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GNE Myopathy

Synonyms: Distal Myopathy with Rimmed Vacuoles (DMRV), Hereditary Inclusion Body Myopathy (HIBM), Inclusion Body Myopathy Type 2 (IBM2), Nonaka Myopathy, Quadriceps-Sparing Myopathy

, MD, , MD, PhD, and , PhD.

Author Information

Initial Posting: ; Last Update: April 9, 2020.

Estimated reading time: 21 minutes

Summary

Clinical characteristics.

GNE myopathy is a slowly progressive muscle disease that typically presents between age 20 and 40 years with bilateral foot drop caused by anterior tibialis weakness. Lower-extremity muscle involvement progresses from the anterior to the posterior compartment of the lower leg, followed by hamstrings, then hip girdle muscles, with relative sparing of the quadriceps. A wheelchair may be needed about ten to 20 years after the onset of manifestations. The upper extremities, which may be affected within five to ten years of disease onset, do not necessarily follow a distal-to-proximal progression. In advanced stages, neck and core muscles can become affected.

Diagnosis/testing.

The diagnosis of GNE myopathy is suspected in a proband with suggestive clinical findings and muscle histopathology (rimmed vacuoles, no inflammation) and is established by the presence of biallelic pathogenic variants in GNE identified by molecular genetic testing.

Management.

Treatment of manifestations: Evaluation and management are often by a multidisciplinary team that includes neuromuscular specialists, physiatrists, and physical and occupational therapists to address issues secondary to muscle weakness, including the use of assistive ambulatory devices (e.g., ankle-foot orthoses, cane, walker, wheelchair, or powerchair). Adaptive devices to support fine motor function and activities of daily living are needed in advanced stages of the disease. Recommended evaluations also include baseline echocardiogram and pulmonary function tests in nonambulatory individuals, with management by pulmonologists as clinically indicated.

Surveillance: Follow up at least annually by neuromuscular specialists, physiatrists, and physical and occupational therapists to evaluate disease progression and address muscle strength, mobility, function, and activities of daily living; by pulmonologists to monitor respiratory muscle function in patients with advanced disease.

Agents/circumstances to avoid: Cautious use of medications/drugs with potential myotoxicity (e.g., colchicine and statins); avoidance of weight-lifting and repetitive activities that cause muscle pain.

Genetic counseling.

GNE myopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GNE pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. When the GNE pathogenic variants have been identified in an affected family member, molecular genetic carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

GNE myopathy should be suspected in individuals with the following findings.

Clinical findings

  • Myopathy presenting in young adults with bilateral foot drop caused by anterior tibialis weakness, followed by slowly progressive skeletal muscle weakness. Although there is relative sparing of the quadriceps, they may become affected at late stages of the disease. The clinical picture varies depending on the stage of disease progression at which individuals are evaluated (see Clinical Description).
  • Serum CK may be normal or up to four times the upper limit of normal.

Muscle histopathology

  • Cryosections of affected muscles show atrophy, variation of fiber size, rimmed vacuoles, and no inflammation. The most prominent finding, the presence of rimmed vacuoles, is best identified in cryosections using modified Gomori trichrome stain and may be missed in paraffin-embedded tissue or hematoxylin and eosin staining. The "rimmed vacuoles" observed on electron microscopy that correspond to autophagic vacuoles are seen in a variety of myopathies with other etiologies that lead to autophagic degeneration (see Differential Diagnosis).
  • Note: (1) Because histopathologic findings may be difficult to identify in biopsies of muscles that are unaffected or that have been replaced by fibro-fatty tissue, muscle strength or muscle MRI may aid in the identification of suitable muscles to biopsy. (2) Muscle biopsy and histopathologic examination may not be required to suspect or establish the diagnosis of GNE myopathy but remain necessary when variants of unknown significance are identified on molecular genetic testing.

Establishing the Diagnosis

The diagnosis of GNE myopathy is established in a proband with suggestive clinical findings, muscle histopathology (if performed), and biallelic pathogenic variants in GNE identified by molecular genetic testing (see Table 1).

Note: Identification of biallelic GNE variants of uncertain significance (or identification of one known GNE pathogenic variant and one GNE variant of uncertain significance) does not establish or rule out a diagnosis of GNE myopathy.

Molecular genetic testing approaches can include gene-targeted testing (single-gene testing in probands with suggestive findings or affected sibs; multigene neuromuscular panel in probands with myopathy but unspecific findings) (see Option 1). In some instances, comprehensive genomic testing (exome sequencing or genome sequencing) is performed (see Option 2).

Option 1

Single-gene testing. Sequence analysis of GNE is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

Note: Targeted analysis for founder pathogenic variants identified in several populations may be appropriate in some circumstances (for more details see Table 6).

A multigene panel that includes GNE and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in GNE Myopathy

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
GNESequence analysis 3>99% 4
Gene-targeted deletion/duplication analysis 5<1% 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Clinical Characteristics

Clinical Description

GNE myopathy is characterized by adult-onset slowly progressive myopathy typically presenting with bilateral foot drop, followed by distal-to-proximal lower-extremity weakness. The upper extremities, which are affected within five to ten years of disease onset, do not necessarily follow a distal-to-proximal progression, in contrast to the lower extremities. In advanced stages, neck and core muscles can also become affected.

Onset. GNE myopathy typically presents in individuals age 20-40 years with foot drop caused by anterior tibialis weakness. Rarely, in case of muscle overuse, other muscles may be affected first [de Dios et al 2014].

Progression. In the lower extremities, the disease progresses to involve muscles from the anterior compartment of the lower leg, followed by calf muscles and hamstrings, followed by hip girdle muscles, with relative sparing of the quadriceps [Argov & Yarom 1984]. The involvement of the quadriceps muscles may become evident in late stages of the disease with the rectus femoris affected first and the vastus lateralis affected last [Huizing et al 2001, Tasca et al 2012, Carrillo et al 2018].

In the upper extremities, shoulder abduction may be affected early in the disease course before grip and hand muscles are affected.

Clinical findings depend on the stage of disease progression at the time of evaluation [Quintana et al 2019]:

  • Disease onset. Young adults describe symptoms such as tripping and changes in gait. On exam, there is bilateral foot drop and inability to stand on the toes or walk on the heels.
  • Within five years of onset. Complete loss of ankle dorsiflexion strength, decreased knee flexion and shoulder abduction strength. Manifestations include steppage gait, some difficulty climbing stairs, and decreased balance, requiring the use of ankle-foot orthoses (AFOs).
  • Five to ten years after onset. Complete loss of knee flexion strength; decreased shoulder abduction, forearm, wrist, and hand strength; quadriceps are unaffected. Manifestations include worsening gait, increased risk of falls, and poor balance requiring the use of assistive walking devices; difficulty moving from a sitting position to a standing position; and significant difficulty climbing stairs. Upper extremities: difficulty performing tasks that involve raising arms above head and initial difficulty with hand function.
  • Ten to 20 years after onset. Decreased strength of hip extensors; quadriceps may be affected; the use of a wheelchair may be needed; significant difficulty with shoulder abduction and fine motor (i.e., hand) tasks. Increasing dependence for assistance with activities of daily living.
  • In advanced stages. The neck, core, and respiratory muscles can be affected.

Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers. Life span is not reduced.

Other

  • Respiratory muscle involvement resulting in decreased forced vital capacity has been described in the late stages of the disease; however, clinically significant involvement is rare and typically limited to individuals who are wheelchair dependent [Mori-Yoshimura et al 2013].
  • Cardiac muscle is typically not affected. While cardiac involvement has been reported in persons with GNE myopathy [Chai et al 2011, Chamova et al 2015], it remains unclear whether this was due to GNE myopathy or of a different etiology.

Laboratory findings

  • Serum creatine kinase (CK) activity may be normal or elevated; it typically does not exceed four times the normal value.
  • Creatinine values decrease over time due to decreased muscle mass; hence, cystatin C should be used instead of creatinine to evaluate renal function.
  • Mild elevation of alanine aminotransferase and aspartate aminotransferase is seen in some individuals, especially those with elevated CK.

Electromyogram and nerve conduction velocity are invasive and do not help with the diagnosis.

Muscle MRI shows fibro-fatty replacement on T1-weighted images; short tau inversion recovery hyperintensity indicates active disease.

Genotype-Phenotype Correlations

Because reports of GNE myopathy consist mainly of single individuals or relatively small series, correlations between genotype and phenotype are difficult.

Penetrance

Penetrance of biallelic GNE pathogenic variants is likely close to 100%. Only two older individuals with biallelic GNE pathogenic variants have been reported to be asymptomatic: One (age 67 years) was homozygous for the common Middle Eastern variant p.Met743Thr [Argov et al 2003] and one (age 60 years) was homozygous for the common Japanese variant p.Asp207Val [Nishino et al 2002].

Nomenclature

In order to unify the nomenclature and avoid confusion with unrelated but similarly named disorders, an international consortium proposed the term "GNE myopathy" to replace historically used terms [Huizing et al 2014].

With the identification of the causative gene, GNE [Eisenberg et al 2001], it became apparent that HIBM was the same disease as DMRV [Nishino et al 2002].

Prevalence

The prevalence of GNE myopathy is estimated at 1-9:1,000,000.

To date, more than 1,000 individuals with GNE myopathy and about 255 GNE variants have been reported worldwide.

The worldwide carrier rate of a pathogenic GNE variant is estimated at 1:203 individuals.

Differential Diagnosis

The differential diagnosis includes adult-onset distal myopathies and myopathies with rimmed vacuoles (see Table 2).

Table 2.

Genes of Interest in the Differential Diagnosis of GNE Myopathy

GeneDisorderMOIAge at Onset (Years)Initial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle Biopsy
ANO5Miyoshi muscular dystrophy 3 (see ANO5 Muscle Disease)AR20-25Posterior lower legs; asymmetry>10x ULNMyopathic changes & (rarely) necrotic fibers
DNAJB6LGMD1D 1 (OMIM 603511)AD18-50Lower leg posterior > anterior; ± dysphagiaNormal to 8x ULNMyofibrillar myopathy 2 & rimmed vacuoles
DYSFMiyoshi distal myopathy (see Dysferlinopathy)AR15-30Posterior lower leg>10x ULNMyopathic changes
LDB3 (ZASP)Zaspopathy 3 (myofibrillar myopathy 4) (OMIM 609452)AD40-70Lower legNormal to 6x ULNMyofibrillar myopathy 2 ± rimmed vacuoles
MATR3Amyotrophic lateral sclerosis 21 4 (OMIM 606070)AD35-60Asymmetric lower leg ± hands; dysphagia; dysphoniaNormal to 8x ULNMyopathic changes & rimmed vacuoles
MYH7Laing distal myopathy 5AD0-50Anterior lower legNormal to 4x ULNType 1 fiber atrophy
MYOTMyotilinopathy 6 (myofibrillar myopathy 3) (OMIM 609200)AD40-70Lower leg post > antNormal to 2x ULNMyofibrillar myopathy 2 ± rimmed vacuoles
TIA1Welander distal myopathy 7 (OMIM 604454)AD40-60Finger extensorsNormal or slightly ↑Myopathic changes & rimmed vacuoles
TTN (exon 364)Udd distal myopathy – tibial muscular dystrophy 8AD>35Anterior lower legNormal or slightly ↑Myopathic changes ± rimmed vacuoles
TTNLimb-girdle muscular dystrophy, autosomal recessive, 10 8 (LGMDR10) (OMIM 608807)AR14-44Anterior lower legNormal to 8x ULNMyopathic changes ± rimmed vacuoles
VCPInclusion body myopathy, Paget disease & frontotemporal dementia 9; (IBMPFD)AD>35Hip girdleNormal to 5x ULNMyopathic changes & rimmed vacuoles

Modified from Udd & Griggs [2001]

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; ULN = upper limit of normal; XL = X-linked

1.
2.

Histopathologic characteristics of myofibrillar myopathies include variation in fiber size, amorphous granular or hyaline deposits on trichrome-stained sections, and decrease of oxidative enzyme activities leading to abnormal fibers.

3.
4.
5.
6.
7.
8.
9.

Management

Individuals with GNE myopathy are often evaluated and managed by a multidisciplinary team that includes clinical geneticists, neuromuscular specialists, physiatrists, physical and occupational therapists, and if needed, pulmonologists.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GNE myopathy, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with GNE Myopathy

System/ConcernEvaluationComment
MusculoskeletalNeuromuscular, physical medicine & rehabilitation/PT/OT evaluationTo determine extent of disease as determined by:
  • Muscle strength
  • Balance
  • Function
  • Fine motor skills
  • Impact on activities of daily living
  • Need for ongoing PT/OT
  • Need for AFOs, & assistive ambulatory devices
  • Need for adaptive devices
  • Need for handicapped parking
RespiratoryRespiratory function tests incl supine & sitting spirometry, MIP, MEPTo evaluate for effects of muscle weakness on respiratory function esp in nonambulatory individuals
CardiacBaseline echocardiogramTo evaluate for evidence of cardiac involvement
Genetic
counseling
By genetics professional 1To review results of genetic testing & to inform patients & families about the nature, MOI, & implications of GNE myopathy to facilitate medical & personal decision making
Family support/
Resources
Assess:
  • Use of community or online resources, including patient advocacy organizations
  • Need for social work involvement for caregiver support

AFOs = ankle-foot orthoses; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

There is no approved therapy for GNE myopathy. Treatment is symptomatic only (see Table 4).

Table 4.

Treatment of Manifestations in Individuals with GNE Myopathy

Manifestation/
Concern
TreatmentConsiderations/Other
MusculoskeletalPT, rehabilitation medicineAmbulatory assistive devices, balanced physical activity, 1 regular exercise as tolerated.
Activities of
daily living
PT
  • Transfers (e.g., from bed to wheelchair, wheelchair to car)
  • Medical alert system for those unable to stand after a fall
OT
  • Techniques & devices to accomplish tasks incl mobility, washing, dressing, eating, cooking, grooming
  • To assist w/household modifications to meet special needs
RespiratoryRespiratory functionA concern mostly in nonambulatory affected individuals

OT = occupational therapy; PT = physical therapy

1.

All affected individuals should consult their physician before beginning an exercise program.

Surveillance

Routine follow up with the multidisciplinary team is recommended annually, or more frequently as determined by managing physician (see Table 5).

Table 5.

Recommended Multidisciplinary Team Surveillance for Individuals with GNE Myopathy

System/ConcernEvaluationFrequency
NeuromuscularEvaluate disease progression; coordinate care.
Rehabilitation
medicine
Evaluation & monitoring of:
  • Muscle strength testing using a quantitative scale, e.g., MMT, hand-held dynamometry, or QMA 1 to evaluate progressive muscle involvement
  • Physical function, e.g., 6-min walk test, AMAT 2
  • Activities of daily living
At least annually
Physical
therapy
Evaluation & management for balance & need for AFOs, cane, walker, wheelchair, & powerchairAt least annually, or more frequently based on needs
Occupational
therapy
Evaluation & management of fine motor skills & hand function, e.g., Jebsen Hand Function Test 3At least annually
RespiratoryPFTs incl supine & sitting spirometry, MIP & MEP on affected individuals at advanced stages of diseaseAs needed, if symptomatic or if abnormal PFTs
CardiacFollow up not needed unless symptomatic, or abnormal findings on initial evaluation

AFOs = ankle-foot orthoses; AMAT = Adult Myopathy Assessment Tool; MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure; MMT= manual muscle testing; PFTs = pulmonary function tests; QMA = Quantitative Muscle Assessment

1.
2.
3.

Agents/Circumstances to Avoid

It may be prudent to use medications/drugs with potential myotoxicity (e.g., colchicine, statins) with caution.

It is strongly recommended that affected individuals have a healthy diet and exercise to avoid developing hypercholesterolemia, in an effort to reduce the risk associated with taking statins.

Individuals with GNE myopathy should avoid lifting weights and performing repetitive activities that result in muscle pain.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

N-acetylmanossamine (ManNAc) is the only therapy currently in clinical development for GNE myopathy [Galeano et al 2007, Malicdan et al 2009, Niethamer et al 2012, Xu et al 2017].

Ultragenyx discontinued the clinical development of extended-release sialic acid (Ace-ER) in 2017 following a Phase III trial that failed to detect clinical efficacy [Lochmüller et al 2019].

Preclinical studies are ongoing to advance gene therapy as a potential therapy for GNE myopathy.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

GNE myopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for a GNE pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk for GNE myopathy.

Offspring of a proband. The offspring of an individual with GNE myopathy are obligate heterozygotes (carriers) for a pathogenic variant in GNE.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a GNE pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the GNE pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the GNE pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Advancement of Research for Myopathies (ARM)
    P.O. Box 261926
    Encino 91426-1926
    Phone: 800-ARM-2000
  • GNE Myopathy International
    Phone: 91-9810881439
    Email: gne.myopathy@gmail.com
  • Neuromuscular Disease Foundation (NDF)
    Phone: 310-721-1605; 516-441-7126
  • TREAT-NMD
    Neuromuscular Network
    Email: info@treat-nmd.eu
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.org
  • Patient Association for Distal Myopathies (PADM)
    Email: yuriko.oda@npopadm.com
  • Remudy - Registry of Muscular Dystrophies
    Japan

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

GNE Myopathy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for GNE Myopathy (View All in OMIM)

603824UDP-N-ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; GNE
605820NONAKA MYOPATHY; NM

Molecular Pathogenesis

GNE encodes UDP-N-acetylglucosamine (GlcNAc) 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE), a key enzyme in the intracellular biosynthesis of N-acetylneuraminic acid (Neu5Ac) [Keppler 1999] (see Figure 1). The downstream product, CMP-Neu5Ac, serves as a donor of Neu5Ac (a form of sialic acid) to glycoproteins in the Golgi which are then secreted or become plasma membrane proteins [Wopereis et al 2006, Cohen & Varki 2010].

Figure 1. . The biosynthesis of sialic acid (Neu5Ac) is an intracellular process with enzymes shown in yellow.

Figure 1.

The biosynthesis of sialic acid (Neu5Ac) is an intracellular process with enzymes shown in yellow. The initial steps of this pathway occur in the cytoplasm with the substrate, UDP-GlcNAc, which derives from glucose. In the rate-limiting step of the pathway, (more...)

Heterozygous pathogenic variants in the allosteric site of GNE cause sialuria, an entity distinct from GNE myopathy (see Genetically Related Disorders) (OMIM 269921).

Mechanism of disease causation. Most pathogenic variants that cause GNE myopathy are missense with several shown to result in decreased epimerase and kinase enzymatic activity [Effertz et al 1999, Nishino et al 2002, Noguchi et al 2004, Sparks et al 2005, Penner et al 2006, Kurochkina et al 2010, Celeste et al 2014, Carrillo et al 2018]. No individuals homozygous for nonsense variants have been reported [Celeste et al 2014, Carrillo et al 2018]. Residual GNE enzyme activity is essential for life; complete lack of enzyme activity as demonstrated by inactivation of Gne in mice is lethal in early embryonic stages [Schwarzkopf et al 2002].

The mechanism by which disruption of GNE enzyme function causes muscle atrophy in GNE myopathy remains unclear; however, evidence suggests that the mechanism involves decreased sialylation of muscle glycoproteins. Muscle biopsies from affected individuals reveal hyposialylation of muscle glycoproteins [Noguchi et al 2004, Tajima et al 2005, Gagiannis et al 2007, Leoyklang et al 2018] including specific skeletal muscle glycoproteins, such as alpha-dystroglycan [Huizing et al 2004], NCAM [Ricci et al 2006], and neprilysin [Broccolini et al 2008].

GNE-specific laboratory technical considerations. Well-established functional studies have reported GNE enzyme activity in cells (lymphoblasts, fibroblasts) of affected individuals [Nishino et al 2002, Noguchi et al 2004, Sparks et al 2005, Celeste et al 2014].

Table 6.

Notable GNE Pathogenic Variants

Reference
Sequences
DNA
Nucleotide
Change
Predicted
Protein
Change
Comment [Reference]
NM_001128227​.2
NP_001121699​.1
c.131G>Cp.Cys44SerPathogenic variant reported in Japanese, Chinese & Korean patients [Cho et al 2014, Zhao et al 2015, Chen et al 2019, Park et al 2019] (~50 reported cases as of Feb 2020)
c.620A>Tp.Asp207ValFounder pathogenic variant common in Japanese patients [Nishino et al 2002, Cho et al 2014, Zhu et al 2017] (~230 reported cases as of Feb 2020)
c.830G>Ap.Arg277GlnPathogenic variant worldwide [Eisenberg et al 2001, Broccolini et al 2004, Celeste et al 2014, Chaouch et al 2014, Cho et al 2014, Cerino et al 2015, Bhattacharya et al 2018, Chen et al 2019] (~30 reported cases as of Feb 2020)
c.1225G>Tp.Asp409TyrIdentified in persons originating from northern Europe, Ireland, & Northern Britain [Celeste et al 2014, Chaouch et al 2014, Cerino et al 2015] (~30 reported cases as of Feb 2020)
c.1664C>Tp.Ala555ValPathogenic variant worldwide [Celeste et al 2014, Cho et al 2014, Cerino et al 2015, Zhao et al 2015, Khadilkar et al 2017, Chen et al 2019, Park et al 2019] (~25 reported cases as of Feb 2020)
c.1807G>Cp.Val603LeuFounder variant that accounts for frequent disease alleles in Japanese population [Arai et al 2002, Nishino et al 2002, Cho et al 2014, Zhu et al 2017] (~300 reported cases as of Feb 2020)
c.1853T>Cp.Ile618ThrFounder variant in Roma Gypsy & Indian (Rajasthan) populations [Chamova et al 2015, Khadilkar et al 2017] (~70 reported case as of Feb 2020)
c.1985C>Tp.Ala662ValPathogenic variant worldwide [Celeste et al 2014, Chaouch et al 2014, Cho et al 2014, Cerino et al 2015] (~50 reported cases as of Feb 2020)
c.2179G>Ap.Val727MetFounder variant in Indian population [Eisenberg et al 2001, Bhattacharya et al 2018] (~80 reported cases as of Feb 2020)
c.2228T>Cp.Met743ThrFounder variant in Middle Eastern population [Eisenberg et al 2001, Argov et al [2003] (~200 reported cases as of Feb 2020)

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

References

Literature Cited

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Chapter Notes

Author Notes

George Karpati, MD, one of the original authors of this GeneReview, was a distinguished physician and scientist. A Hungarian-born Holocaust survivor, he became a leading expert in muscular dystrophy and other neuromuscular disorders; he held the IW Killam Chair and was Professor of Neurology and Neurosurgery at McGill University. Dr Karpati died suddenly on February 6, 2009. He leaves behind family and many close friends in Canada, the United States, Israel, and Hungary.

Acknowledgments

This study was supported Intramural Program of the National Human Genome Research Institute of the National Institutes of Health, Bethesda, Maryland, USA.

Author History

Nuria Carrillo, MD (2020-present)
Marjan Huizing, PhD (2020-present)
George Karpati, MD, FRCP(C), FRS(C), OC; McGill University (2004-2009)
May Christine Malicdan, MD, PhD (2020-present)
Erin K O'Ferrall, MD, MSc, FRCPC; Montreal Neurological Institute (2009-2020)
Michael Sinnreich, MD, PhD; University Hospital Basel (2004-2020)

Revision History

  • 9 April 2020 (bp) Comprehensive update posted live
  • 7 March 2013 (me) Comprehensive update posted live
  • 6 August 2009 (me) Comprehensive update posted live
  • 24 May 2006 (me) Comprehensive update posted live
  • 26 March 2004 (me) Review posted live
  • 17 November 2003 (gk) Original submission

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