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GNE-Related Myopathy

Synonyms: Distal Myopathy with Rimmed Vacuoles (DMRV), Hereditary Inclusion Body Myopathy 2 (HIBM), Nonaka Myopathy

, MD, MSc, FRCPC and , MD, PhD.

Author Information
, MD, MSc, FRCPC
Neuromuscular Research Department
Montreal Neurological Institute
Montreal, Quebec
, MD, PhD
Department of Neurology
Neuromuscular Center
University Hospital Basel
Basel, Switzerland

Initial Posting: ; Last Update: March 7, 2013.

Summary

Disease characteristics. GNE-related myopathy, also known as inclusion body myopathy 2, is characterized by slowly progressive distal muscle weakness that begins in the late teens to early adult years with gait disturbance and foot drop secondary to anterior tibialis muscle weakness. Weakness eventually includes the hand and thigh muscles but commonly spares the quadriceps muscles, even in advanced disease. Affected individuals are usually wheelchair bound about 20 years after onset. If quadriceps sparing is incomplete, loss of ambulation tends to occur earlier.

Diagnosis/testing. The diagnosis of GNE-related myopathy is based on clinical and histopathologic criteria. Because simplex cases (i.e. a single occurrence in a family) are common, the presence of affected relatives is not obligatory for the diagnosis. Muscle histopathology typically shows rimmed vacuoles and characteristic filamentous inclusions. GNE, which encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, is the only gene in which mutations are known to cause GNE-related myopathy.

Management. Treatment of manifestations: Treatment is symptomatic. Individuals are often evaluated and managed by a multidisciplinary team including neurologists, geneticists and physiatrists, as well as physical and occupational therapists. All affected individuals should consult their physician before beginning an exercise program.

Surveillance: Annual routine follow up with the multidisciplinary team, including screening for signs and symptoms of cardiac and respiratory dysfunction.

Agents/circumstances to avoid: Medications/drugs with potential myotoxicity should be used with caution.

Genetic counseling. GNE-related myopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has 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. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

The following clinical diagnostic criteria for GNE-related myopathy have been proposed [Griggs et al 1995, Argov et al 2003]:

  • A primary skeletal muscle disease, usually presenting with weakness in the legs
  • Sustained quadriceps sparing despite marked weakness of all other proximal lower-extremity muscles
  • Onset in late teenage years or early adulthood
  • Modest elevation of serum creatine kinase activity, between two and four times the normal value
  • Muscle biopsy
    • On cryostat sections, the most prominent finding is the presence of rimmed vacuoles, lined by basophilic granular material on H&E staining and purple-red in color with the modified Gomori trichrome stain. The vacuoles themselves do not stain with oil red orange or PAS stains, and lack acid phosphatase activity; however, with the latter, a few vacuoles show faint activity in the periphery. The vacuoles either appear empty or contain granular or amorphous basophilic inclusions or congophilic masses. Fiber size varies, with both atrophic and hypertrophic fibers observed. Endomysial fibrosis may be considerable. Many fibers contain internal myonuclei and fiber splitting occurs [Mizusawa et al 1987, Sadeh et al 1993].

      Note: The origin of the rimmed vacuoles and their contents remains controversial. It has been suggested that they may be autophagic in nature, but the lack of acid phosphatase activity argues against this suggestion. Some authors have suggested that they arise from the membranous structures of the cell (SR, T-tubules, Golgi). Others have suggested that they arise when myonuclei burst and discharge their basophilic content into the cytoplasm [Griggs et al 1995].
    • On ultrastructural analysis, the vacuoles do not appear as empty spaces but are filled with membranous whorls and cytoplasmic debris. Certain fibers harbor cytoplasmic or nuclear tubulo-filamentous inclusions with a diameter of 16-18 nm.
    • In general, inflammation is not observed in an affected muscle. However, a modest inflammatory response has been noted in a few individuals [Argov et al 2003, Krause et al 2003, Yabe et al 2003] and inflammatory cell invasion of non-necrotic muscle fibers is rarely reported [Krause et al 2003].
  • Early changes in certain muscle groups (before clinical weakness is detected) visualized by the following [Mizusawa et al 1987, Sadeh et al 1993]:
    • Electromyogram showing myopathic motor unit potentials in association with spontaneous activity, similar to the pattern seen in inflammatory myopathies
    • CT or MRI examination of muscle showing fatty replacement of muscle
  • Normal nerve conduction velocity studies

Because simplex cases are common, presence of affected relatives is not obligatory for the diagnosis.

Molecular Genetic Testing

Gene. GNE, encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, is the only gene in which mutations are known to cause GNE-related myopathy [Eisenberg et al 2001].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in GNE-Related Myopathy

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
GNETargeted mutation analysisp.Met712ThrMiddle Eastern Jewish population ~100% 4
Sequence / mutation scanning analysis 5 Sequence variants 660%-80% 7
Deletion / duplication testing 8Exonic or whole-gene deletions 9Unknown

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. The p.Met712Thr mutation is predominant in Middle Eastern Jewish individuals but has also been identified in a small number of non-Jewish families [Eisenberg et al 2003].

5. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. Detection rate varies by certainty of clinical diagnosis.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. A large deletion involving exons 1 to 9 has also been reported [Del Bo et al 2003]. The frequency and detection rates are not known.

Testing Strategy

To confirm/establish the diagnosis in a proband. Convenient and cost-effective diagnostic algorithm:

1.

History to determine age of onset, pattern of muscle weakness, and progression over time; physical examination with particular attention to quadriceps sparing

2.

Family history and examination of suspected members

3.

Electromyogram to help identify the pattern of muscle involvement

4.

Serum creatine kinase activity

In an individual with one or more affected family members who presents with the typical clinical phenotype (i.e., distal-onset weakness in early adulthood with progressive, symmetric leg weakness sparing the quadriceps), the following testing should be considered:

  • Sequence analysis of GNE (muscle biopsy not required in this case)
  • In individuals of Middle Eastern Jewish descent, targeted mutation analysis may be performed first, followed by full gene sequencing if two disease causing mutation are not found.
  • Deletion/duplication testing can be considered if the above tests are normal

In individuals with no known family history of muscle disease and/or an atypical clinical presentation (such as sparing of the quadriceps), the following testing algorithm should be considered:

  • Muscle biopsy.
  • If the muscle biopsy demonstrates typical findings of GNE-related myopathy, sequence analysis of GNE can then be pursued.

Muscle biopsy may be useful in two additional scenarios:

  • In individuals where genetic testing has revealed previously unreported GNE variants of unknown pathogenicity, muscle biopsy may be helpful. If the typical myopathology of GNE-related myopathy is demonstrated by the muscle biopsy this would support the pathogenicity of the GNE variant.
    • In individuals with previously unreported GNE variants of unknown pathogenicity, analysis of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase enzyme activity in lymphocytes may also be helpful.
  • Muscle biopsy is important in any individual with recent onset of weakness to exclude a treatable inflammatory myopathy.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Weakness starts in young adulthood, usually in the second part of the third decade, with a predilection for distal limb muscles. The initial symptom is difficulty with gait as a result of foot drop secondary to anterior tibialis muscle weakness. The weakness spreads and within several years involves thigh and hand muscles. Shoulder girdle muscles are weak, with relative sparing of the triceps. Neck flexors are commonly involved.

The striking feature is quadriceps sparing even at advanced stages of the disease. However, based on results of molecular genetic testing, it is now recognized that quadriceps sparing is not a constant feature; some individuals without this finding have been identified [Argov et al 2003].

Affected individuals are usually wheelchair bound about 20 years after onset. If quadriceps sparing is incomplete, loss of ambulation tends to occur earlier.

Ocular, pharyngeal, and cardiac muscles are usually spared. A single affected individual has been described with respiratory involvement resulting in a reduced FEV1 (forced expiratory volume in 1 second) and vital capacity [Weihl et al 2011].

Occasionally, affected individuals may have facial weakness [Argov et al 1998].

Intellectual abilities are unaffected. The impact of GNE-related myopathy on life expectancy for affected individuals with modern multidisciplinary medical care is unclear.

Genotype-Phenotype Correlations

To date, more than 60 mutations in GNE have been described [reviewed in Huizing & Krasnewich 2009]. Because reports of individuals with GNE-related myopathy consist mainly of single case reports or relatively small case series, correlations between genotype and phenotype are difficult. However, a recent study of 71 Japanese individuals with GNE-related myopathy has suggested that those harboring a homozygous mutation (p.Val572Leu) in the N-acetylmannosamine kinase domain have an earlier disease onset than those who are compound heterozygotes for mutations in the epimerase and kinase domains [Mori-Yoshimura et al 2012]. The individuals with two kinase domain mutants were also more frequently nonambulatory. These findings need to be confirmed in other populations.

Penetrance

Penetrance is probably not 100%; three individuals with two disease-causing mutations were asymptomatic at advanced age. Two were homozygous [Argov et al 2003] and one was compound heterozygous [Nishino et al 2002].

Nomenclature

The entity of hereditary inclusion body myopathy 2 (h-IBM2) was likely first recognized in Japan. In 1981, Nonaka and coworkers described an autosomal recessive distal myopathy with rimmed vacuoles (DMRV) in the Western literature [Nonaka et al 1981, Sunohara et al 1989]; they give credit to Sasaki et al [1969] and Ideta et al [1973] for having previously described in the Japanese literature possibly similar cases.

Argov & Yarom [1984] published nine cases from four Jewish families of Iranian descent of autosomal recessive "rimmed vacuole myopathy" sparing the quadriceps. A larger series of Iranian Jewish individuals with the same disorder was subsequently published by a group from Tel Aviv [Sadeh et al 1993]. The disorder was characterized by progressive distal and proximal weakness and wasting beginning in the legs and sparing the quadriceps, even in advanced stages. The disease was subsequently found in other ethnic groups [Sivakumar & Dalakas 1996]; with the identification of the gene in which mutation is causative [Eisenberg et al 2001], it became apparent that the disorder was the same disease as DMRV [Nishino et al 2002].

Prevalence

To date, more than 200 individuals with GNE-related myopathy have been described: about 160 of Iranian Jewish descent with the p.Met712Thr homozygous founder mutation, 15 Japanese individuals with the p.Val572Leu founder mutation, and the remainder with over 60 mutations in compound heterozygous pattern [Huizing & Krasnewich 2009].

In Israel random testing of 75 Iranian Jewish individuals, unrelated to individuals with IBM, identified five carriers [Eisenberg et al 2001].

Considering a worldwide Iranian Jewish population of 150,000-300,000 reported by the Iranian Jewish society in Los Angeles and Israel, prevalence rate appears to be between 1:500 and 1:1000 in Iranian Jews.

Individuals with GNE-related myopathy have been reported in Tunisia [Amouri et al 2005] and Italy [Broccolini et al 2004]. Mutations in GNE have been reported worldwide.

Differential Diagnosis

Several forms of hereditary inclusion body myopathy (IBM) have been described under various names, each with its own clinical characteristics and ethnic clustering (see Table 2):

  • Inclusion body myopathy 3 (IBM3) (OMIM 605637), reported in a Swedish family, caused by a missense mutation in the gene encoding the myosin heavy chain IIa (chromosome 17p) [Martinsson et al 2000]
  • Inclusion body myopathy associated with Paget disease of the bone and/or frontotemporal dementia, or IBMPFD, characterized by adult-onset proximal and distal muscle weakness (clinically resembling a limb-girdle muscular dystrophy syndrome), early-onset Paget disease of the bone (PDB), and premature frontotemporal dementia (FTD). Muscle weakness progresses to involve other limb and respiratory muscles. Cardiac failure and cardiomyopathy have been observed in later stages. PDB involves focal areas of increased bone turnover that typically lead to spine and/or hip pain and localized enlargement and deformity of the long bones; pathologic fractures occasionally occur. Early stages of FTD are characterized by dysnomia, dyscalculia, comprehension deficits, paraphasic errors, and relative preservation of memory; and later stages by inability to speak, auditory comprehension deficits for even one-step commands, alexia, and agraphia. Mean age at diagnosis for muscle disease and PDB is 42 years; for FTD, 55 years. VCP is the only gene in which mutations are known to cause IBMPFD. Inheritance is autosomal dominant.
  • Autosomal dominant limb-girdle muscular dystrophy type 1A (LGMD1A, OMIM 159000), which presents with rimmed vacuoles on histologic examination and is caused by mutations in the gene encoding myotilin [Hauser et al 2000]. See Limb-Girdle Muscular Dystrophy Overview.
  • Autosomal recessive limb-girdle muscular dystrophy type 2J caused by mutations in TTN, the gene encoding titin, may also demonstrate rimmed vacuoles [Udd et al 2005]. See Limb-Girdle Muscular Dystrophy Overview.
  • A French-Canadian familial myopathy, with changes resembling inclusion body myopathy and periventricular leukoencephalopathy [Cole et al 1988, Argov et al 1998]

Table 2. Distal Myopathies

Disease NameMean Age at Onset (in Years)Initial Muscle Group InvolvedSerum Creatine Kinase ConcentrationMuscle BiopsyGene Symbol (Locus 1)
Autosomal Dominant
Welander distal myopathy>40Distal upper limbs (finger and wrist extensors)Normal or slightly increasedRimmed vacuoles(2p13)
Udd distal myopathy>35Anterior compartment in legs± Rimmed vacuolesTTN
Markesbery-Griggs late-onset distal myopathy (zaspopathy)>40Vacuolar and myofibrillar myopathyLDB3
Distal myotilinopathy>40Posterior > anterior in legsSlightly increasedVacuolar and myofibrillarMYOT
Laing early-onset distal myopathy (MPD1)<20Anterior compartment in legs and neck flexorsModerately increasedType 1 fiber atrophy in tibial anterior muscles; disproportion in proximal musclesMYH7
Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg and hands; dysphonia1-8 timesRimmed vacuoles(5q)
Distal myopathy with pes cavus and areflexia15-50Anterior and posterior lower leg; dysphonia and dysphagia2-6 timesDystrophic, rimmed vacuoles(19p13)
New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg1-4 timesDystrophic; rimmed vacuoles; eosinophilic inclusions(8p22-q11 and 12q13-q22)
Autosomal Recessive
Miyoshi early-adult-onset myopathy 19Posterior compartment in legs>10 timesMyopathic changesDYSF
Miyoshi muscular dystrophy 3 (MMD3) 20-25Posterior compartment in legs , asymmetry>10 timesMyopathic changes and, infrequently, rimmed vacuolesANO5

Modified from Udd & Griggs [2001]

1. Locus given only if gene is unknown

Myopathology. Rimmed vacuoles are induced by freezing of muscle for preparation of cryostat sections. On plastic embedded semi-thin sections, corresponding areas do not appear as vacuoles but contain clusters of refractile granules, composed of membranous whorls as seen on electron microscopy. Such structures are nonspecific, as they can be found in many unrelated diseases including oculopharyngeal muscular dystrophy [Abu-Baker & Rouleau 2007], sporadic inclusion body myositis [Karpati & O’Ferrall 2009], Markesbery-Griggs-Udd myopathy (zaspopathy) [Markesbery et al 1977, Borg et al 1991, Lindberg et al 1991, Udd et al 1993], familial inclusion body myopathy 3 [Martinsson et al 2000], LGMD2J [Udd et al 2005], and LGMD 1A [Hauser et al 2000]. They can be generated experimentally by chloroquine [Macdonald & Engel 1970] or vincristine [Clarke et al 1972] and are even found in chronic denervating conditions [Fukuhara et al 1980].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GNE-related myopathy, the following evaluations are recommended:

  • Neurologic examination
  • Medical genetics consultation

Treatment of Manifestations

Treatment is symptomatic only:

  • Individuals with GNE-related myopathy may benefit from consultation with physiatrists, physiotherapists, and occupational therapists.
  • Foot drop bracing and other mechanical aids may improve the function of individuals with GNE-related myopathy.
  • Consultation with a pulmonologist to evaluate for nocturnal hypoventilation or sleep apnea may be considered in symptomatic individuals.
  • All affected individuals should consult their physician before beginning an exercise program.

Prevention of Primary Manifestations

No treatment that reverses or slows the natural history of muscle weakness in GNE-related myopathy is available.

Surveillance

Annual routine follow-up with the multidisciplinary team is recommended. Affected individuals should be screened for signs and symptoms of cardiac dysfunction, as two affected siblings with cardiomyopathy have been reported [Chai et al 2011]. Affected individuals should also be evaluated for respiratory dysfunction, with appropriate investigations and treatment as needed.

Agents/Circumstances to Avoid

It may be prudent to use medications/drugs with potential myotoxicity (for example: colchicine) with caution.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Several therapies are under investigation for GNE-related myopathy including oral sialic acid or its metabolites, intravenous immune globulin and gene replacement therapy.

Some investigators believe that the reduction of the sialylation status of glycoproteins in muscle of individuals with GNE-related myopathy is causative of the disease [Huizing et al 2004, Noguchi et al 2004, Saito et al 2004]. Muscle atrophy and weakness in a mouse model of GNE-related myopathy are prevented by administration of sialic acid metabolites [Malicdan et al 2009]. Several oral exogenous forms of sialic acid (e.g., sialic acid-extended release and N-acetylmannosaminic acid) are currently being investigated in clinical trials for human GNE-related myopathy (see ClinicalTrials.gov for details).

Intravenous immune globulin (IVIG) is a glycoprotein which can be metabolized by neuraminidase to provide free sialic acid. A single trial of IVIG in four affected individuals resulted in mild improvement in muscle strength [Sparks et al 2007].

A single affected individual has been treated with intramuscular injections of a GNE expression vector in a lipoplex vehicle [Nemunaitis et al 2010]. The same person was later treated with intravenous infusion of the GNE-lipoplex preparation [Nemunaitis et al 2011]. No conclusions can yet be made about the efficacy of such treatment. Reported side effects of the latter treatment included low-grade fever, tachycardia, myalgia, transaminase elevation, hyponatremia, and hypotension. Further studies are required before these therapies will be available for widespread use.

Search ClinicalTrials.gov 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-related myopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • Parents of an affected individual are obligate heterozygotes; therefore, each carries one of the GNE alleles present in the proband.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has 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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with a GNE-related myopathy are obligate heterozygotes (carriers) of one of the GNE mutations present in the proband.

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

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family are known.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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.

  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • Myositis Association
    1737 King Street
    Suite 600
    Alexandria VA 22314
    Phone: 800-821-7356 (toll-free); 703-299-4850
    Fax: 703-535-6752
    Email: tma@myositis.org

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-Related Myopathy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for GNE-Related Myopathy (View All in OMIM)

600737INCLUSION BODY MYOPATHY 2, AUTOSOMAL RECESSIVE; IBM2
603824UDP-N-ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; GNE
605820NONAKA MYOPATHY; NM

Molecular Genetic Pathogenesis

UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is the key enzyme in the biosynthetic pathway of sialic acids, which are the most abundant terminal monosaccharides on glycoconjugates in eukaryotic cells. The first two steps of sialic acid biosynthesis are catalyzed by each one of the two distinct functional domains of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. First, the UDP-GlcNAc 2-epimerase domain forms ManNAc from UDP-GlcNAc with simultaneous release of UDP. ManNAc is then phosphorylated at C6 by a specific kinase; subsequently, sialic acid is formed by condensation of N-acetylmannosamine-6-phosphate and phosphoenolpyruvate, and activated by CTP to form CMP-sialic acid [Effertz et al 1999].

Normal allelic variants. Alternative splicing of GNE results in transcript variants encoding different isoforms. The transcript variant NM_005476.5 has 12 exons and a length of 5329 base pairs (see also Ensembl Genome Browser, gene ID ENSG00000159921).

Pathologic allelic variants. More than 60 different GNE-related myopathy -causing mutations in GNE have been identified to date [reviewed in Broccolini et al 2002, Nishino et al 2002, Del Bo et al 2003, Eisenberg et al 2003, Krause et al 2003, Saito et al 2004, Huizing & Krasnewich 2009]. Most are missense mutations affecting either the epimerase or the kinase domain, although nonsense, splice site, and deletion mutations have been reported. In Middle Eastern Jewish individuals, the homozygous p.Met712Thr mutation is the only mutation identified to date [Eisenberg et al 2003], and in Japanese individuals, the homozygous p.Val572Leu mutation seems to be more common [Arai et al 2002], reflecting the respective founder effects. Note, however, that additional mutations, including p.Met712Thr, have been described in individuals of Japanese origin [Tomimitsu et al 2004, Mori-Yoshimura et al 2012]. (For more information, see Table A.)

Table 3. Selected GNE Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.527A>Tp.Asp176ValNM_005476​.5
NP_005467​.1
c.1714G>C 1p.Val572Leu
c.2135T>C 1p.Met712Thr

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

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

1. See Prevalence for population-specific information.

Normal gene product. UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, NP_005467.1 an isoform of 722 residues, is the key enzyme in the biosynthetic pathway of sialic acid [Effertz et al 1999]. Sialic acids are the most abundant terminal monosaccharides on glycoconjugates of eukaryotic cells. Sialic acids influence adhesion processes, which play an important role in many cellular functions including cell migration, transformation of tissues, inflammation, wound healing, and metastasis. The first step of sialic acid biosynthesis is the formation of ManNAc from UDPGlcNAc with the simultaneous release of UDP. ManNAc is then phosphorylated by a specific kinase. These two steps are synthesized by the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase [Effertz et al 1999], which is highly conserved among mammalian species. In the following steps, sialic acid is formed by condensation of ManNAc-6-phosphate and phosphoenolpyruvate and activated by CTP to form CMP-sialic acid. This nucleotide sugar is finally used as a substrate of sialyltransferases in glycoconjugate biosynthesis [Penner et al 2006].

Abnormal gene product. Mutations at the allosteric site of the epimerase abolish the feedback inhibition by CMP-sialic acid, resulting in overproduction of sialic acid and leading to the childhood disease sialuria, an entity distinct from GNE-related myopathy (see Genetically Related Disorders) [Seppala et al 1999]. At the current time, it is unclear why mutations in either the epimerase or kinase moiety lead to the phenotype seen in GNE-related myopathy skeletal muscle (see also discussion in Genotype-Phenotype Correlations).

Residual 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 crystal structure of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase has recently been solved [Tong et al 2009] and should provide insights into the effect of disease-causing mutations.

It is hypothesized that reduced enzymatic activity is responsible for the skeletal muscle phenotype, although this remains a matter of controversy. Hypoglycosylation of alpha-dystroglycan can lead to neurologic syndromes with prominent involvement of skeletal muscle including Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEBD), Fukuyama congenital muscular dystrophy (FCMD), congenital muscular dystrophy type 1C (CMD1C), congenital muscular dystrophy type 1D (CMD1D; see Congenital Muscular Dystrophy Overview), limb-girdle-muscular dystrophy type 2I (LGMD2I), and limb-girdle-muscular dystrophy type 2K (LGMD2K; see Limb-Girdle Muscular Dystrophy Overview); thus, it is tempting to speculate that mutations in GNE would influence the glycosylation status of alpha-dystroglycan or other skeletal muscle proteins. Several laboratories have studied the glycosylation pattern in skeletal muscle and cultured muscle cells from individuals with GNE-related myopathy. Some laboratories have found a reduction of the sialylation status in muscle of individuals with GNE-related myopathy [Huizing et al 2004, Noguchi et al 2004, Saito et al 2004], while others have not [Salama et al 2005].

A mouse model for GNE-related myopathy has been generated by expressing the human GNE disease allele p.Asp176Val as a transgene on a mouse Gne knockout background [Malicdan et al 2007]. The myopathology is similar to that seen in humans and demonstrates scattered small angular fibers, inclusion bodies, and accumulation of several aberrant molecules (beta amyloid, beta-amyloid precursor protein, tau, phosphorylated neurofilaments, proteins of the unfolded protein response, and ubiquitin). The mice exhibit marked hyposialylation. Stimulation of sialylation delayed the muscle atrophy and weakness [Malicdan et al 2009].

A second mouse model for GNE-related myopathy was generated by introduction of the p.Met712Thr kinase domain mutation into the endogenous mouse gene Gne [Galeano et al 2007]. Surprisingly, this mouse model did not recapitulate the human muscle disease since the mice died within the first 72 hours of life from renal disease (glomerular podocytopathology). However is it interesting to note that the phenotype was rescued by administration of an oral sialic acid precursor, thus supporting the hypothesis that the biochemical defect is related to reduced sialylation.

Broccolini et al [2008] found that neprilysin, a metallopeptidase that cleaves beta-amyloid is hyposialylated in GNE-related myopathy and has reduced enzymatic activity when hyposialylated. The authors hypothesize that hyposialylated neprilysin may reduce beta-amyloid clearance and contribute to its accumulation in muscle fibers.

Data from the proteomic profile of patients with GNE-related myopathy may yield further insights into the pathophysiology. Sela et al [2011] found that proteins involved in ubiquitination, stress response, mitochondrial processes and cytoskeleton and sarcomere organization may be involved in GNE-related myopathy.

References

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Chapter Notes

Author Notes

George Karpati, MD 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 by the Canadian Institutes of Health Research, the Muscular Dystrophy Association of Canada and USA, the Association Française contre les Myopathies, the Geneva University Hospital, and the Lichtensteinstiftung, Basel, Switzerland.

Author History

Erin O’Ferrall, MD, MSc, FRCPC (2009-present)
George Karpati, MD, FRCP(C), FRS(C), OC; McGill University (2004-2009)
Michael Sinnreich, MD, PhD (2004-present)

Revision History

  • 7 March 2013 (me) Comprehensive update posted live
  • 6 August 2009 (me) Comprehensive update posted live
  • 24 May 2006 (me) Comprehensive update posted to live Web site
  • 26 March 2004 (me) Review posted to live Web site
  • 17 November 2003 (gk) Original submission
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