamilli BR, Bhutada A, Hegde M, Gandhi K, Faldu HD, et al. A report on GNE myopathy: Individuals of Rajasthan ancestry share the Roma gene. J Neurol Sci 2017;375:239-40.  Back to cited text no. 12
    
13.
Boyden SE, Duncan AR, Estrella EA, Lidov HG, Mahoney LJ, Katz JS, et al. Molecular diagnosis of hereditary inclusion body myopathy by linkage analysis and identification of a novel splice site mutation in GNE. BMC Med Genet 2011;12:87.  Back to cited text no. 13
    
14.
Mori-Yoshimura M, Monma K, Suzuki N, Kumamoto T, Tanaka K, Tomimitsu H, et al. Heterozygous UDP-GlcNAc 2-epimerase and N-acetylmannosamine kinase domain mutations in the GNE gene result in a less severe GNE myopathy phenotype compared to homozygous N-acetylmannosamine kinase domain mutations. J Neurol Sci 2012;318:100-5.  Back to cited text no. 14
    
15.
Cho A, Hayashi YK, Monma K, Oya Y, Noguchi S, Nonaka I, et al. Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy). J Neurol Neurosurg Psychiatry 2014;85:914-7.  Back to cited text no. 15
    
16.
Huizing M, Malicdan MC, Krasnewich D, Manoli I, Carrillo-Carrasco N. GNE myopathy. In: Scriver CR, Childs B, Sly WS, Valle D, Beaudet AL, Vogelstein B, et al., editors. Scriver's Online Metabolic and Molecular Bases of Inherited Disease. Chapter 216.1 New York: McGraw-Hill; 2014a.  Back to cited text no. 16
    
17.
Mori-Yoshimura M, Oya Y, Yajima H, Yonemoto N, Kobayashi Y, Hayashi YK, et al. GNE myopathy: A prospective natural history study of disease progression. Neuromuscul Disord 2014;24:380-86.  Back to cited text no. 17
    
18.
Yunis EJ, Samaha FJ. Inclusion body myositis. Lab Invest 1971;25:240-8.  Back to cited text no. 18
    
19.
Nonaka I, Sunohara N, Ishiura S, Satoyoshi E. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 1981;51:141-55.  Back to cited text no. 19
    
20.
Griggs RC, Askanas V, DiMauro S, Engel A, Karpati G, Mendell JR, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705-13.  Back to cited text no. 20
    
21.
Noguchi S, Keira Y, Murayama K, Ogawa M, Fujita M, Kawahara G, et al. Reduction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase activity and sialylation in distal myopathy with rimmed vacuoles. J Biol Chem 2004;279:11402-7.  Back to cited text no. 21
    
22.
Tajima Y, Uyama E, Go S, Sato C, Tao N, Kotani M, et al. Distal myopathy with rimmed vacuoles: Impaired O-glycan formation in muscular glycoproteins. Am J Pathol 2005;166:1121-30.  Back to cited text no. 22
    
23.
Malicdan MC, Noguchi S, Hayashi YK, Nonaka I, Nishino I. Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV-hIBM mouse model. Nat Med 2009;15:690-5.  Back to cited text no. 23
    
24.
Nemunaitis G, Jay CM, Maples PB, Gahl WA, Huizing M, Yardeni T, et al. Hereditary inclusion body myopathy: Single patient response to intravenous dosing of GNE gene lipoplex. Hum Gene Ther 2011;22:1331-41.  Back to cited text no. 24
    
25.
Preethish-Kumar V, Pogoryelova O, Polavarapu K, Gayathri N, Seena V, Hudson J, et al. Beevor's sign: A potential clinical marker for GNE myopathy. Eur J Neurol 2016;23:e46-8.  Back to cited text no. 25
    
26.
Gagiannis D, Orthmann A, Danssmann I, Schwarzkopf M, Weidemann W, Horstkorte R. Reduced sialylation status in UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE)-deficient mice. Glycoconj J 2007;24:125-30.  Back to cited text no. 26
    
27.
Salama I, Hinderlich S, Shlomai Z, Eisenberg I, Krause S, Yarema K, et al. No overall hyposialylation in hereditary inclusion body myopathy myoblasts carrying the homozygous M712T GNE mutation. Biochem Biophys Res Commun 2005;328:221-6.  Back to cited text no. 27
    
28.
Huizing M, Rakocevic G, Sparks SE, Mamali I, Shatunov A, Goldfarb L, et al. Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations. Mol Genet Metab 2004;81:196-202.  Back to cited text no. 28
    
29.
Tajima Y, Uyama E, Go S, Sato C, Tao N, Kotani M, et al. Distal myopathy with rimmed vacuoles: Impaired O-glycan formation in muscular glycoproteins. Am J Pathol 2005;166:1121-30.  Back to cited text no. 29
    
30.
Ricci E, Broccolini A, Gidaro T, Morosetti R, Gliubizzi C, Frusciante R, et al. NCAM is hyposialylated in hereditary inclusion body myopathy due to GNE mutations. Neurology 2006;66:755-8.  Back to cited text no. 30
    
31.
Broccolini A, Gidaro T, De Cristofaro R, Morosetti R, Gliubizzi C, Ricci E, et al. Hyposialylation of neprilysin possibly affects its expression and enzymatic activity in hereditary inclusion-body myopathy muscle. J Neurochem 2008;105:971-81.  Back to cited text no. 31
    
32.
Patzel KA, Yardeni T, Le Poec-Celic E, Leoyklang P, Dorward H, Alonzi DS, et al. Non-specific accumulation of glycosphingolipids in GNE myopathy. J Inherit Metab Dis 2014;37:297-308.  Back to cited text no. 32
    
33.
Sela I, Milman Krentsis I, Shlomai Z, Sadeh M, Dabby R, Argov Z, et al. The proteomic profile of hereditary inclusion body myopathy. PLoS One 2011;6:e16334.  Back to cited text no. 33
    
34.
Kemmner W, Kessel P, Sanchez-Ruderisch H, Möller H, Hinderlich S, Schlag PM, et al. Loss of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) induces apoptotic processes in pancreatic carcinoma cells. FASEB J 2012;26:938-46.  Back to cited text no. 34
    
35.
Li H, Chen Q, Liu F., Zhang X, Li W, Liu S, et al. Unfolded protein response and activated degradative pathways regulation in GNE myopathy. PLoS One 2013;8:e58116.  Back to cited text no. 35
    
36.
Harazi A, Becker-Cohen M, Zer H, Moshel O, Hinderlich S, Mitrani-Rosenbaum S. The interaction of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) and alpha-actinin 2 is altered in GNE myopathy M743T mutant. Mol Neurobiol 2017;54:2928-38.  Back to cited text no. 36
    
37.
Chanana P, Padhy G, Bhargava K, Arya R. Mutation in GNE downregulates peroxiredoxin IV altering ER redox homeostasis. Neuromolecular Med 2017;19:525-40.  Back to cited text no. 37
    
38.
Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011;365:2357-65.  Back to cited text no. 38
    
39.
Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med 2014;371:1994-2004.  Back to cited text no. 39
    
40.
Cho A, Christine M, Malicdan V, Miyakawa M, Nonaka I, Nishino I, et al. Sialic acid deficiency is associated with oxidative stress leading to muscle atrophy and weakness in GNE myopathy. Hum Mol Genet 2017;26:3081-93.  Back to cited text no. 40
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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