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Calpainopathy and eosinophilic myositis.

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Calpainopathy and
Eosinophilic Myositis
In recent years, it has become clear that there are multiple causes of myositis. Particularly informative is the
observation that primary muscular dystrophies, which
were not conventionally thought to perturb the immune system, can evoke robust, nonspecific inflammatory responses in skeletal muscle. Myositis with a preponderance of eosinophils usually is ascribed to specific
adverse stimuli including parasitic infections, vasculitides (eg, Churg–Straus syndrome), nonhematological
and hematological malignancies (T-cell lymphomas,
aplastic anemia, hypereosinophilic syndrome), toxins
(toxic oil and L-tryptophan), and rare conditions such
as idiopathic eosinophilic fasciitis (Shulman syndrome).1
In this issue of Annals of Neurology, Krahn and colleagues2 demonstrate that eosinophilic myositis can
also occur as a secondary consequence of primary mutations in the gene encoding the muscle protein
calpain-3. This is of considerable importance, because
mutations of calpain-3 gene are the most common
cause of adult-onset, recessively inherited limb girdle
muscular dystrophy (LGMD1A or calpainopathy). The
six cases reported in this study share distinctive clinical
features: (1) childhood onset (mean, 7.5 years); (2)
substantially elevated levels of the enzyme creatine kinase (mean 8,025 1u, or 20- to 40-fold elevated); (3)
subtle or no motor findings; (4) variable peripheral eosinophilia; (5) absence of agents known to provoke eosinophilia; and (6) compound heterozygosity or homozygosity for calpain mutations (some of which
clearly predict loss of calpain function). One of the
cases was reported previously as eosinophilic myositis.3
In the six cases, there is not an obvious relation between the eosinophilia and specific mutations, because
these patients harbored seven different calpain gene
mutations of which only one was novel.
Krahn and colleagues’ report2 teaches several points
and raises important questions, including the seven issues discussed in this editorial. First, children in the
first decade of life with hyperCKemia and evidence either of hypereosinophilia or eosinophilic myositis
should be screened for calpain mutations.
Second, in contrast with other dystrophies, which
are associated with nonspecific muscle inflammation,
calpainopathies predispose to hypereosinophilia and an
eosinophilic immune response in calpain-3–deficient
muscle. In dystrophinopathies, the infiltrate is composed mainly of macrophages and CD8⫹ cytotoxic T
cells, which generally are present in and around ne-
crotic muscle fibers.4 Occasionally, the inflammation
can be so prominent with certain types of dystrophy
(ie, congenital, facioscapulohumeral, and dysferlindeficient dystrophy) that patients are misdiagnosed
with polymyositis.5–13 However, eosinophilic infiltrates
in muscle have only rarely been described in muscular
dystrophy. One report describes a child eventually diagnosed with a dystrophinopathy who presented as a
floppy infant14 and whose muscle biopsy had the appearance of eosinophilic myositis. Eosinophilia also has
been described as a prominent feature of the necrotic
phase in the dystrophin-deficient MDX mouse.15 This
study suggested that eosinophilia in dystrophindeficient muscle was promoted by at least two mechanisms: (1) perforin-dependent cytotoxicity of effector T
cells, and (2) T-cell production of interleukin-5 (IL-5)
leading to differentiation and activation of eosinophils.15
Third, how calpain-3 deficiency activates eosinophils
warrants study. Eosinophilia in these conditions, as
well as the eosinophilic immune response in calpaindeficient muscle, may be the result of a perverse effect
on T-cell clones.16,17 Of note, there is oligoclonal expansion of T cells within the muscle in polymyositis.18,19 The destruction of muscle tissue may lead to
exposure of antigen-presenting cells to previously unseen molecules, inducing an inflammatory cell response. T cells and macrophages are most often recruited to sites of damaged fibers. As noted
previously,15 T lymphocytes secrete IL-5 and IL-3, cytokines that are required for the growth and differentiation of eosinophils20 and are powerful chemoattractants for these cells. Eosinophils, in turn, damage
muscle fibers by their release of the eosinophilic major
basic protein, which causes lysis of the membranes of
target cells.20
Because T cells presumably are recruited in any dystrophy, the further question is why there is such a
striking eosinophilic specificity in response to the absence of calpain-3. It may be relevant that calpain-3 is
highly expressed in T lymphocytes.21 Conceivably, loss
of calpain-3 function perturbs T-cell function in some
manner that leads to eosinophilia.
Less likely, but formally possible, is a model in
which calpain-3–deficient T lymphocytes allow infection of muscle with cryptic pathogens that are the
proximal triggers of muscle inflammation and the attractants for muscle eosinophils.
Fourth, it will be instructive to quantitate the reciprocal relation between calpain status and eosinophilic
myositis, defining the fraction of calpainopathies that
begin with an insidious eosinophilic response in muscle
and/or peripheral eosinophilia and, conversely, the percentage of cases of eosinophilic myositis that correlate
with calpain gene defects. In the investigation of muscle biopsies, it should be noted that eosinophils may
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
not be apparent on muscle biopsies, but markers of
their presence (eg, immunostaining for eosinophilic
major basic protein) may nonetheless be positive.22
Fifth, if only a fraction of calpain-negative dystrophy
cases develop an eosinophilic response, can one define
gene variants that modulate the propensity to develop
eosinophilia in susceptible individuals? A large segment
of the literature documents the role of genetic background as a determinant of susceptibility to autoimmune disorders, with perhaps the greatest focus on human leukocyte antigen variants. It therefore appears
likely that molecular variants will be identified that
predispose to eosinophilic immunoreactivity. In recent
years, genetic studies in a number of disorders associated with eosinophilia have defined inherited variants
that indeed contribute to this phenomenon. As one example, polymorphisms in the Rantes gene are now implicated in an aggressive, sometimes lethal form of
asthma in China.23 Variants in surfactant proteins apparently modify the degree of eosinophilia and total
IgE levels in allergic bronchopulmonary aspergillosis.24
In mice, it is clear that strain differences regulate levels
of eosinophilia in some circumstances.25,26 Careful
analyses of individuals in which calpainopathy correlates with eosinophilic myositis may demonstrate correlations with genetic variants that influence the occurrence and degree of eosinophilic response.
Sixth, what features help the clinician and pathologist to distinguish dystrophy with inflammation from a
primary inflammatory myopathy (myositis)? Scapular
winging, prominent facial weakness, and asymmetrical
involvement are common in fascioscapulohumeral dystrophy, but not myositis. Patients who have severe
proximal weakness (ie, Medical Research Council grade
3 or less) but normal strength distally (wrists and ankles) would be more likely to have a form of a LGMD
as opposed to a primary inflammatory myopathy. Dysferlinopathies can manifest with a LGMD pattern of
weakness, early gastrocnemius weakness and atrophy,
tibialis anterior weakness, or any combination of
the above and markedly elevated serum creatine kinase
Features on the muscle biopsy can also help to distinguish a dystrophy from polymyositis. Invasion of
nonnecrotic muscle fibers by mononuclear inflammatory cells is uncommon in muscular dystrophies,
whereas some suggest this feature is essential for the
definite diagnosis of polymyositis. Expression of major
histocompatibility antigen 1 is ubiquitous in polymyositis,27 but is present in only scattered fibers in muscular dystrophy.12 Also, deposition of MAC may be seen
on the sarcolemma of scattered nonnecrotic fibers in
fascioscapulohumeral dystrophy, LGMD, and dysferlinopathies, but not in PM, DM, or IBM.13,28
Finally, the seventh issue is what are the treatment
implications of Krahn and colleagues’2 study? Because
Annals of Neurology
Vol 59
No 6
June 2006
they often show marked inflammatory cell infiltrates,
glucocorticoids often are tried in treatment of dystrophies. However, with the exception of the modest response in children with Duchenne’s muscular dystrophy, the use of glucocorticoids has been disappointing
in the small series of patients reported with inflammatory dystrophies. The previously reported asymptomatic patient with eosinophilic myositis and calpainopathy had normal strength but an elevated serum creatine
kinase level, which was not improved by treatment
with glucocorticoids.2,3
Robert H. Brown, JR, D.Phil, MD and Anthony
Amato, MD
Neurology Service, Massachusetts General Hospital,
Charlestown, MA and 2Neurology, Brigham and
Women’s Hospital, Harvard Medical School
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CAPN3 mutations in patients with idiopathic eosinophilic myositis. Ann Neurol 2006;59:905–911.
3. Pena Segura JL, Adrados I, Jimenez Bustos JM, et al. Eosinophilic myositis in a 9 year old boy. Rev Neurol 2001;33:
960 –963.
4. Arahata K, Engel AG. Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according
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DOI: 10.1002/ana.20900
Diet and the Risk for
Alzheimer’s Disease
For centuries, the role of diet in the causation and prevention of disease has engaged scientific and lay interest. The hope, presumably, is that by identifying (and
consuming) significant amounts of a single nutrient or
set of nutrients, we can prevent disease and promote
longevity. Clinical studies of vitamins and other micronutrients are published regularly in support of this notion, and the results are highlighted routinely in newspapers, magazines, and popular media.
In this issue of Annals of Neurology, Scarmeas and
colleagues1 report an observational study of the Mediterranean diet and risk for Alzheimer’s disease (AD) in
a multiethnic population sample in northern Manhattan. The Mediterranean diet is characterized by high
intake of foods and nutrients that have been reported
to be beneficial in AD, including fruits, vegetables,
fish, unsaturated fatty acids, and modest amounts of
wine. After adjustment for numerous potential confounders, individual food groups were not significantly
associated with risk for AD, but the composite Mediterranean dietary pattern (highest tertile) was associated
with a 40% reduction in AD risk when compared with
the lowest tertile (hazard ratio, 0.60; confidence interval, 0.42– 0.87). The results of Scarmeas and colleagues’ study1 are consistent with other studies that
show benefit of the composite Mediterranean diet on
cognitive performance,2 as well as mortality cardiovascular disease, and cancer outcomes.3–5
The work of Scarmeas and colleagues1 extends the
approach in the study of diet and AD risk from individual foods and nutrients to a composite dietary
pattern. As they emphasize, “defining diet by dietary
patterns has the ability to capture its multidimensionality…because patterns can integrate complex or subtle interactive effects.…” It makes scientific
sense to consider dietary patterns because this conception more closely approximates the way people consume our nutrients. Defining diet by dietary patterns,
of course, also has limitations. In particular, we can
only speculate on the key mechanisms and interactive
effects underlying any observed benefits of a dietary
pattern. Some components of the diet may actually be
antagonistic or even harmful, and these effects would
be difficult to detect.
To be considered causal, a risk or protective factor
should satisfy criteria including consistency or replication of findings, specificity of the association, proper
© 2006 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
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calpainopathy, eosinophilia, myositis
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