Hereditary Inclusion Body Myopathy: A decade of progress
Marjan Huizinga, Donna M. Krasnewichb,⁎
aCell Biology of Metabolic Disorders Unit, National Human Genome Research Institute, National institutes of Health, Bethesda, MD 20892, USA
bOffice of the Clinical Director, National Human Genome Research Institute, National institutes of Health, Bethesda, MD 20892, USA
a b s t r a c t a r t i c l e i n f o
Received 24 March 2009
Received in revised form 29 June 2009
Accepted 1 July 2009
Available online 24 July 2009
Sialic acid synthesis
UDP-GlcNAc 2-epimerase/ManNAc kinase
HIBM mouse model
Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, quadriceps sparing type commonly
referred to as HIBM but also termed h-IBM or Inclusion Body Myopathy 2 (IBM2). The clinical manifestations
begin with muscle weakness progressing over the next 10–20 years uniquely sparing the quadriceps until the
most advanced stage of the disease. Histopathology of an HIBM muscle biopsy shows rimmed vacuoles on
Gomori's trichrome stain, small fibers in groups and tubulofilaments without evidence of inflammation. In
affected individuals distinct mutations have been identified in the GNE gene, which encodes the bifunctional
enzyme uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase/N-acetyl-mannosamine (Man-
NAc) kinase (GNE/MNK). GNE/MNK catalyzes the first two committed steps in the biosynthesis of
acetylneuraminic acid (Neu5Ac), an abundant and functionally important sugar. The generation of HIBM
animal models has led to novel insights into both the disease and the role of GNE/MNK in pathophysiology.
Recent advances in therapeutic approaches for HIBM, including administration of N-acetyl-mannosamine
(ManNAc), a precursor of Neu5Ac will be discussed.
Published by Elsevier B.V.
Inclusion Body Myositis (IBM) was described by Yunis and Samaha
on the basis of distinctive inclusions containing tubulofilaments in a
is further classified into “sporadic inclusion body myositis” (s-IBM;
OMIM#137421), which invariably has inflammation, and “hereditary
inclusion body myopathy” which shows familial inheritance and no
inflammation [2,3]. This review will focus on the molecular basis,
pathophysiology and clinical features of a specific type of Hereditary
type commonly referred to as HIBM but also termed h-IBM, or
Inclusion Body Myopathy 2 (IBM2) (OMIM#600737), which is allelic
to the Japanese disorder Distal Myopathy with Rimmed Vacuoles
(DMRV) or Nonaka Myopathy (OMIM#605820) [4,5]. We henceforth
refer to this disorder as HIBM.
2. Clinical features and pathology
2.1. Clinical features
Argov and Yarom  first described the disorder HIBM in Jews of
Persian descent characterized clinically by progressive proximal and
distal muscle weakness and wasting of the upper and lower limbs
usually beginning after age 20. Apart from the Persian-Jewish popula-
tion, affected individuals have now been described worldwide, in-
cluding patients of Caucasian, Indian, Thai, Japanese and African
The clinical course of HIBM is relentless. Progression of muscle
weakness after onset continues over the next 10 to 20 years. Typically,
however, there is sparing of the quadriceps muscles, partially or
completely, even in the advanced stages of the disease, a unique
manifests as impaired foot dorsiflexion at an early stage of the disease
without involvement of the ocular, pharyngeal, and respiratory
muscles. Cognition, cranial nerves, sensation and coordination remain
normal. In more advanced stages of this disorder the muscles of the
shoulder girdle are severely affected, with relative sparing of the
deltoid, biceps, and triceps. As lower extremity weakness becomes
widespread the most characteristic clinical finding, sparing of the
quadriceps, becomes obvious. Even as muscle weakness progresses in
other groups, the quadriceps remains strong so that affected
individuals are able to stand and walk until the clinical pathology is
quite advanced [5,8]. By two to three decades after diagnosis affected
individuals require a wheelchair for mobility. HIBM has also been
associated with cardiac involvement in a small number of affected
patients with severe muscle disease.
Creatine kinase levels arenormal oronly mildlyelevated and nerve
conduction velocity is typically normal. MRI T1 weighted images of
the thighs showed fatty or fibrous replacement of the hamstring
muscles with sparing of the quadriceps (Fig.1). The diagnosis of HIBM
Biochimica et Biophysica Acta 1792 (2009) 881–887
⁎ Corresponding author. NIH/NHGRI, Bldg. 10/CRC Room 3-2551, 10 Center Drive,
Bethesda, Maryland 20892, USA. Tel.: +1 301 402 8255; fax: +1 301 496 7157.
E-mail address: firstname.lastname@example.org (D.M. Krasnewich).
0925-4439/$ – see front matter. Published by Elsevier B.V.
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is based on both clinical symptoms as well as the histopathology of a
Histopathology of a muscle biopsy from an HIBM affected indi-
vidual typically demonstrates red rimmed vacuoles with Gomori's
trichrome stain, small fibers in groups, occasionally amyloid deposit,
seen with Congo-red staining visualized with rhodamine filters, and
15 to18 nm tubulofilaments [2,6,11]. These “non-storage vacuoles”
have granular staining, basophilic on H&E and red on Gomori
trichrome stains. It was suggested that these vacuoles are autophagic
. Presumptive evidence of an autophagocytic process in the
rimmed vacuole areas is supported by high acid phosphatase activity,
reactivity with lysosomal markers, and the presence of multilammelar
bodies on electron microscopy .
HIBM muscle immunohistochemistry shows normal cytoskeletal
and membrane protein staining patterns. Many degenerating, vacuo-
lated muscle cells show immunoreactivity to neural cell adhesion
molecule, NCAM1, which is a fetal muscle antigen. NCAM1 is almost
undetectable in normal control muscles, however, it is detectable in
regenerating fibers . There is no apparent autoimmune basis for
the myopathy as only macrophages around necrotic fibers were noted
without the presence of lymphocytes . Electron microscopy on
muscle biopsy reveals cytoplasmic and nuclear inclusion bodies
containing membrane degradation products with some proliferation
of mitochondria with irregular size and shape as well as cytoplasmic
3. Molecular genetics
3.1. GNE gene identification
Initial genome-wide linkage analyses in nine Persian-Jewish fami-
lies with HIBM revealed evidence for both autosomal recessive inheri-
tance as well as linkage to 9p1–q1 . Linkage results to the same
region in Japanese families with autosomal recessive distal myopathy
suggested that this disorder, Nonaka myopathy or DMRV, and HIBM
were allelic . The gene was further localized to a 700 kb region
within 9p13–p12 in Middle Eastern Jews and haplotype analysis of the
chromosomal region in 104 affected people from 47 Middle Eastern
families revealed one unique ancestral founder chromosome [17,18].
Single non-Jewish families from India, U.S., and the Bahamas with
linkage to the same region, had three distinct haplotypes. Using a
candidate gene approach in Middle Eastern patients, Eisenberg et al.
identified a shared single homozygous missense mutations in the GNE
gene, p.M712T; while affected individuals of other ethnic origins were
compound heterozygotes for other distinct mutations .
The GNE gene (GenBank NM_005476) spans ∼44 kb of genomic
DNA and its major transcript consists of 13 exons, exons 1 and 13 are
non-coding. GNE is ubiquitously expressed, with the highest levels in
3.2. GNE mutation analysis
Over the last 8 years, the genetic heterogeneity of HIBM has
expanded.There arenowover 60 GNE mutations describedworldwide
associated with HIBM/DMRV in patients of different ethnic back-
grounds (listed in Table 1). These mutations are predominantly
missense (82%) and scattered throughout the GNE gene.
Of all 62 reported GNE mutations associated with HIBM so far, only
11 (18%) are ‘null’ mutations, nonsense or frame shift mutations,
highlighted in gray in Table 1, which likely result in nonsense
mediated RNA decay and limited or no protein expression. GNE null
mutations have never been identified on both alleles in a patient; this
would most likely be lethal, also suggested by a Gne knock-out mouse
model, which did not survive past the embryonic stage .
Among the GNE missense mutations there appear to exist at
least 3 founder mutations. p.M712T is the most predominant, iden-
tified in patients of Persian-Jewish decent [19,21,22], however,
surprisingly this mutation has also been described in an Italian
patient , a Japanese patient , and two unrelated Middle
Eastern Moslem families . The second most common GNE muta-
tion is p.V572L, predominantly identified in patients of Japanese
descent, but also found in some other Asian patients [25–27]. A
third GNE founder mutation is p.D176V, occurring in the Japanese
Other interesting findings among GNE mutations suggest a
presence of genetic “hotspots” for mutation. Several distinct amino
acids are mutated in different ways: p.G206S or p.G206fsX4 , p.
R246W or p.R246Q [19,22,28–30], p.303V or p.303X [19,25], p.P511H
or p.P511L [10,31], and p.A631T and p.A631V [5,19,21,25,32]. Also
some specific GNE mutations arose presumably independently in
multiple ethnicities: p.R246Q in Italy, Bahamas and Taiwan
[19,28,29], p.D378Y in Japan and Ireland [5,21], p.A524V in Thailand,
Mexico and France [10,22,32], p.I557T in Italy and Japan [21,24], p.
A631V in Germany, Ireland and Japan [5,21,25], and p.V696M in
Thailand, India and Algeria [10,19,32,33].
Fig. 1. T1 weighted magnetic resonance images of the thigh of an individual affected with HIBM. “R” denotes right side, “P” denotes posterior and “I” denotes interior. Bracketed
numbers are the levels of the imaging cuts. (A) Axial image showing fibrotic muscles of the posterior compartment or “hamstring” muscles (H) with comparatively less involvement
of the quadriceps femoris (Q). (B) Coronal image showing similar findings.
M. Huizing, D.M. Krasnewich / Biochimica et Biophysica Acta 1792 (2009) 881–887
GNE mutations associated with HIBM [71–78].
aGray background: severe mutations, likely resulting in nonsense mediated RNA decay and limited GNE/MNK protein expression.
bGNE/MNK amino acid residues 1–378 are suggested to regulate epimerase enzymatic activity, and residues 410–722 regulate kinase enzymatic activity .
M. Huizing, D.M. Krasnewich / Biochimica et Biophysica Acta 1792 (2009) 881–887
4. Protein function and biochemistry
GNE mRNA is translated into the 722 amino acid bifunctional
enzyme uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) 2-
epimerase/N-acetyl-mannosamine (ManNAc) kinase (GNE/MNK)
[34–36]. GNE/MNK is ubiquitously expressed and catalyzes the
first 2 committed, rate-limiting steps in the biosynthesis of 5-N-
acetylneuraminic acid (Neu5Ac), also known as sialic acid. Neu5Ac,
further referred to as ‘sialic acid’, is the most abundant mammalian
sialic acid and is typically found as the terminal sugar on glyco-
conjugates, where it plays a role in a variety of cellular signaling
The N-terminal portion of GNE/MNK (amino acids 1–378) has
UDP-GlcNAc 2-epimerase catalytic activity (EC 184.108.40.206) , which
catalyzes the epimerization of UDP-GlcNAc to ManNAc with release
of UDP. The C-terminal portion (amino acids 410–722) has ManNAc
kinase catalytic activity (EC 220.127.116.11), which phosphorylates
ManNAc to ManNAc-6-P and phosphoenolpyruvate. ManNAc-6-P
is then further condensed to sialic acid (Fig. 2). The exact locations
of the active sites within these domains remain to be determined.
The activated form of sialic acid, cytidine monophosphate (CMP)-
sialic acid, is utilized as substrate for sialyltransferases by the Golgi
complex in the sialylation of glycoconjugates . Cytosolic CMP-
sialic acid regulates GNE/MNK epimerase catalytic activity through
a negative feedback mechanism at its allosteric site (amino acids
263–266) [40–42]. Interestingly, heterozygous missense mutations
within the GNE/MNK allosteric site lead to another human
disorder, sialuria (OMIM#269921). Sialuria cells have lost GNE/
MNK feedback inhibition by CMP-sialic acid, resulting in cytoplas-
mic accumulation and urinary excretion of large quantities of free
sialic acid [40–42].
GNE/MNK is a soluble protein, localizing to the cytoplasm, the
Golgi-region and the cell nucleus . The role of GNE/MNK in the
nucleus remains elusive. GNE/MNK is not predicted to undergo
glycosylation, but it has several potential phosphorylation sites .
In addition, the GNE/MNK enzyme forms a homohexamer by
oligomerization. As a monomer, GNE/MNK has no enzymatic activity;
its dimer exhibits only MNK activity, and the hexameric state displays
both GNE and MNK activities [34,38,45].
5. HIBM pathology
Since mutations in the GNE gene are associated with HIBM, the
presumed mechanism of pathophysiology would be: GNE mutations
(mostly missense, Table 1) lead to decreased GNE/MNK enzymatic
activities resulting in decreased production of sialic acid. The decrease
in intracellular sialic acid content would then lead to the muscle
degeneration in HIBM. Although excellent experimental work has
been done in pursuit of supportive evidence of this hypothesis, the
exact cellular mechanisms behind the development of the myopathy
in HIBM have remained elusive.
The effects of GNE mutations on the enzymatic properties of
GNE/MNK were assessed by assays of both GNE-epimerase and
MNK-kinase activities, which were reduced, but not absent, in HIBM
muscle biopsies, as well as in cultured HIBM fibroblasts, lympho-
blasts, and myoblasts [5,30,45,46]. In vitro studies, in which specific
human GNE mutations were expressed in Sf6 insect cells [38,47], in
COS-7 cells , or in a cell-free in vitro transcription–translation
system , revealed that the reduction in GNE and MNK enzymatic
activity is mutation-dependent. Moreover, mutations in one enzy-
matic domain affect not only that domain's enzyme activity but also
the activity of the other domain. Compared with enzyme activities in
a cell-free system, fibroblasts exhibited higher residual activities of
both GNE and MNK, suggesting the presence in fibroblasts of addi-
tional sugar epimerases and kinases with overlapping substrate
These experiments revealed that the mechanism of pathology is
not that of a typical autosomal recessive disorder with low enzyme
activity in the gene product. Rather the total functional activity of
GNE/MNK activity in a cell may be dependent both on the location
or domain of the mutation in the GNE/MNK protein as well as the
activity of other enzymes in metabolically interconnected pathways.
Equally enigmatic are the results of several investigators
analyzing sialic acid levels in tissue from individuals affected with
HIBM. Hinderlich et al. demonstrated normal membrane bound
sialic acid levels in lymphoblastoid lines with the p.M712T mutation
. Yet, cultured muscle cells from patients with a variation of GNE
mutations, showed variable sialylation, ranging from the normal
range to significantly decreased [45,46,50]. These studies suggested
that muscle cells with a strong reduction in epimerase activity,
below 35% of normal, resulting from at least one GNE mutation in
the epimerase domain, consistently showed measurable decreased
sialylation [45,46,50]. However, isoelectric focusing studies of serum
transferrin, which contains only N-GlcNAc linked glycans, and
serum apolipoprotein CIII, which contains only O-GalNAc linked
glycans, appeared normal in all HIBM patients tested so far. This
suggests that unaffected serum N-GlcNAc linked and O-GalNAc
linked glycosylation in hepatically derived serum glycoproteins in
individuals with HIBM [51,52]. Hyposialylation of specific glycosy-
lated proteins in HIBM muscle was reported for PSA, polysialic acid,
on NCAM  and for α-dystroglycan [33,53], but was reported to
be unaffected in other studies [46,54]. Hyposialylation of O-linked
glycans in HIBM muscle cells was also demonstrated by use of
specific lectins [45,53]. Importantly, Noguchi et al. showed that the
hyposialylation of these cells can be reversed by the addition of
ManNAc, a substrate in sialic acid synthesis, or sialic acid itself to
the media of the cells .
Fig. 2. Sialic acid synthesis pathway. The biosynthesis of sialic acid (Neu5Ac) occurs in
the cytosol, where glucose undergoes several modifications to become UDP-GlcNAc.
The UDP-GlcNAc 2-epimerase activity of GNE/MNK then epimerizes UDP-GlcNAc into
ManNAc, after which its ManNAc kinase activity further converts this to ManNAc-6-P,
which is then converted in several steps to the downstream product CMP-sialic acid.
CMP-sialic acid is utilized by the Golgi complex to sialylate glycoconjugates. CMP-sialic
acid can feedback-inhibit the UDP-GlcNAc 2-epimerase enzymatic activity in its
allosteric site. For more details, see text.
M. Huizing, D.M. Krasnewich / Biochimica et Biophysica Acta 1792 (2009) 881–887
Since HIBM is an adult onset disease, and patients have residual
GNE/MNK enzymatic activity, the effects of sialic acid deficiency may
appear gradually. Some glycoconjugates, for example N-linked, might
be more readily sialylated than others, for example O-linked or PSA
linked. Thus, when a shortage of sialic acid occurs, specific proteins
may be inadequately glycosylated, such as PSA-NCAM or alpha-
dystroglycan, contributing to the pathology of HIBM.
Apart from hyposialylation, other hypotheses have arisen for the
role of mutated GNE/MNK in the pathology of HIBM. These include
the unusual compartmentalization of GNE/MNK in cells , leading
to speculation of additional GNE/MNK enzymatic activities in cells.
Exploration of this phenomenon showed no difference in the com-
partmentalization of GNE/MNK in either skeletal muscle or primary
myoblasts from individuals affected with HIBM . In addition, two
novel isoforms of GNE/MNK (GNE1) were identified, which have
extended (GNE2) or partially deleted N-termini (GNE3), and display
tissue-specific expression , which maycontribute tothe pathology
of HIBM. Furthermore, impaired apoptotic signaling in HIBM cells was
reported, implicating involvement of apoptotic pathways in HIBM
pathophysiology . Another intriguing finding is that GNE/MNK
may control sialyltransferase expression, ganglioside production and
modulation of proliferation and apoptosis, independent of sialic acid
production . In another study, microarray RNA expression and
muscle morphology analysis indicated that mitochondrial processes
may be affected in HIBM muscle . And recently, co-immunopre-
cipitation assays identified alpha-actinin 1, an actin binding and
crosslinking protein, as a ligand of GNE/MNK . The relevance of α-
actinin 1 function in skeletal muscle and its role in HIBM pathophy-
siology remain elusive.
The above findings underscore that there is more to be learned
about the cellularsite of pathology and the mechanism of muscle cell
degeneration in HIBM. To further analyze these pathways on a whole
animal, as well as explore potential treatment methods, efforts to
study HIBM mouse models are ongoing.
6. HIBM mouse models
Generating a mouse model for HIBM has been complicated
because initial trials showed that a complete knock-out of the Gne
gene led to embryonic lethality . Despite this hurdle, two models
were generated by different groups.
Malicdan et al. developed an animal model for HIBM showing the
pathologic muscle phenotype over time. They generated a transgenic
mouse which expressed the human GNE cDNA with the p.D176V
epimerase domain mutation, common among Japanese patients, on a
mouse background with a disrupted mouse Gne gene; Gne(−/−)
hGNED176V-Tg [61,62]. The mutant offspring of this cross appeared
normal at birth but had decreased levels of sialic acid in serum and
different organs. These mice developed poor motor performance and
increasingserumcreatine kinaselevels mimicking someaspectsof the
muscle phenotype seen in the human disease. By 40 weeks of age the
mice showed significant changes in muscle pathology with intracy-
toplasmic rimmed vacuoles which were immunoreactive to lysosomal
markers, amyloid and phosphorylated tau and neurofilaments.
Ultrastructural and immunohistochemical studies confirmed the pre-
sence of autophagosomes in affected mouse muscle. Of interest, the
the possible involvement of other muscles types besides skeletal
muscle. The phenotype of this p.D176V transgenic mouse model
appeared reminiscent of the clinical, pathologic and biochemical fea-
tures of HIBM/DMRV in humans [61,62].
A second HIBM mouse model created by our group produced an
intriguing, unexpected outcome. This Gne knock-in mouse was
created by homologous recombination which introduced the p.
M712T kinase domain mutation, common among Persian-Jews, into
the endogenous mouse Gne gene; GneM712T/M712T. Surprisingly,
mutant mice died within 72 h of birth with severe glomerular disease
including proteinuria, podocytopathy, segmental splitting of the
glomerular basement membrane and effacement of the podocyte
foot processes. Biochemical analysis of the mutant mice kidneys
revealed decreased Gne/Mnk expression and activity and deficient
sialylation of the major podocyte sialoprotein, podocalyxin, suggest-
ing that decreased production of sialic acid may lead to lethality in
We then proceeded with oral administration of the sialic acid
precursor N-acetyl-mannosamine (ManNAc) to the pregnant and
nursing mothers, which resulted in survival of 43% of the mutant
GneM712T/M712Tpups beyond 72 h. Mutant survivors exhibited
improved renal histology, increased sialylation of podocalyxin, and
increased Gne/Mnk protein expression and Gne-epimerase activities.
These findings established this GneM712T/M712Tknock-in mouse as the
first genetic model of podocyte injury due to hyposialylation [63,64].
In HIBM patients, no indications of renal abnormalities have been
reported. Humans and mice may differ in the relative importance of
sialic acidtothekidney, andproteinglycosylationpatterns alsovary; it
is known that podoxalyxin differs among species in the contingent of
O- and N-linked glycosylation sites . The type of sialic acid present
also differs, most mammalian species utilize the sialic acid N-
glycolylneuraminic acid (Neu5Gc), but humans have lost the ability
to synthesize Neu5Gc , and mainly utilize N-acetyl neuraminic
Our recent findings of abnormal histology in muscle tissue starting
at 6 months of age in surviving mutant GneM712T/M712Tmice (not
receiving ManNAc) areencouraging in that this may mimic thehuman
disorder (authors unpublished data). Further research is required to
elucidate phenotypic differences between the transgenic Gne(−/−)
hGNED176V-Tg model and the knock-in GneM712T/M712Tmodel.
In spite of these still obscure phenotypic differences between
HIBM mouse models, the encouraging results of the ManNAc
supplementation of the murine knock-in model  support evalua-
tion of ManNAc, a well-tolerated intervention, not only as a treatment
for HIBM, but also as a treatment for renal disorders involving
proteinuria and hematuria due to podocytopathy and/or segmental
splitting of the glomerular basement membrane.
No therapies are currently available for HIBM. Dietary modifica-
tions were proposed, including avoidance of excess selenium, copper
and zinc (inhibitors of GNE/MNK activity), reduced consumption of
ethanol, ethanol promotes hydrolysis of sialoconjugates, and dietary
promotion of magnesium, an essential co-factor of GNE/MNK .
Other suggested strategies of therapy for HIBM invoke the concept
that hyposialylation is the basis of the pathophysiology in affected
individuals. The hypothesis that increasing total body sialic acid
through exogenous means will lead to clinical benefit, was recently
tested in our center through a pilot study on four affected patients
(http://clinicaltrials.gov: Identifier NCT00195637) . The HIBM
patients were loaded with 1 g/kg intravenous immunoglobulin G
(IVIG) on two consecutive days followed by 3 doses of 400 mg/kg at
weekly intervals. It was hypothesized that the large sialic acid content
on IgG (∼8 μmol of sialic acid/g) could be utilized to sialylate other
glycoproteins. This study showed improvement in mean quadriceps
strength both after loading (+22%) and at the end of the study
(+35%). Mean shoulder strength showed similar findings at (+44%)
and (+46%) respectively. A composite of 8 other muscle groups
showed improvements as well after loading (+8%) and (+19) at the
end of the study . Although immunohistochemical staining and
immunoblotting of muscle biopsies for alpha-dystroglycan and NCAM
did not show indisputable evidence of increased sialylation after IVIG
treatment, patients did report subjective improvement in their ability
to perform routine daily activities. Though follow-up studies are
M. Huizing, D.M. Krasnewich / Biochimica et Biophysica Acta 1792 (2009) 881–887
needed, this protocol reveals issues surrounding therapeutic strate-
gies for HIBM and opens the door to other possible therapeutic
options. These include the administration of other forms of sialic acid,
in particular the sialic acid precursor ManNAc.
ManNAc is an uncharged, natural compound and feeds into the
sialic acid biosynthesis pathway distal to the rate-limiting GNE-epi-
merase step (Fig. 2). Residual MNK activity in HIBM patients, or
ancillary kinases (e.g., GlcNAc kinase) , might convert ManNAc
into ManNAc-6P and aid synthesis of free sialic acid. Hyposialylated,
Gne-deficient mouse embryonic stem cells  and human HIBM/
DMRV cultured myotubes  became resialylated after the growth
mediumwas supplemented with ManNAc. Furthermore, incubation of
cultured cells with ‘unnatural’ ManNAc derivatives (ManLev, N-
levulinoylmannosamine or ManNAz, N-azidoacetylmannosamine)
resulted in incorporation of the downstream sialic acid analogs,
SiaLev (N-levulinoyl sialic acid) or SiaNAz (N-azidoacetyl sialic acid),
into cell surface glycoconjugates [69,70]. Of greatest significance, the
salutary effect of oral ManNAc supplementation on survival and sialy-
lation status of our HIBM knock-in mouse model  holds promise
for potential benefit in a futurehuman clinical treatment protocol. Our
center is pursuing the design of a formal trial of ManNAc in humans,
which has yet to be approved by regulatory authorities.
Apart from manipulating products and/or substrates in the
GNE/MNK pathway, another future treatment option could be the
delivery of a healthy GNE gene, gene therapy, or a healthy GNE/MNK
enzyme via stem cells, to patients' cells and tissues, in particular to
the muscle. Continued work in this field will elucidate insights both
into the pathophysiology of this devastating disorder as well as
other human diseases caused by the perturbation of glycobiologic
This work was supported by the Intramural Research Program of
the National Human Genome Research Institute, National Institutes of
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