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Amyloid myopathy An underdiagnosed entity.

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Amyloid Myopathy:
An Underdiagnosed Entity
Simone Spuler, MD,* Alison Emslie-Smith, MD, PhD, and Andrew G. Engel, M D
Amyloidosis can involve multiple organs, including kidney, heart, peripheral nerve, skin, joints, and skeletal muscle, but
rarely presents as a myopathy. We studied 13 adults with muscle weakness for between 3 months and 4 years in whom
the diagnosis of systemic amyloidosis was unsuspected before or until just before the time of the muscle biopsy. All
muscle specimens demonstrated congophilic deposits around blood vessels and muscle fibers, some necrotic and regenerating fibers, and signs of mild denervation. Immunostains in 10 patients revealed immunoglobulin amyloidosis in 7
and gelsolin amyloidosis in 1. Apolipoprotein E co-localized with the congophilic deposits in all 10, and a C-terminal
epitope of the P-amyloid precursor protein was detected in 6. The frequency of the diagnosis of amyloid myopathy
increased 10-fold when we adopted the fluorescent Congo red stain as a routine procedure in assessing muscle biopsy
specimens.
Spuler S, Emslie-Smith A, Engel AG. Amyloid myopathy: an underdiagnosed entity.
Ann Neurol 1998;43:719-728
Skeletal muscle, together with kidney, skin, peripheral
nerve, heart, and other organs, can be involved in systemic amyloidosis. Muscle involvement is associated
with amyloid deposits around small blood vessels and
muscle fibers.283Typically, patients with systemic amyloidosis present with nonmuscle symptoms.
Before 1995, we searched for amyloid deposits in
muscle in unsuspected cases of amyloidosis only when
we saw abnormal thickening and homogenization of
the mural elements of intramuscular blood vessels or
unusual homogeneous endomysial deposits. To detect
amyloid, we relied on metachromasia in crystal violetstained sections or on green birefringence with polarization microscopy in Congo red-stained sections. After the detection of small congophilic deposits in
inclusion-body myositis (IBM)4 and report of an improved fluorescence method for visualizing congophilic
material,5 we searched for congophilic inclusions in
suspected cases of IBM, and also in other muscle disease~,~,'
using rhodamine optics. After we included the
Congo red stain in the routine evaluation of all muscle
biopsy specimens in 1995, we began to detect unsuspected amyloid myopathy in patients in whom muscle
weakness was a presenting symptom.
To determine the cause of amyloid deposition in
muscle, we immunolocalized proteins associated with
various forms of systemic amyloidosis,' namely, transthyretin,',' serum amyloid A component,'0p'2 K and h
light-chain proteins,l o and the amyloid-associated pro-
teins apolipoprotein E (ApoE) and serum amyloid P
component.
Because of their potential role in the
pathogenesis of Alzheimer's disease, we also searched
proteins found in plaques in Alzheimer's disease,
namely, amyloid (3-protein (Ap), epitopes of (3-amyloid
precursor protein ((3APP),13 c-w,-anti~hymotrypsin,"~
and the C5b9 complement membrane attack com-
From the Department of Neurology and Neuromuscular Research
Laboratory, Mayo Clinic, Rochester, MN.
Received Jun 11, 1997, and in revised form Dec 5. Accepted for
publication Dec 17, 1997.
*Present address: Neurological Clinic, Grossharden, 8 1366, Munich, Germany.
Address correspondence to Dr Engel, Department of Neurology,
Mayo Clinic, Rochester, M N 55905.
'
Plex.'4,'6,'7
AP induces apoptosis in cultured
and
there is evidence for DNA damage and apoptosis in
brain in Alzheimer's disease.20 Furthermore, physical
contact of neurons with amyloid deposits in brain increases the risk of neuronal death.21 We therefore
tested the idea that other forms of amyloid could induce apoptosis. To this end, we searched for DNA
fragmentation using the TUNEL assay and looked for
apoptotic nuclei by electron microscopy in cellular elements of infiltrated blood vessels and in muscle fibers
enveloped by amyloid deposits.
Patients
and Methods
Patients
Patients were selected retrospectively by the following criteria: (1) The patient presented with muscle weakness; (2)
amyloidosis was unsuspected on clinical grounds before the
muscle biopsy; and (3) the muscle sample contained extracellular amyloid deposits. Histologically, normal muscle specimens from subjects without objective evidence of muscle
disease were used as controls.
Copyright 0 1998 by the American Neurological Association 719
Light and Electron Microscopy
For routine histochemical studies, limb muscle specimens
were flash-frozen in isopentane chilled by liquid nitrogen.
Ten-micron-thick frozen serial sections were processed for
hematoxylin-eosin, modified Gomori trichrome, NADHand succinate dehydrogenase, ATPase (preincubation at pH
4.3, 4.5, and 9.4), acid phosphatase, periodic acid-Schiff, oil
red 0, and nonspecific esterase.” To detect amyloid deposits
in frozen sections, we employed the alkaline Congo red
stainz3 in combination with polarization or, more recently,
fluorescence microscopy,5224using rhodamine optics. Those
sections initially examined under polarization microscopy
were reexamined under rhodamine optics.
TUNEL Assay
For the TUNEL assay, sections were fixed with 4% glutaraldehyde for 15 minutes and preincubated with TdT buffer
(30 mM Trizma base, 140 mM sodium cacodylate, pH 7.2,
1 mM cobalt chloride). The reaction mixture consisted of
140 mM biotin-1 1-dUTP (Boehringer Mannheim, Indianapolis, IN) and 0.3 units/mL final solution of terminal deoxynucleotidyl transferase (Boehringer Mannheim) in TdT
buffer. After incubation for 60 minutes at 37°C the reaction
mixture was terminated by treatment for 15 minutes with a
solution containing 300 mM NaCl and 30 mM sodium citrate (pH 8.0). After washing and incubation with 10%
mouse serum for 10 minutes, the sections were developed
with streptavidin-peroxidase (KPL, Histomark-Kit, Gaithersburg, MD).25
ies were localized with biotinylated donkey-antirabbit antibodies (multiabsorbed, Jackson Immunoresearch, West
Grove, PA; 2.5 mg/mL). The sections were developed with
streptavidin-FITC (Jackson Immunoresearch, 0.85 mg/mL),
streptavidin-Cy3 (Jackson Immunoresearch, 0.8 mg/mL) or
with streptavidin-peroxidase (KPL, Histomark-Kit). Controls
consisted of substituting isotype-matched irrelevant antibodies or rabbit immunoglobulin for the primary antibody.
ApoE Genotyping
Genomic DNA was purified from muscle specimens using
the QIAmp Tissue Kit (QIAGEN, Chatsworth, CA). We
amplified a 227-bp DNA fragment spanning two polymorphic sites of the ApoE gene.” The polymerase chain reaction
mixture included 60 mM Tris-HCI (pH 8.5), 15 mM
(NH4),S04, 2.0 mM MgCI,, 0.25 mM dNTP, 0.8 p M
each primer with 200 ng of DNA and 0.5 U of Taq DNA
polymerase (Boehringer Mannheim) in 25 pL. The cycling
protocol consisted of denaturation at 94°C for 5 minutes, 40
cycles of 94°C for 1 minute, 65°C for 1 minute, 70°C for 2
minutes, and final extension at 70°C for 10 minutes in a
RoboCycler (Stratagene, La Jolla, CA). The polymerase
chain reaction product (4 p,L) was mixed with 10 units of
HbaI (New England Biolabs, Beverly, MA) in a lO-p,L reaction mixture containing an appropriate buffer and incubated at 37°C for 2 hours. The products were sizefractionated on 20% acrylamide gel and then stained with
0.5 mg/mL ethidium bromide.
Results
Immunocytocbernistry
Serial 6-pm frozen sections were processed by immunofluorescence or by immunoperoxidase staining. Table 1 lists the
primary antibodies used to detect amyloid-related proteins or
epitopes of the P-amyloid precursor protein (PAPP). Mouse
primary antibodies were localized with biotinylated goat antimouse IgG (KPL, Histomark-Kit); rabbit primary antibod-
Clinical Data
Table 2 summarizes the clinical data in 13 patients
with amyloidosis. All had proximal muscle weakness
except Patient 8, who had slowly progressive distal
weakness. Five patients had additional nonneurologic
symptoms: diarrhea (Patients 3, 4, and 6 ) , easy bruis-
Table I . Primary Antibodies for Immunocytocbemisg,
Antigen
Raised in
A Light chain
K Light chain
Amyloid P
Amyloid A
Albumin
Gelsolin
Transthyretin
&-Microglobulin
PAPP, N-terminal epitopes7’
PAPP, KPI domain (residues 293-3 15)71
Amyloid P protein (residues 8-17)72
PAPP, C-terminal (residues 676-695)73
Ubiquitin
cx ,-Antichymotrypsin
ApoE
Prion protein, prp 27-30
C5b9 (MAC)
Rabbit
Rabbit
Rabbit
Mouse
Rabbit
Mouse
Rabbit
Mouse
Mouse
Rabbit
Mouse
Rabbit
Mouse
Rabbit
Mouse
Rabbit
Mouse
PAPP = P-amyloid precursor protein; KPI
MC1
2C4
NAMB- 1
22c11
KPI-15
1G10/2/2
C8
3D12
R073
aEl1
DilutiodConc.
Source
1.1 pg/mL
1 pgimL
9 pg/mL
1/50
7 pg/mL
1:400
1:50
1:25
2 pg/mL
1:1,500
1:lOO
1:4,000
1:50
1:1,000
1:lO
1:400
2 pg/mL
Dako
Dako
Calbiochem
Dako
Dako
Sigma
Boehringer
Boehringer
Boehringer
D. J. Selkoe
G. G. Glenner
D. J. Selkoe
Chemicon
Dako
Accurate Chemical
S. B. Prusiner
Dako
Kunitz protease inhibitor; all rabbit antibodies are polyclond; all mouse antibodies are mono-
clonal.
720 Annals of Neurology Vol 43
Clone
No 6
June 1998
follow-up was available (see Table 2). Patients 9 and
11 had multiple myeloma.
ing (Patient 3 ) , nephrotic syndrome (Patient lo), and
nephrosclerosis (Patient 13). None had a positive family hisrory for amyloidosis. The tongue and masseter
muscle were enlarged in Patient 1; no muscle enlargement was noted in the others.
The serum creatine kinase level was elevated 2- to
5-fold in 8 patients, 10-fold in Patient 12, and 70-fold
in Patient 8 (see Table 2). Electromyography revealed
rapidly recruiting short-duration motor unit potentials
(MUPs) consistent with myopathy in a11 patients.
Long-duration MUPs consistent with reinnervation
were present in distal muscles in Patients 2, 5, and 8;
in proximal and distal muscles of Patient 1; and in deltoid and lumbar paraspinal muscles of Patient 6. Seven
had fibrillation potentials (Patients 2, 3, 5 , 6, 7, 8, and
10). In all 7, the fibrillation potentials were present in
proximal as well as distal muscles. Patient 4 also had
high-frequency repetitive discharges, and Patient 7 had
rare myotonic discharges in a few muscles. In addition,
Patient 4 had an ulnar entrapment neuropathy, Patient
5 had a mild carpal tunnel syndrome, and Patients 7
and 10 had a mild sensorimotor neuropathy. Patient 7,
however, also had long-standing diabetes.
Involvement of other organ systems was subsequently demonstrated in the 8 patients in whom
Biopsy Findings
The muscle fibers varied abnormally in size, with the
smallest fiber diameters ranging from 3 to 25 mm and
the largest ones from 60 to 120 mm in the different
specimens. Hypertrophied fibers larger than 75 mm
were detected in seven specimens. Fiber atrophy due to
compression by amyloid was noted only in specimens
from Patients 2 and 4. Necrotic and regenerating fibers
(Fig 1A) and signs of mild denervation atrophy were
detected in all specimens. The frequency of necrotic
fibers per low-power field was less than one in 9 patients, one or two in Patients 3, 12, and 13, and two to
five in Patient 8, who also had the highest serum creatine kinase level.
In Congo red-stained sections all specimens displayed congophilic amyloid deposits. When the sections were examined under rhodamine optics, the deposits infiltrated and surrounded the walls of small
arterioles and venules in all specimens and surrounded
few to numerous capillaries in six (Patients 5, 7, 8, 10,
11, and 12). In all but three specimens (Patients 4,9,
and 13), the deposits partly or completely encased sin-
Table 2. Patients with Primary Amyloidosis Presenting with Muscle Weakness
Patient Age (yr)/ Duration of
Sex
Weakness Other Signs or Symptoms
No.
-
CK
Subsequent Studies
NA
Autopsy 12 months after biopsy: amyloid deposits in
gastrointestinal tract and endocrine glands
A Chain in urine; concentric cardiomyopathy; amyloid in bone marrow and rectum
A Chain and K chain in urine, cardiomyopathy, factor X deficiency
Biclonal gammopathy with IgA A and IgA K; 8%
plasma cells in bone marrow
Concentric cardiomyopathy; amyloid in heart and
bone marrow
Monoclonal A gammopathy; concentric cardiomyopathy; amyloid in rectum
A Chain in urine; amyloid in subcutaneous fat and
bone marrow; 10-20Yo plasma cells in bone marrow
NA
A Chain in urine; 20% plasma cells in bone marrow; lytic bone lesions consistent with multiple
myeloma
A Chain in urine and serum; concentric cardiomyopathy; amyloid deposits in kidney
K Chain in urine and serum; bone marrow infiltrated with atypical plasma cells; lytic bone lesions
consistent with multiple myeloma
NA
A Chain in urine and serum; 5% plasma cells in
bone marrow; amyloid in kidney and bone marrow; hepatomegaly 3 months after muscle biopsy
~
1
53lM
4 mo
2
66lM
3 Yr
Firm muscles, enlarged
tongue and masseter
Easy bruising
3
531F
3 mo
Easy bruising, diarrhea
4
801M
6 mo
Diarrhea
5
69lM
1.5 yr
6
651F
5 Y'
Carpal tunnel syndrome,
myalgias, congestive failure
Diarrhea, orthopnea
7
71lM
3 Yr
8
9
26lM
77lF
4 Y'
10
67lM
4 mo
11
73lM
1 Yr
12
13
791M
661M
2 mo
3 mo
Diabetes mellitus, neuropathy, easy bruising
220
320
70
350
306
483
15,210
578
6 mo
60
Nephrotic syndrome, neuropathy
NA
Nephrosclerosis
2,100
640
NA = not available.
Spuler et al: Amyloidosis Involving Skeletal Muscle 721
Fig 1. (A) Trichrome section. Note abnormal
variation in fiber diameters and necrotic and
regenerating fibers. (B) Trichrome section showing small perimysial blood vessel surrounded and
in$ltrated by homogeneous material. The lumen
is nearly obliterated by swollen endothelial cells.
(C and D) Congo red-stained sections viewed
under rhodamine optics. Note infiltration of vessel wall in C and encasement of perifscicular
muscle fibers in D by congophilic material. (E
and F) Nonadjacent sections immunostained f . r
K (E) and A (F) immunoglobulin light chain.
The K light chain deposits are mainly perivascular; A light chain deposits surround both blood
vessels and muscle fibers. (C and H) C5b9 membrane attack complex (red signal, (G) co-localizes
with gelsolin (green signal in H ) in patient
with gelsolin-amyloidosis. (I and J Nonadjacent
sections demonstrating identical localization of
congophilic deposits (red signal in I ) and the
C-terminal epitope of PAPP green signal in 1).
(K and L) Adjacent sections demonstrating identical localization of congophilic deposits (red signal in K ) and apoE deposits (green signal in L)
around Congo red-positive muscle fibers (red
signal). (A, X 60; B, X 240; C, X 100; D t o
J, X 150; K and L X 95.)
gle muscle fibers (see Fig 1C and D). Fiber encasement
was most marked in the peripheral regions of the fascicles. Examination of hematoxylin and eosin-stained
722 Annals of Neurology
Vol 43
No 6 June 1998
or trichrome-stained sections, in contrast, revealed abnormal blood vessels only in 6 patients (see Fig lB),
even when they were reviewed after the diagnosis of
amyloidosis was already established. Sparse perivascular
inflammatory cells occurred in two specimens (Patients
2 and 10).
ULtrastmcturaLAnalysis
Electron microscopy was performed on four muscle
specimens from patients with amyloid myopathy (Fig
2). The amyloid filaments were present around small
blood vessels and muscle fibers. Short, nonbranching
fibrils, about 10 nm wide, accumulated adjacent to the
contraluminal surface of the endothelial cells (see Fig
2A) and extended to variable distances into the inter-
stitial connective tissue and around nearby muscle fibers (see Fig 2A and B). Subsarcolemmal regions of
muscle fibers surrounded by amyloid fibrils contained
an increased number of rough endoplasmic reticulum
profiles, mitochondria, and myeloid structures. Degenerate residues of papillary projections of muscle fibers
were often present in the amyloid envelope encasing
the fibers (see Fig 2B). No apoptotic nuclei were detected in endothelial cells or smooth muscle fibers of
blood vessels infiltrated by amyloid or in muscle fibers
partly or completely encased by amyloid.
Fig 2.Microfibrillary amyloid deposits around capillary (A) and muscle fibers (A and B) in K light-chain amyloidosis. Fibroblast
processes (arrows) abut on boundaries of the amyloid deposits. Degenerate residues of papillary projections of muscle jbers (arrowheads) extend into the amyloid envelope encasing them. (A, X
IZ IOO; B,
X
19,400.)
Spuler et al: Amyloidosis Involving Skeletal Muscle
723
Amyloidosis-Rehted Proteins
Table 3 summarizes the immunohistochemical studies
in 10 patients. Seven of the 10 had immunoglobulin
amyloidosis. Lambda light-chain deposits were found
in 3 (Patients 3, 6, and 7), K light-chain deposits were
found in 2 (Patients 5 and 11), and X plus K lightchain deposits were found in 2 (Patients 4 and 10).
The K light-chain deposits were mainly perivascular
(see Fig 1E), and the X light-chain deposits were both
perivascular and around the muscle fibers. Immunostains for amyloid P were positive in all cases.
Patient 8 had gelsolin-amyloidosis (see Fig 1H). Interestingly, the gelsolin deposits co-localized with the
C5b9 membrane attack complex (see Fig 1G). C5b9
deposits were also present in necrotic fibers in all specimens, which is a nonspecific finding.” Stains for
other amyloidosis-related proteins (ie, transthyretin,
amyloid A, and &-microglobulin) were negative.
p-Amyloid Precursor Protein (/3APP) Epitopes and
Amyloid-Associuted Proteins
PAPP is a widely distributed protein, and one of its
peptide fragments is a major constituent of amyloid deposits in Alzheimer’s disease. We therefore tested for
the presence of various epitopes in the N-terminal,
Kunitz protease inhibitor, amyloid P-protein, and
C-terminal regions of PAPP. Immunostains for the
C-terminal epitope of pAPP (residues 676-695) were
brightly positive in 6 of 10 biopsy specimens (Patients
2, 3, 6, 7, 9, and 10). The anatomical distribution resembled that of the congophilic deposits but was
slightly less extensive (see Fig 11 and J). Immunostains
for other PAW epitopes were negative.
To assess the presence of amyloid-associated proteins
in the amyloid deposits, we immunostained for ApoE,
a,-antichymotrypsin, prion protein, and ubiquitin.
ApoE deposits occurred in all muscle specimens, and
their distribution corresponded to that of the congophilic deposits (see Fig 1K and L). Immunostains for
Table 3. Composition of Amyloid Deposits
Patient No.
2 3 4 5 6 7 8 9 10 11
A Light chain
K Light chain
Amyloid P
Gelsolin
C5b9 (MAC)
pAPP residues 676-695
ApoE
-_ +_ + - + + - - +
++---- + +
-_ +_ +_ +_ +_ +_ -+- - + +
-
-
_ _ _ _ _ _ + -
+ +
- -
++
-
-
-
-
+ +
-
++++++++ + +
Immunostains for transthyretin, P,-microglobulin. amyloid A,
N-terminal PAPP, KPI epitope of PAW, PAPP peptides 8-17 and
17-24, ubiquitin, and prion protein were negative.
MAC = membrane attack complex; APP = amyloid precursor protein; KPI = Kunitz protease inhibitor.
724 Annals of Neurology
Vol 43
No 6
June 1998
the prion protein and for ubiquitin were negative.
There was no significant accumulation of a,-antichymotrypsin in the amyloid deposits.
TUNEL Assay
This assay detected no apoptotic nuclei in cellular elements of blood vessels or in the muscle fibers in any of
the specimens.
ApoE Alleles
All 10 patients tested for the ApoE genotype carried
the ~3 allele. Two patients were heterozygous, one being € 2 1 ~ 3and one ~ 4 1 ~ This
3 . distribution of ApoE
alleles follows that of the normal population.
Discussion
We report a group of 13 patients in whom muscle
weakness was the presenting and sometimes the only
symptom of systemic amyloidosis. Before 1995 and the
routine use of the fluorescent Congo red stain, we
greatly underestimated the frequency of amyloidosis involving muscle. Between 1965 and 1995, we detected
6 cases of amyloid myopathy in 12,000 muscle specimens, but between 1996 and May 1997 we diagnosed
7 additional cases in 1,400 muscle specimens. We attribute the 10-fold increase in diagnostic sensitivity to
the routine use of the fluorescent Congo red stain in
the study of the muscle biopsy.
Signs or symptoms of systemic involvement may or
may not be present when the muscle symptoms appear.
In the present series, the occurrence of nonmuscle
symptoms did not correlate with the duration of the
weakness; in some patients, slowly progressive weakness
was the only symptom for 4 years; others had symptoms consistent with amyloidosis soon after the onset
of weakness.
Comparison with Prior Reports of Amyloid Myopathy
We reviewed 43 cases of amyloid myopathy published
since 1968. Thirty-two were shown to have light-chain
immunoglobulin amyloidosis (AL),3*28-455 had familial amyloidosis (AF),2,46and none had secondary amyloidosis (AA). The diagnosis of AL was established by
serum or urine immunoelectrophoresis or bone marrow
studies. The light-chain dysproteinemia was of the h
type in 20 and of the K type in 12, and in 9 patients
it was associated with multiple myeloma. Most patients
had muscle weakness. This was p r o ~ i m a l , ~ ’ , ~ d’
~1s,~~,~’
or unspecified
tal,30 proximal and dista1,35,3’240242345,46
in d i ~ t r i b u t i o n .In
~ , ~some, the weakness was accompaor. ~by
nied by m y a l g i a ~ ~ ~
’ muscle induration or stiffness.29-32,34,35,38,39
Three patients had little or no
failure had only diw e a k n e s ~ ~ ~ ,1’ with
~ , ~ ~respiratory
;
aphragm and tongue inv01vement~~;and 2 had
exercise-induced claudication owing to amyloid angipa thy.",^^ Nineteen had enlarged muscles, with or
without
macroglossia2~3~29-32~34~37-39.41~45.
, had
5
iso-
The site of amyloid deposits may also depend on the
lated macroglossia33~35*3”39;
and 15 had normal or
amyloid-associated proteins, such as amyloid P and
reduced muscle b ~ l k . ~ , ~ ~Electromyog, ~ ~ , ~ ~ , ApoE.49-51
~ ~ , ~ ~Because some of these proteins are norraphy revealed motor unit potentials consistent with
mally present in the basement membrane52,53or, like
myopathy and signs of abnormal electrical irritaApoE, are involved in membrane repair,54 factors rebility consisting of fibrillation potentials and possiding in the basement membrane or the extracellular
itive waves,31332,38,40,42,43245 high-frequency repetitive
matrix of specific organs might determine the organ or
d i s ~ h a r g e s , ~ and
~,~~
rare
, ~ ~myotonic discharge^.^'
tissue distributions of the amyloid deposits.55 The ~4
Ten patients had a coexistent peripheral neuropaallele of the ApoE gene is a risk factor for developing
thy,3,31,34,36,38,43 and 6 had carpal tunnel synAlzheimer’s disease56 and for amyloid @-protein depodr~me.~,~~,~’
sition after head injury.57 Because ApoE immunoreacConsistent with previous reports of amyloid myoptivity was consistently co-localized with the extracelluathy, 10 of the 13 patients in our series had AL amylar amyloid deposits, we searched for a possible
loidosis. Two of these had multiple myeloma, and the
correlation with ApoE ~4 allele positivity in our paAL amyloidosis was more frequently due to h than K
tients but did not detect this correlation in our small
light-chain dysproteinemia. The findings on electroseries. However, our findings support the idea that
myography were similar to those noted in previous
ApoE becomes associated with amyloid in different
types of systemic amyloidosis.”
reports.
PAPP is also widely distributed in human tissues,
Only 1 of our 13 patients, as compared with 19 of
including skeletal muscle.58 It binds to extracellular
43 reported previously, had enlarged muscles. Our
findings, however, are comparable with those of Gertz
matrix and basement membrane constituents, including laminin and collagen.23 The expression and bioand
who found only 3 patients with enlarged
muscles among 12 with muscle amyloidosis. The difgenesis of PAPP is strongly influenced by tissue remodferences in the frequency of muscle enlargement in the
eling and repair.59 Therefore, the presence of PAPP
different series may owe to different criteria for selecepitopes in extracellular amyloid in 6 of 10 patients
tested might reflect local tissue injury rather than being
tion of patients for biopsy and to the criteria by which
a key pathogenic event in the course of the disease.
patients were included in the present study. A proporThat only a C-terminal PAPP was associated with the
tion of the patients in the previously published cases
extracellular amyloid deposits was of special interest.
may have undergone biopsy because they had enlarged
Because the localization was substantive (see Fig 1J)
muscles or because they had involvement of other tisand not observed when isotope-matched mouse IgG
sue or organs suggesting amyloidosis. By contrast, the
was substituted for the primary antibody, the localizapatients reported by Gertz and Kyle include several
tion was not due to adsorption of mouse IgG to the
with muscle weakness in whom the monoclonal proamyloid deposits. Artifactual lack of reactivity with
tein was the only clinical clue to amyloidosis, and in
other antibodies directed against the N-terminal
our 13 patients the diagnosis of amyloidosis was unepitopes of PAPI? and against A@ residues 8-17 was
suspected before or until just before the time of muscle
excluded by binding of these antibodies to neuritic
biopsy. The routine screening of muscle samples from
plaques and target formations. One possible explanapatients with weakness of undetermined origin by the
tion is that circulating PAPI’ is passively adsorbed to
fluorescent Congo red stain likely detects an earlier
the amyloid deposits and then partially degraded by sestage of amyloid myopathy, before the muscles enlarge.
rum proteases destroying certain epitopes. An alternaAlternatively, the muscle enlargement in amyloid mytive possibility would be that the antibody against the
opathy is uncommon if patients are not preselected for
C-terminal region of PAPP cross-reacts with light-chain
biopsy because they have enlarged muscles.
sequences. However, a search of the GenBank database
revealed no homologies between these sequences.
Sites of Extracellular Amyloid Deposition and
One can compare the association of C-terminal
Amyloid-Associated Proteins
@APP epitopes in extracellular amyloid deposits in
The predilection of a particular type of amyloid prosome cases of amyloid myopathy (see Table 3) with the
tein for a particular organ is an unresolved question in
intracellular expression of PAPP epitopes in vacuolated
amyloidogenesis. Both a review of the literature and
fibers in IBM‘O and chloroquine-induced myopaour observations indicate that most cases of muscle
in abnormal fibers in myofibrillar myopathy,6
amyloidosis are due to deposition of light-chain immuand in target formations.’ All PAPP epitopes can
noglobulins. Light-chain amyloid deposits isolated
be immunolocalized in the vacuolated fibers of IBM
from different organs of a given patient may differ in
molecular weight?8 This implies that immunoglobulin
and chloroquine-induced myopathy as in the neuritic
polymerization into amyloid is affected by tissueplaques of Alzheimer’s disease. By contrast, only
specific factors.
N-terminal PAPP epitopes and residues 8-17 of AP
Spuler et al: Amyloidosis Involving Skeletal Muscle
725
are present in abnormal fibers in myofibrillar myopathy and in target formations. ApoE co-localizes with
the amyloid deposits in both amyloid myopathy and
IBM, whereas ubiquitin and a,-antichymotrypsin associate with intracellular congophilic material in myofibrillar myopathy and IBM. P protein is detected with
extracellular amyloid in most cases of amyloid myopathy but is absent from intracellular amyloid deposits.
Considering the divergent etiologies of these diseases,
the differences are not surprising.
Gelsolin Amyloidosis
The typical clinical features of gelsolin amyloidosis are
lattice corneal dystrophy, cranial neuropathy followed
by polyneuropathy, and cutaneous i n d ~ r a t i o n . ~The
"~
gelsolin gene mutations reported to date are autosomal
dominant in Finnish,65 Japanese,66 and American6'
lundreds. Our patient with gelsolin amyloidosis is an
Arab and has no similarly affected family members. He
presented with distal myopathy and had no neuropathy, symptoms of corneal dystrophy, or cutaneous induration. Because the gelsolin deposits in muscle were
not discovered until after the patient left the country, a
search for corneal dystrophy by slit lamp examination
was not performed. That his clinical features are different from those of other patients with gelsolin amyloidosis may well be due to genetic heterogeneity in the
disease. The lack of family history suggests a gelsolin
mutation arising in the parental germ line, or the patient could be a somatic mosaic, or he might have a
unique recessive form of gelsolin amyloidosis.
Other Comments
The mechanism by which amyloid deposits cause muscle fiber injury is not understood. The ultrastructural
analysis and the TUNEL assay revealed no hint of apoptotic cell damage. A possible mediator of fiber injury
would be the C5b9 membrane attack complex. Indeed,
complement activation in neuritic plaques is implicated
in the pathogenesis of Alzheimer's
However, in our series only the patient with gelsolin amyloidosis had C5b9 deposits in muscle.
Muscle fiber damage also could result from chronic,
subacute, or acute ischemia caused by narrowing and
obstruction of small blood vessels,44946or encasement
of muscle fibers by amyloid could interfere with diffusion of nutrients. Regardless of the exact cause of the
fiber injury, it is important to realize that necrotic and
regenerating muscle fibers can result from amyloidosis
involving skeletal muscle.
We are grateful to Drs Selkoe and Prusiner and the late Dr Glenner
for generous gifts of antibodies. We thank Dr Kinji Ohno for genetic analysis of ApoE haplotypes and Linda Murphy for excellent
technical assistance.
726 AnnaIs of Neurology
Vol 43
No 6
June 1998
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