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: email@example.com (D.M. Krasnewich).
0925-4439/$ – see front matter. Published by Elsevier B.V.
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M. Huizing, D.M. Krasnewich / Biochimica et Biophysica Acta 1792 (2009) 881–887