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rotein Aggregate Myopathiesans H. Goebel, MD, and Harald D. Müller, MD

Protein aggregate myopathies (PAMs) based on the morphologic phenomenon of aggre-gation of proteins within muscle fibers may occur in children (selenoproteinopathies,actinopathies, and myosinopathies) or adults (certain myofibrillar myopathies and myosi-nopathies). They may be mutation related, which includes virtually all childhood forms butcertain other forms as well, or sporadic, which are largely seen in adults. Their classifica-tion as myofibrillar or desmin-related myopathies, actinopathies, or myosinopathies isbased on the identification of respective mutant proteins, most of them components of thesarcomeres. Recognition of PAM requires muscle biopsy and an extensive immunohisto-chemical and electron microscopic workup of the biopsied muscle tissue after whichmolecular analysis of morphologically ascertained proteins should ensue to permit recog-nition of individual entities and genetic counseling of patients and families. Becausepathogenetic principles in PAMs are still incompletely known, causative therapy, at thistime, is not available.Semin Pediatr Neurol 13:96-103 © 2006 Elsevier Inc. All rights reserved.

KEYWORDS protein aggregation, myopathies, actinopathy, desminopathy, myosinopathy

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rotein aggregate disorders are conditions morphologi-cally marked by the aggregation of proteins in tissues.

hey are classified among the slowly progressive degener-tive diseases. They might be hereditary/familial or non-ereditary/sporadic. Certain conditions may fall into bothategories (eg, Alzheimer disease and Parkinson disease).rotein aggregation may affect multiple organs representedy the various forms of amyloidoses or restricted to particularrgans, largely the brain or muscle. Proteins may aggregateithin cells or in the extracellular space, the latter examples

ontaining primary forms such as amyloidoses or secondarynes in which primary intracellular protein aggregates re-ain in the extracellular space after cell death (eg, neurofi-

rillary ghost tangles in Alzheimer disease).Protein aggregation within cells occurs outside of the lyso-

omal compartment; hence, protein aggregate disorders areot lysosomal diseases, which are marked by deficiencies ofnzymes, mostly with a genetic basis resulting in intralysoso-al accretion of noncatabolizable substrates. Lysosomal dis-

ases belong to metabolic diseases. Cause and pathogenesisf protein aggregation are still incompletely understood.

rom the Department of Neuropathology, Johannes Gutenberg University,Mainz, Germany.

ddress reprint requests to Hans H. Goebel, MD, Department of Neuropa-thology, Johannes Gutenberg University Mainz, Medical Center, Langen-beckstrasse 1, Bldg. 706, 55131 Mainz, Germany. E-mail: goebel@

tneuropatho.klinik.uni-mainz.de

6 1071-9091/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.spen.2006.06.005

mong the hereditary forms, mutations result in the forma-ion of mutant proteins. These mutant proteins may defyroper extralysosomal proteolytic degradation followed byrotein aggregation. Such a process may affect more than theutant protein, resulting in accumulation of a multitude ofiverse proteins, for instance aggregates marked by desminnd other proteins. Involvement of the ubiquitin-proteasomeystem in protein aggregation in muscle fibers1 attests to thisxtralysosomal protein degradation. On the other hand, mu-ant proteins may resist proper integration into physiologicaltructures during development.

An important nosological feature of many diseases is thenset of clinical symptoms. Among the protein aggregateisorders, there are some commencing in childhood, others

n adulthood, and few show a wide spectrum, encompassinghose of infantile and adult onset. Although brain and skeletaluscle are the most frequently affected organs in protein

ggregate disorders, it is the skeletal muscle that is not infre-uently involved in those forms of protein aggregate myop-thies, which commence in childhood. It is this group amonghe protein aggregate disorders, childhood protein aggregateyopathies, formerly also termed protein surplus myopa-

hies,2 which are the topic of this article. Protein aggregateyopathies are a very telling example of forward genetics in

hat immunohistochemical identification of proteins withinrotein aggregates had led to respective genes and to identi-cation of mutations. Concerning desmin-related myopa-hies, desminopathies, actinopathies, and myosinopathies,
hese principles and pathways have gainfully been pursued.

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Protein aggregate myopathies 97

roteinggregation in Muscle Fibers

ggregation of proteins within muscle fibers may be a non-pecific feature when it is observed in ragged red fibers oraps,3 in neurogenic “targets”4 and cores, both of central coreisease4 and multiminicore disease.5 These lesions (ie, raggeded fibers, caps, and core-targetoid features) have a lack inntact regular sarcomeres in common. Because ragged redbers are not developmental defects but rather occur overime in mitochondrial myopathies and core-targetoid fea-ures may indicate damage to muscle fiber innervation, theyhow disturbance of structural integrity and destruction ofrimarily normal sarcomeres. It appears that proteins are notegularly catabolized when intact structures of sarcomeresave been compromised. Progressive failure to maintaintructural integrity of abnormal sarcomeres seems to impairxtralysosomal proteolytic capacities in such sarcomeres ando result in extralysosomal aggregation of noncatabolizedroteins. It is conceivable, although to our knowledge not yetocumented, that other such sarcomere-defective areas withinuscle fibers, such as sarcoplasmic masses, may also show ag-

regation of proteins.Morphologically, aggregates of proteins may be ill defined

uch as in ragged red fibers and core-targetoid lesions or mayorm distinct and well-described inclusion bodies, some-imes patches or plaques. In the context of protein aggrega-ion, certain inclusion bodies within muscle fibers have al-eady been shown to contain proteins such as nemalineodies, actin filament aggregates, cytoplasmic, and otheresmin-containing bodies. Even if the entire spectrum ofroteins composing individual inclusion bodies may not benown, certain inclusions within muscle fibers contain sev-ral proteins, but not a single individual protein, only. Othernclusions have not successfully been analyzed such as re-ucing bodies, cylindrical spirals, and others encountered iniopsied muscle tissues of respective congenital myopathies.

yofibrillar Myopathiesyofibrillar myopathies (MFMs)6 are the longest-known

nd largest group of PAM, also designated as desmin-relatedyopathies,7 because desmin, the intermediate filament of

triated and smooth muscle cells, is a consistent componentf their protein aggregates. Hence, MFMs can be further sub-ivided according to mutations in proteins (ie, desminopa-hies,8 �-B crystallinopathies,9 selenoproteinopathy,10 myo-ilinopathies,11 ZASPopathies,12 filaminopathy,13 and mostecently also a form of laminopathy14 in which the majority ofatients are adults) (Table 1). Because MFMs indicate a mor-hologically defined muscle lesion, namely derangement andestruction of sarcomeres, together with aggregation of proteinsmong them desmin and other proteins, electron microscopi-ally either as inclusion bodies [eg, cytoplasmic bodies (Fig-re 1)], or granulofilamentous material, genetically not com-letely identified forms seem to exist among MFM, for

nstance when related to gene loci 2q21,15 10q23,16 chromo- m

ome 12,17 or, recently, 15q22.18 Although the majority ofatients with MFM have an adult onset of muscle weakness,ften more distally than proximally and not infrequently as-ociated with cardiomyopathy, some MFMs commenced atarious stages of childhood in several patients (Table 2).2

Selenoproteinopathy has often been observed in childrenecause it originated from observations earlier designated asparticular form of congenital muscular dystrophy, the

ichsfeld type, by Goebel and coworkers19 or later as Malloryody-like inclusion myopathy by Fidzianska and cowork-rs.20 These children have proximal or generalized muscleeakness, scoliosis, and often severe respiratory failure lead-

ng to premature death. Selenoproteinopathies are markedy mutations in the selenoprotein N1 gene10 and may mor-hologically show accumulation of desmin and other pro-eins,20,21 thus, qualifying as a myofibrillar myopathy, al-hough the aggregation of selenoprotein has not yet beenlearly documented, perhaps because of lacking availabilityf a suitable antibody. Other conditions occurring in child-ood, originating from mutations in the selenoprotein N1,re multiminicore disease, multiminicores also marked byccumulation of diverse proteins,5,22 and a rigid spine syn-rome.23 At another instance, Mallory body-like inclusionsere found in biopsied muscle tissue of 2 children, althoughot related to a mutation in the SEPN1 gene.24 This suggestedhat heterogeneity of the descriptively labeled myopathy with

allory body-like inclusions was further confirmed by an-ther study on 3 adolescents/young adults who had Malloryody-like inclusions in their biopsied muscle specimens buto mutations in the SEPN1 gene.25

Spheroid body myopathy, known for many years to affectlarge kinship,26,27 has a wide clinical spectrum with child-ood onset of muscle weakness in several patients. Presencef aggregated proteins, among them desmin in and aroundhe spheroid bodies27 as well as recently myotilin,28 promp-ed final recognition of a missense mutation, S39F, in exon 2f the myotilin gene (MYOT/TTID).28

A particular mutation in the desmin gene, R406W, in the Cerminus vicinity of the 2B helix (exon 6) of the desmin geneas repeatedly and independently been observed in Westernurope, associated with onset in adolescence of severe car-iomyopathy and subsequent skeletal muscle weakness.29

One patient with a heterozygous mutation in the desminene had a rather early (ie, childhood onset of clinical symp-oms) and a severe course because, in addition, he had aecond heterozygous mutation in the lamin A/C (LAMNA)ene.30 This observation not only indicated aggravation oflinical symptoms and, thus, perhaps, of clinical severity be-ause beside the desmin mutation recently a LAMNA muta-ion14 has been found independently causing MFM, but itepresents also one of the still rare although increasinglymerging digenic conditions.

ctin Filamentggregate Myopathy

ctin filament aggregate myopathy (AFAM) is a congenital
yopathy morphologically marked by aggregation of actin

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98 H.H. Goebel and H.D. Müller

laments (Fig 2) within muscle fiber because of mutations inhe sarcomeric ACTA1 gene. Less than a dozen sporadic pa-ients have been reported since the apparently first publica-ion,31 although, then, its nosological connotation had notet been realized. AFAM is a congenital condition, often rap-dly progressing to death within the first year of life. The

Figure 1 Desminopathies: (A) eosinophilic inclusions (aaggregates of desmin within muscle fibers and beneagranulofilamentous material spreads across a muscle fibonline.)

atients are floppy, and their respiration is severely dis- e

ressed, requiring artificial ventilation (often until their pre-ature demise). Recognition of AFAM requires a muscle

iopsy. Muscle tissue shows, by light microscopy, areas ofrregular size with condensed structures in histological prep-rations, devoid of both oxidative enzyme and ATPase reac-ions. Sometimes, such actin filament aggregates may fill the

) in skeletal muscle fibers, hematoxilin and eosin; (B)sarcolemma, immunohistochemistry; and (C) typicalctron micrograph. (Color version of figure is available

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ther muscle fibers, areas of actin filament aggregation maye sharply demarcated from intact sarcomeres. No increasedopulations of lysosomes or autophagic vacuoles, the latterften seen in desmin-related protein aggregation, have beendentified within affected muscle fibers. Because actin fila-

ents usually extend from Z-disks into normal sarcomeres, its not surprising to find associated rods in muscle fibers asvidence of an apparent nemaline myopathy. What is moreurprising is that some patients, in addition or exclusively,ad intranuclear rods beside their actin filament aggregates.n 1 patient’s muscle tissue, small sarcoplasmic rods or mi-irods were observed within muscle fibers.32

So far, each patient tested has had a heterozygous mutationn the ACTA1 gene, largely of the missense type, whereas thearents were always free of such mutations, indicating thatach ACTA1 mutation in the respective patient had been a deovo mutation. Even a single patient, first reported to haveo ACTA1 mutation,33 later was found to have a de novo Gly5 Arg mutation in his ACTA1 gene, although it was notresent in both his parents. Patients with AFAM and ACTA1utations represent a small fraction of the now large group ofatients with nemaline myopathy having mutations in theCTA1 gene, which may be encountered in one fourth to one

hird of all identified nemaline myopathy patients. A recentublication34 documents a Val 163 Met mutation in theCTA1 gene in a 4-generation–affected family with infantilelinical onset but long duration marked by cytoplasmic andntranuclear rods, in which accumulation of actin filaments

Figure 2 Actinopathies: (A) variation in fiber diameterssenting aggregates of actin filaments, modified Gomori-trand (B) large subsarcolemmal aggregate of actin filamefigure is available online.)

as only in passing and preliminarily mentioned. ACTA1 Z

utations have also been encountered in other congenitalyopathies (Table 3).The morphogenesis of actin filament aggregation in these

atients with ACTA1 mutations is unkown. As always, only 1CTA1 allele shows the mutation; there is a mixture of mu-

ant and wild-type actin present in patients’ muscle tissues,ut the precise distribution of these 2 types of actin anderhaps actin filaments and their presence in or absence fromegular sarcomeres as well as actin filament aggregates arenknown. It is conceivable that, at least in the actin filamentggregates, mutant actin is present with or without wild-typectin, which has been prevented or eliminated from integra-ion into sarcomeres. Early onset of AFAM, congenital or innfancy; the lack of a considerable number and amounts ofther proteins coaggregated with actin quite unlike the mul-

mogeneous areas within muscle fibers (arrows) repre-e (courtesy of Dr C. Bönnemann, Göttingen, Germany)

a muscle fiber, electron micrograph. (Color version of

able 1 Myofibrillar Myopathies

. Genetically identified B. Genetically incompletelyidentified

esminopathies 2q21lpha-B crystallinopathies 10q23yotilinopathies 12qASPopathies 15q22elenoproteinopathiesilaminopathiesaminopathiesalosinopathy

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itude of additional proteins seen together with desmin accu-ulation; and the absence of autophagy close to the actinlament aggregates or within muscle fibers with actin fila-ent aggregates suggest anabolic or synthetic/developmentalefects rather than a degradative/catabolic one as seen inesmin-related protein aggregation.

yosin Storageyopathy or Myosinopathy

yosin storage myopathy, in the premolecular era known as

able 2 Myofibrillar Myopathies in Children and Adolescents

Onset y/gender Presentation We

ith desmin mutationChildhood Cardiomyopathy

Conduction defectYoung adult:

prog. to prmuscles in

15 y/F Cardiac conductiondefect

Distal, legs (

18 y/M Atrial tachycardia Anterior tibia

ith other mutations3 y/F Difficulty running

No cardiac signsLimb girdle

Childhood Muscle weaknessNo cardiac signs

Proximal

Early childhood HypotoniaRespiratory distress

Proximal & fa

o known mutationAge 10 years Tiptoe walking Head flexion

weaknessPeripheral ne

Age 12 years Syncope Distal weaknCardiac dysrhythmia Bulbar musc

Age 14 years Dyspnoea Proximal & dChest pain Hoarse voice

o known mutationInfancy Delayed milestones Proximal andInfancy Weak suck Never able tInfancy Severe dysphagia Hypotonia

Ophthalmoplegia Persisting mEarly childhood Exercise intolerance None

Abnormal heart rateChildhood Waddling gait Axial and proChildhood Exercise intolerance

TirednessTeens: Proxi

muscle weAge 8 years Exercise intolerance

DyspnoeaLimb-girdle-lPolyneuropa

o known mutationAge 8 years Exercise intolerance

Heart murmurGeneral mus

(marked diperipheral

Age 9 years Frequent fallsWaddling gait

Limb-girdle-l

� female; M � male; prog. to prox. � progressive to proximal; (c

yaline body myopathy35 or originally as “myofibrillar lysis a

yopathy,”36 is now, after identification of mutations in theYH7 gene,38,39 considered a myosinopathy. Although theajority of patients are adults, some were only diagnosed as

dults but, retrospectively, had been affected since child-ood.40,41 As a matter of fact, the original report36 concernedvery young siblings affected by muscle weakness and whatad been termed “myofibrillar lysis” suggesting autosomal-ecessive inheritance. Another family with autosomal-domi-ant heredity has also been described.42 Affected childrenad mild proximal weakness, somewhat enlarged calves,36

nd slight elevation of creatine kinase. The electromyogram

rted Before and After 2002)2

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Cardiomyopathy 47

.) Cardiomyopathy 29, Pat. 2R406W

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No cardiomyopathy 14 W498CLMNA

No cardiomyopathyRespiratory insufficiency

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Respiratory insufficiency 10 SEPN1 del

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olvedeakness Cardiomyopathy 46

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Cardiomegaly 54CardiomyopathyECG normal 21

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Restrictive cardiomyopathy 45

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tricted, one of the orginally described siblings36 has died asyoung adult and had a novel MYH7 Leal793Pro mutation.37

ardiomyopathy is not a consistent feature, although a mildentricular hypertrophy was recorded by echocardiogra-hy.40,41 However, mutations in the MYH7 gene may causeardiomyopathy. Diagnosis is established by muscle biopsy,hich shows, largely subsarcolemmally, hyaline bodies (ie,nely granular, homogeneous, sharply demarcated pale areasithin muscle fibers [Fig 3] that lack oxidative enzyme activ-

ties but show fibrillar/myosin adenosine triphosphataseATPase] activity, especially in type I fibers, where these hy-line bodies prevail). Immunohistochemically, slow myosinay be encountered in these hyaline bodies, which, togetherith the histochemical myofibrillar ATPase activity, actuallyrompted mutational studies of the MYH7 gene. Two mis-ense mutations have separately been identified in differentatients: an Arg 1845 Trp mutation in European patients38,41

nd a His 1904 Leu mutation in a large Saudi family.43 The Arg

Figure 3 Myosinopathy: large homogeneous, opaque(arrows), modified trichrome preparation (courtesy of

able 3 Congenital Myopathies With ACTA1 Mutations

Nemaline/Rod myopathy57

With or without intranuclear rodsWith intranuclear rods only

Actin filament aggregate myopathy57

Core myopathy58

Congenital fiber type disproportion59

available online.)

845 Trp mutation is said to prevent myosin polymerizationnd, apparently, filament formation because, by electron mi-roscopy, the hyaline bodies consist of finely granular non-embrane-bound material, suggesting a developmental de-

ect, although incomplete extralysosomal degradation ofyosin proteins has not been ruled out. A second gene locus

n autosomal-recessive hyaline body myopathy has been es-ablished at 3p22.2 to 21.32,44 although a defective proteinas not yet been communicated from this gene locus.Hyaline body myopathy is a telling example how primaryorphologic studies of muscle tissue have prompted ade-

uate and successful molecular analysis (ie, from granularTPase-positive myosin to mutations in its MYH7 gene).

onclusionslthough aggregation of proteins is now a firmly recognizedorphologic phenomenon in muscle fibers, formerly encom-assing inclusion bodies of varying types (ie, filamentous orranular material), although now further characterized byheir protein composition having given rise to the group ofrotein aggregate myopathies among neuromuscular disor-ers, both in childhood and adulthood, progress in under-tanding these slowly or rapidly progressing disorders haseen accelerated by molecular identification of new formseg, selenoproteinopathies and myosinopathies) or additionf newly identified mutations in desminopathies and acti-

ccupy major parts of cross-sectioned muscle fiberszzarelli, Indianapolis, IN). (Color version of figure is

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opathies. Recent studies have brought some insight into theathogenetic mechanisms linking pathomorphologic fea-ures to molecular defects as well as clinical phenotypes. Athis time, however, our understanding of the basic principlesnvolved in the formation of protein aggregates in musclebers is still too scant to allow any promising therapeuticpproaches. Such basic principles entail extralysosomal pro-eolytic degradation as well as development, integration, andaturation of sarcomeric protein components, both pro-

esses resulting in faulty aggregation of proteins. The originalltrastructural description of aggregates and their subse-uent immunohistochemical characterization has led to suc-essful molecular analyses in many but possibly not all PAMs.his investigative path of morphologic features leading toolecular data ought to be further pursued in still-unidenti-ed individual PAMs and their patients. Recognition of still-nknown sarcomeric proteins may also add, enlarge, andurther clarify PAMs as a growing cohort of neuromuscularisorders with both early and late clinical onset.

cknowledgmentse are grateful to Walther Wagner for photographic support

nd to Astrid Wöber for editorial assistance.

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