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New developments in hereditary inclusion body myopathies.

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New Developments in Hereditary
InclusionlBody Myopathies
The term inclusion body myositis was introduced in
1971 by Yunis and Samaha [I] to describe a subset of
patients with chronic polymyositis whose muscle biopsies showed, in addition to inflammation, abnormal
muscle fibers containing vacuoles and characteristic filamentous inclusions in the cytoplasm and nuclei.
Since that time, sporadic inclusion body myositis
(s-IBM), now recognized as the most common muscle
disease in patients older than age 50, has received considerable attention (reviewed in References 2 and 3).
Recent interest in s-IBM has been stimulated by the
identification within s-IBM muscle fibers of congophilic amyloid [4] and other striking pathologic features that had not been thought to occur in diseased
human muscle [2]. Those features include abnormal
accumulation of P-amyloid protein (AP), two other
epitopes of the P-amyloid precursor protein (PAPP),
hyperphosphorylated T, a,-antichymotrypsin, apolipoprotein E (ApoE), and ubiquitin. Accumulations of
these same proteins are also characteristic of Alzheimer
disease (AD) brain [2].
A few years ago, we introduced the term hereditary
inclusion body myopathies (h-IBMs) [5] to encompass
hereditary progressive muscle diseases with muscle pathology that strikingly resembled pathology of s-IBM,
except for lack of lymphocytic inflammation; hence,
the term myopathy instead of myositis.
In the past, several autosomal dominant and recessive vacuolar myopathies have been described under
various names (reviewed in References 2 and 3 ) . When
filamentous inclusions characteristic of IBM were identified in muscle fibers of some of those families, the
terms familial inclusion body myositis and familial inclusion body myositis-like syndromes were used by some of
the authors (reviewed in References 2 and 3 ) . Diagnostic criteria of the h-IBMs have not yet been widely established, and patients having what appears to be a
form of typical h-IBM are still being described as other
In several Iranian (Persian) Jewish families, an autosoma1 recessive quadriceps-sparing vacuolar myopathy,
associated with weakness distally in lower limbs, was
described in 1984 [6]. Subsequently, an identical
quadriceps-sparing vacuolar myopathy, also with distal
lower-limb weakness and having cytoplasmic and nuclear filamentous inclusions, was described in KurdishIranian and Afghani Jews (reviewed in References 2
and 3). Their pathologic resemblance to s-IBM was
emphasized [7]. Recently, in vacuolated muscle fibers
of Iranian-Jewish patients with h-IBM, it has been
shown that there are abnormal accumulations of the
same Alzheimer-characteristic proteins as are present in
s-IBM [2], except for paucity of congophilia and of
some epitopes of phosphorylated I [2], and different
expression of ApoE immunoreactivity [8].
In 1996, a major step forward was localization of the
abnormal gene in h-IBM Iranian-Jewish families to
chromosome 9 p l - q l [9]. Now Argov and colleagues
[lo] report new data demonstrating the same gene locus in two Afghani-Jewish families, in one Iraqi-Jewish
family, and in one non-Jewish family from India. All
patients had in their muscle biopsies pathology characteristic of h-IBM, and it is interesting that in all of
them the quadriceps muscle was either spared or the
least affected (thus, they are clinically and pathologically similar, not of “various types” as stated in the title) [lo]. By contrast, one large autosomal recessive
French-Canadian family having typical h-IBM muscle
pathology, but no sparing of quadriceps and having additional central nervous system involvement [ 111, did
not link to the chromosome 9 p l - q l locus [lo].
Japanese patients having an autosomal recessive distal myopathy with rimmed vacuoles were described in
1981 by Nonaka and associates [ 121. Muscle pathology
of this syndrome is strikingly similar to that of h-IBM
in Iranian Jews, including the same spectrum of abnormal proteins within the vacuolated muscle fibers [13].
Moreover, as in the h-IBM of Iranian Jews, the quadriceps muscle was reported to be spared in several Japanese patients, and in all patients it was less affected
than other distal muscles [14]. Now Ikeuchi and coworkers [ 151 report that the abnormal gene of this Japanese vacuolar myopathy also maps to chromosome 9
The studies by Argov and colleagues [ 101 and Ikeuchi and co-workers [15] are important because they
show the same chromosome 9 pl-ql locus in patients
with autosomal recessive vacuolar myopathy of different ethnicity. Moreover, in an autosomal recessive quadriceps-sparing Mexican family with h-IBM [ 161, we
have identified the same gene locus as well as confirmed it in h-IBM of Iranian Jews living in the United
States (Middleton LT, Christodoulou K, Engel WK,
Askanas V, unpublished data).
Although the p l - q l gene locus is still large and there
is no obvious candidate gene, studies by Argov and col-
Copyright 0 1997 by the American Neurological Association
leagues and Ikeuchi and co-workers illustrate the importance of correlating data from molecular genetics
with characteristic pathology and clinical presentation.
It is apparent that Japanese “distal myopathy with
rimmed vacuoles” and the above examples of “quadriceps-sparing h-IBM” are the same disorder or very
closely related disorders. Now it is very important to
establish a classification and nomenclature for the hereditary IBMs, which include some “distal myopathies.”
(Autosomal dominant forms of h-IBM have muscle
pathology like that of autosomal recessive h-IBM [reviewed in References 2 and 31, but they will not be
herein discussed.)
It is of particular interest that s-IBM and all recessive
and dominant forms of the h-IBMs have specific
pathologic features in common, including vacuolar degeneration of muscle fibers; filamentous inclusions
composed of paired-helical filaments containing phosphorylated T ; and accumulations of PAPI’ epitopes,
ApoE, and other Alzheimer-characteristic proteins [2].
The forms of h-IBM with different genetic transmission probably have different genetic defects, and s-IBM
has a definitely different, yet unknown (possibly viral
[2]), etiology. The following two important questions
emerge: (1) What causes the Alzheimer-like pathologic
features in s- and h-IBM muscle fibers? And (2) are
those abnormalities the result of the same final pathogenic cascade occurring in all forms of the IBMs, despite their different etiologies? We have suggested that
in the IBMs various causes lead to the same pathologic
process [2].
The same questions are being asked regarding AD.
Despite three different genetic defects (identified thus
far) causing early-onset familial AD, and the ApoE genetic risk factor existing in some late-onset sporadic
AD patients, all forms of AD have virtually the same
brain pathology [ 171, suggesting that the final common
pathway is the same in familial and sporadic AD [ 171.
In a recent editorial, Hyman [18] has similarly concluded that it is one “Alzheimer disease” rather than
several “Alzheimer diseases” because, despite different
etiologies, there is a common pathophysiologic process
to which various genetic and other factors contribute.
In neither the IBMs nor the ADS is the pathogenic
cascade well understood. With the genetic locus of one
form of autosomal recessive h-IBM now identified, delineation of the abnormal gene will follow. Knowledge
of what this abnormal gene is and how it affects the
muscle fiber, coupled with detailed analyses of possible
factors causing s-IBM, can lead to clarification of the
proposed common pathway causing the characteristic
Annals of Neurology
Vol 41
No 4
April 1997
IBM-type of vacuolar muscle degeneration and, more
important, to methods of its treatment and prevention.
Valerie Askanas, MD, PhD
USC Neuromuscular Center
Department of Neurology
Universily of Southern Calfornia School of Medicine
Good Samaritan Hospital
Los Angeles, CA
1. Yunis EJ, Samaha FJ. Inclusion-body myositis. Lab Invest
2. Askanas V, Engel WK. New advances in the understanding of
sporadic inclusion-body myositis and hereditary inclusion-body
myopathies. Curr Opin Rheumatol 1995;7:486-496
3. Griggs RC, Askanas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705-713
4. Mendell JR, Sahenk Z, Gales T, Paul L. Amyloid filaments in
inclusion body myositis. Arch Neurol 199 I ;48:1229-1234
5 . Askanas V, Engel WK. New advances in inclusion-body myositis. Curr Opin Rheumatol 1993;5:732-741
6. Argov Z, Yarom R. “Rimmed vacuole myopathy” sparing the
quadriceps: a unique disorder in Iranian Jews. J Neurol Sci
7. Massa R, Weller B, Karpati G, et al. Familial inclusion body
myositis among Kurdish-Iranian Jews. Arch Neurol 1991 ;48:
8. Mirabella M, Alvarez RB, Engel WK, et al. Apolipoprotein E
and apolipoprotein E messenger RNA in muscle of inclusionbody myositis and myopathies. Ann Neurol 1996;40:864-872
9 Mitrani-Rosenbauni S, Argov Z, Blumenfeld A, et al. Hereditary inclusion body myopathy maps to chromosome 9p 1 -ql .
Hum Mol Genet 1996;5:159-163
10 Argov Z, Tiram E, Eisenberg I, et al. Various types of hereditary inclusion body myopathies map to chromosome 9pl-ql.
Ann Neurol 1997;41:548-551
11 Cole AJ, Kuzniecky R, Karpati G, et al. Familial myopathy
with changes resembling inclusion body myositis and pcriventricular leukoencephalopathy: a new syndrome. Brain 1988;
1 11:1025-1 037
12. Nonaka I, Sunohara N, Ishiura S, Satoyoshi E. Familial distal
myopathy with rimmed vacuoles and lamellar (myeloid) body
formation. J Neurol Sci 1981;51:141-155
13. Murakami N, Ihara Y, Nonaka 1. Muscle fiber degeneration in
distal myopathy with rimmed vacuole formation. Acta Neuropathol 1995;89:29-34
14. Sunohara N, Nonaka I, Kamei N, Satoyoshi E. Distal myopathy with rimmed vacuole formation: a follow-up study. Brain
15. lkeuchi T, Asaka T, Saito M, et al. Gene locus for autosomal
recessive distal myopathy with rimmed vacuoles maps to chromosome 9. A n n Neurol 1997;41:432-437
16. Fardeau M, Askanas V, Tom6 FMS, et al. Hereditary neuromuscular disorder with inclusion-body myositis-like filamentous
inclusions: clinical, pathological, and tissue culture studies.
Neurology 1990;40:120
17. Lippa CF, Saunders AM, Smith TW, et al. Familial and sporadic Alzheimer’s disease: neuropathology cannot exclude a final
common pathway. Neurology 1996;46:406-412
18. Hyman BT. Alzheimer’s disease or Alzheimer’s diseases? Clues
from molecular epidemiology. Ann Neurol 1996;40:135-136
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