Clinical Diagnosis

The following clinical diagnostic criteria for inclusion body myopathy 2 (IBM2) 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 norm

• 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 and 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 hypertrophied 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].

• Changes in certain muscle groups before clinical involvement is evident, visualized by [Mizusawa et al 1987, Sadeh et al 1993]:

  • Electromyogram (EMG) showing myopathic motor unit potentials in association with spontaneous activity, similar to a pattern seen in inflammatory myopathies;

  • CT examination of muscle showing fatty replacement of muscle.

• Normal nerve conduction velocity (NCV) 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 known to be associated with IBM2 [Eisenberg et al 2001].

Clinical testing

• Targeted mutation analysis. The Met712Thr (M712T) 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].

• Sequence analysis. Systematic studies evaluating the detection rate of sequence analysis have not been published.

• Deletion/duplication testing. 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.

Table 1. Summary of Molecular Genetic Testing Used in IBM2

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
GNE	Targeted mutation analysis	Met712Thr	Middle Eastern Jewish population ~100% 2	Clinical
	Sequence analysis	Sequence variants	60%-80% 3
	Deletion/duplication testing4	Exonic or whole-gene deletions	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Eisenberg et al [2003]

3. Detection rate varies by certainty of clinical diagnosis.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming/establishing the diagnosis in a proband. Convenient and cost-effective diagnostic algorithm:

1.

Physical examination with particular attention to quadriceps sparing

2.

Family history and examination of suspected members

3.

Electromyogram

4.

Serum creatine kinase activity

Findings from steps 1-4 may lead to a strong diagnostic suspicion. However, the following tests are necessary for confirmation of the diagnosis:

5.

Muscle biopsy with discriminating light and electron microscopic scrutiny

6.

Molecular genetic testing of GNE

The above work-up usually establishes a firm diagnosis; however, if necessary, an additional test may be used:

7.

Activity analysis of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase enzyme in lymphocytes

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.

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

Genetically Related (Allelic) Disorders

Mutations in GNE also cause sialuria. In this disorder, the mutations occur at the allosteric site of the epimerase, abolishing the feedback inhibition mechanism by CMP-sialic acid that results in overproduction of sialic acid [Seppala et al 1999]. Affected individuals exhibit variable degrees of developmental delay, coarse facial features, and hepatomegaly. Inheritance is autosomal dominant.

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 become severely incapacitated about 20 years after onset, mainly as a result of inability to walk; they 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, although individuals with complete heart block producing syncope and necessitating a pacemaker have been reported [Sunohara et al 1989].

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

Genotype-Phenotype Correlations

The IBM2 phenotype is similar in affected individuals regardless of their specific GNE mutations.

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 described in the Japanese literature possibly similar cases before them.

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 causative gene [Eisenberg et al 2001], it became apparent that the disorder was the same disease as DMRV [Nishino et al 2002].

Prevalence

To date, approximately 220 individuals with IBM2 have been described: about 160 of Iranian Jewish descent with the Met712Thr (ATG>ACG) homozygous founder mutation, 15 Japanese individuals with Val572Leu (GTG>CTG) founder mutation, and the remainder with over 36 mutations in compound heterozygous pattern.

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 leaders of 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 IBM2 have been reported in Tunisia [Amouri et al 2005] and Italy [Broccolini et al 2004]. Mutations in GNE have been reported worldwide.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with inclusion body myopathy 2 (IBM2), the following evaluations are recommended:

• Neurologic examination

• EMG

• Serum CK concentration

• Muscle biopsy

Treatment of Manifestations

Treatment is symptomatic only.

Individuals are often evaluated and managed by a multidisciplinary team including neurologists and physiatrists as well as physical and occupational therapists.

Prevention of Primary Manifestations

No treatment that reverses or slows the natural history of muscle weakness in IBM2 is available.

Surveillance

Annual routine follow-up with the multidisciplinary team is recommended.

Testing 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

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

IBM2 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 IBM2 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. 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, particularly when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

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. GNE contains 13 exons with a transcript length of 3742 base pairs (Ensembl Genome Browser accession number ENSG00000159921).

Pathologic allelic variants. Approximately 40 different IBM2-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]. Most are missense mutations affecting either the epimerase or the kinase domain, but nonsense mutations, splice site mutations, and deletions have been reported. In Middle Eastern Jewish individuals, the homozygous Met712Thr mutation is the only mutation identified to date [Eisenberg et al 2003]. In Japanese individuals, the homozygous Val572Leu mutation seems to be more common [Arai et al 2002], reflecting the respective founder effects; however, it should be noted that additional mutations, including Met712Thr, have been described in individuals of Japanese origin [Tomimitsu et al 2004]. (For more information, see Table A.)

Normal gene product. UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, a protein 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 such as 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 IBM2 (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 IBM2 skeletal muscle.

Residual enzyme activity is essential for life; complete lack of enzyme activity as demonstrated by inactivation of the GNE gene in mice is lethal in early embryonic stages [Schwarzkopf et al 2002]. Furthermore, a loss of UDP-GlcNAc 2-epimerase in lymphoblastoid cell lines results in loss of immune functions [Keppler et al 1999], a defect that is not seen in individuals with IBM2. Some laboratories have demonstrated slightly reduced epimerase activity in lymphoblastoid cell lines derived from individuals with IBM2 [Hinderlich et al 2003].

Whether reduced enzymatic activity is responsible for the skeletal muscle phenotype 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 whether 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 IBM2. Some laboratories have found a reduction of the sialylation status in muscle of individuals with IBM2 [Huizing et al 2004, Noguchi et al 2004, Saito et al 2004], while others have not [Salama et al 2005].

A mouse model for IBM2 has been generated by expressing the human GNE disease allele Asp176Val (D176V) 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].

Broccolini et al [2008] found that neprilysin, a metallopeptidase that cleaves beta-amyloid is hyposialylated in IBM2 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.

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Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

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

• 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