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Apolipoprotein E 4 in inclusion body myositis.

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Apolipoprotein E €4in
Inhu$on Body Myositis
teins, apolipoprotein E (APO E), hyperphosphorylated
and proteins associated with the motor endplate including acetylcholine receptor proteins [2, 6, 71. It is
unclear whether the deposition of AP is a consequence
of the disease process or is an initiating event in the
induction of myositis.
A number of these proteins, particularly AP, are also
found associated with the characteristic plaques seen
in the brains of patients with Alzheimer's disease (AD)
{ S ] . The €4 variant of APO E has been shown to be
strongly associated with late-onset familial and sporadic
AD [9-111 and the gene dose is related to age of onset
and degree of amyloid staining at autopsy [12, 131.
Investigations of the properties of the allelic variants
of APO E have demonstrated that APO E4 differs
from APO E3 and APO E2 in its binding to AP and
T proteins [13, 141. These properties may be relevant
to the deposition of AP in the brain and the development of neuronal damage in AD [13].
In the light of the similarities in protein content between the inclusions in the muscle in IBM and the
amyloid plaques in the brain in AD we have compared
the APO E allele frequencies in a group of patients
with IBM with those frequencies in patients with other
inflammatory muscle diseases and in the general population.
T,
Michael J. Garlepp, PhD,"t Hyacinth Tabarias,"
Frank M. van Bockxmeer, PhD,$ Paul J. Zilko, MD,"
Beverley Laing," and Frank L. Mastaglia, MD"t
The genetic predisposition to inclusion body myositis
(IBM) is probably multifactorial. The deposition of the
P-amyloid protein is a characteristic histological feature
of both IBM and Alzheimer's disease (AD). The ~4 allele
of apolipoprotein E (APO E) has been strongly associated with familial and late-onset AD. We therefore compared the APO E allele frequencies in a group of 14
patients with IBM with those in a group of patients with
other inflammatory muscle diseases and in the general
population. The frequency of the ~4 allele in IBM was
increased (0.29) compared with that in patients with
other inflammatory muscle diseases (0.15) and the general population (0.13) ( p < 0.05). These data suggest that
APO E genotype may be one of the factors involved in
determining the predisposition to the development of
IBM.
Garlepp MJ, Tabarias H, van Bockxmeer FM,
Zilko PJ, Laing B, Mastaglia FL. Apolipoprotein E
~4 in inclusion body myositis. Ann Neurol
1995;38:957-959
Inclusion body myositis (IBM) is increasingly diagnosed among older patients who present with inflammatory myopathy [l, 2). It can be distinguished clinically from polymyositis and dermatomyositis by the
characteristic distribution of affected muscles, the absence of skin involvement, and its relative resistance
to corticosteroid and other immunosuppressive therapy C3, 41. The inflammatory infiltrates characteristically contain a high proportion of CD8' T cells that
are often closely associated with nonnecrotic muscle
fibers [4, 51. The defining histological feature, however, is the presence of characteristic rimmed vacuoles
that show immunohistochemical evidence of the Pamyloid fragment (AP) of the P-amyloid precursor protein (P-APP) and ubiquitin [3, 41. More recently, several other proteins and mRNA species have been
localized to these inclusions. These include prion pro-
From the "Australian Neuromuscular Research Institute and the
tDepartment of Medicine, University of Western Australia, Nedlands, and SDepmment of Biochemistry, Royal Perth Hospital,
Perth, Western Australia, Australia.
Received Apr 13, 1995, and in revised form Aug 3. Accepted for
publication Aug 3, 1995.
Address correspondence to Dr Garlepp, Australian Neuromuscular
Research Institute, Queen Elizabeth I1 Medical Centre, Verdun
Street, Nedlands, Western Australia. 6009 Australia.
Patients and Methods
Clinical details of the patients with IBM are shown in Table
1. All patients were Caucasian. Blood samples were obtained
from 14 patients with IBM, 11 with dermatomyositis,and 6
with polymyositis, all of whom attended the neuromuscular
clinic at Queen Elizabeth I1 Medical Centre, Western Australia. All patients with IBM had the characteristic pattern of
muscle involvement seen in IBM, with particularly severe
involvement of the quadriceps femoris muscles in the lower
limbs and of the forearm flexor muscles in the upper limbs
14, 151. Only 1 patient had shown any response to corticosteroid or other immunosuppressive therapy. The diagnosis of
inflammatory myopathy was confirmed by muscle biopsy,
which demonstrated the presence of rimmed vacuoles and
the characteristic 18- to 20-nm tubulofilamentousinclusions.
One patient (Subject 11) was not biopsied due to his advanced age but fulfilled all the clinical and electromyographic
criteria for IBM. APO E allele frequencies in a healthy Western Australian Caucasian population were taken from previously published data [ 161. Allele frequencies were compared
using the normal approximation of the binomial distribution
[16] and ages of onset in ~4-negativeand positive patients
with IBM were compared using the Wilcoxon rank sum test.
DNA was extracted from peripheral blood leukocytes using standard phenol/chloroform/isoamyl alcohol techniques.
APO E genotyping was performed at the Department of
Clinical Biochemistry, Royal Perth Hospital, using a previously described technique 1171 based upon amplification of
the gene by the polymerase chain reaction (PCR) followed
by digestion of the PCR product with the restriction endonuclease HhaI and polyacrylamide gel electrophoresis. In this
way three alleles can be detected, ie, ~ 2~, 3and
, ~ 4 .
Copyright 0 1995 by the American Neurological Association 957
Table I . Patients with Inclu.rion Body Myositir
Subject
Sex
1
2
M
F
F
M
F
M
3
4
5
6
7
8
7
10
11
12
13
14
APO E
Age at
Onset (yr)
APO E
Genotype
76
50
NA
37
56
50
61
61
65
54
32
62
83
72
54
55
314
313
314
313
62
70
66
67
M
69
F
M
M
65
43
83
88
77
M
M
F
M
=
Age
(yr)
59
61
apolipoprotein E; NA
=
313
314
414
313
313
314
314
313
213
214
not available
Results
The APO E genotypes of the individual patients with
IBM are shown in Table 1. The frequency of the ~4
allele in IBM was twice that seen in the healthy population (Table 2) and this increase remained significant
( p < 0.05) even when Subject 11 was excluded from
the analysis. No significant increase in ~4 frequency
was demonstrable in a similar number of patients with
polymyositis/dermatomyositis (see Table 2). The presence of the ~4 allele was not related to the age of onset
or severity of disease at presentation. Six of the 9 men
with IBM had ~4 (allele frequency = 0.39) but only
1 of 5 women did (allele frequency = 0.10).
Discussion
The mechanism responsible for the deposition of AP
and the other proteins that comprise the inclusion bodies of IBM, and their role in the pathogenesis of the
disease are unknown. The similarity in protein content
between these inclusions and the amyloid-containing
Table 2. APO E Allele Frequencies in Patients with
Inflammatory Muscle Disease
APO E
Allele Frequencies
Population
IBM
PMIDM
Controlsb
Number of
Alleles
28
34
E2
E3
E4
0.07
0.64
0.79
0.81
0.29"
0.15
0.13"
0.06
0.06
a p < 0.05.
bAllele frequencies taken from [161.
APO E = apolipoprotein E; IBM = inclusion body myositis; PM
= polymyositis; DM = derrnatomyositis.
958
Annals of Neurology Vol 38
plaques of AD is remarkable. APO E has been detected in both and the frequency of the ~4 allele is
also increased in our group of patients with IBM. This
increased frequency was not seen in a similarly sized
group of patients with other forms of idiopathic inflammatory muscle disease. APO E allele frequencies
have also been analyzed in a number of other conditions in which amyloid deposition is a feature. APO E
~4 was increased in cortical Lewy body disease, in
which AD pathology is often seen E18) but not in familial Creutzfeldt-Jakob disease, Down's syndrome, or
familial amyloidotic polyneuropathy [lo, 181.
The data presented here differ from those derived
from a recent study of 11 patients with IBM 1191 in
which a small but statistically insignificant increase in
~4 was reported. This difference may reflect the small
numbers of patients in each study but could also reflect
genetic heterogeneity in this disease. The genetic predisposition to the development of IBM is probably
multifactorial. We have recently demonstrated that
more than 90% of patients with IBM bear the human
leukocyte (HLA) antigen DR3 and virtually all patients
had a deletion of at least one of the genes encoding
complement factor 4 that are present in the major
histocompatibility complex [20). This very strong
HLA association with IBM provides some support for
an autoimmune mechanism in this disease. The relationship between the inclusion bodies and the lymphocytic infiltrate is unclear. Whether the T cells that accumulate in these lesions are directed at proteins
represented in the inclusion bodies, including AP, is
unknown. The association with ~4 is less striking than
the HLA association and requires confirmation. Nevertheless, the frequency of this allele in IBM approaches
that seen in A D (0.33-0.41) G9-13, 18, 191. However,
a significant proportion of patients are negative for the
~4 allele in both diseases, emphasizing the likelihood
that alternate factors may contribute to the development of the characteristic pathology seen in these diseases.
Despite the clear evidence that ~4 is a predisposing
factor to the development of AD, its precise role in
the pathogenesis of the disease is unknown. It has been
proposed that the increased rate of binding of AP by
APO E4 may play a role in its increased deposition
113, 141. In addition, the decreased binding of APO
E4 to the 7 protein may increase the rate of development of neurofibrillary tangles and neuronal damage
[13]. A role of APO E4 in IBM is also unclear. APO
E performs a number of functions apart from its role
in lipid redistribution between and within tissues. For
example, it has been implicated in the process of nerve
regeneration and repair and in smooth muscle proliferation and differentiation, although a role in skeletal
muscle metabolism has not been defined [21). It is
interesting that APO E is believed to be capable of
No 6 December 1995
modulating T-lymphocyte activation by mitogens or
antigen [21}. Since IBM is characterized by the intramuscular accumulation of T lymphocytes and macrophages, the latter cell type being a potent producer of
APO E, a role in the immune response to muscle cannot be excluded. O n the other hand, APO E4 may
play a role in facilitating the deposition of excess A@
in skeletal muscle, thus contributing to ultimate muscle
cell degeneration. The demonstration of increased levels of mRNA encoding @-APP (suggesting overproduction of @-APP)and the demonstration of APO E
in the inclusions of IBM [G, 7) are consistent with this
possibility.
This study was supported by grants from the Australian Neuromuscular Research Institute, The National Health and Medical Research
Council o f Australia, and the Arthritis Foundation of Western Australia.
We thank Professor Byron Kakulas and Dr Peter Robbins for their
expert assistance in the histopathological assessment of the muscle
biopsies.
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Brief Communication: Garlepp e t al: APO E s4 in IBM
959
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