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PThatihereditary/sporadic. Certain conditions may fall into bothcategories (eg, Alzheimer disease and Parkinson disease).Probyorgwicononmabri
Amtiopropromutant protein, resulting in accumulation of a multitude ofdiverse proteins, for instance aggregates marked by desmin
96tein aggregation may affect multiple organs representedthe various forms of amyloidoses or restricted to particularans, largely the brain or muscle. Proteins may aggregatethin cells or in the extracellular space, the latter examplestaining primary forms such as amyloidoses or secondaryes in which primary intracellular protein aggregates re-in in the extracellular space after cell death (eg, neurofi-llary ghost tangles in Alzheimer disease).Protein aggregation within cells occurs outside of the lyso-al compartment; hence, protein aggregate disorders are
t lysosomal diseases, which are marked by deficiencies ofzymes, mostly with a genetic basis resulting in intralysoso-l accretion of noncatabolizable substrates. Lysosomal dis-es belong to metabolic diseases. Cause and pathogenesisprotein aggregation are still incompletely understood.
and other proteins. Involvement of the ubiquitin-proteasomesystem in protein aggregation in muscle fibers1 attests to thisextralysosomal protein degradation. On the other hand, mu-tant proteins may resist proper integration into physiologicalstructures during development.
An important nosological feature of many diseases is theonset of clinical symptoms. Among the protein aggregatedisorders, there are some commencing in childhood, othersin adulthood, and few show a wide spectrum, encompassingthose of infantile and adult onset. Although brain and skeletalmuscle are the most frequently affected organs in proteinaggregate disorders, it is the skeletal muscle that is not infre-quently involved in those forms of protein aggregate myop-athies, which commence in childhood. It is this group amongthe protein aggregate disorders, childhood protein aggregatemyopathies, formerly also termed protein surplus myopa-thies,2 which are the topic of this article. Protein aggregatemyopathies are a very telling example of forward genetics inthat immunohistochemical identification of proteins withinprotein aggregates had led to respective genes and to identi-fication of mutations. Concerning desmin-related myopa-
m the Department of Neuropathology, Johannes Gutenberg University,Mainz, Germany.ress reprint requests to Hans H. Goebel, MD, Department of Neuropa-thology, Johannes Gutenberg UniversityMainz,Medical Center, Langen-rotein Aggregate Myopathns H. Goebel, MD, and Harald D. Mller, M
Protein aggregate myopathies (PAMs) basedgation of proteins within muscle fibers maactinopathies, and myosinopathies) or adultsnopathies). They may be mutation related, wcertain other forms as well, or sporadic, whition as myofibrillar or desmin-related myopbased on the identification of respective mutsarcomeres. Recognition of PAM requires mchemical and electron microscopic workupmolecular analysis of morphologically ascertnition of individual entities and genetic copathogenetic principles in PAMs are still intime, is not available.Semin Pediatr Neurol 13:96-103 2006 Els
KEYWORDS protein aggregation, myopathies, ac
rotein aggregate disorders are conditions morphologi-cally marked by the aggregation of proteins in tissues.ey are classified among the slowly progressive degener-ve diseases. They might be hereditary/familial or non-thithe
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he morphologic phenomenon of aggre-ur in children (selenoproteinopathies,ain myofibrillar myopathies and myosi-cludes virtually all childhood forms butlargely seen in adults. Their classifica-, actinopathies, or myosinopathies isteins, most of them components of thebiopsy and an extensive immunohisto-e biopsied muscle tissue after whichproteins should ensue to permit recog-ing of patients and families. Becauseetely known, causative therapy, at this
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athy, desminopathy, myosinopathy
ong the hereditary forms, mutations result in the forma-n of mutant proteins. These mutant proteins may defyper extralysosomal proteolytic degradation followed bytein aggregation. Such a process may affect more than thees, desminopathies, actinopathies, and myosinopathies,se principles and pathways have gainfully been pursued.
Protein aggregate myopathies 97roteinggregation in Muscle Fibersgregation of proteins within muscle fibers may be a non-cific feature when it is observed in ragged red fibers ors,3 in neurogenic targets4 and cores, both of central coreease4 andmultiminicore disease.5 These lesions (ie, raggedfibers, caps, and core-targetoid features) have a lack in
act regular sarcomeres in common. Because ragged reders are not developmental defects but rather occur overe in mitochondrial myopathies and core-targetoid fea-es may indicate damage to muscle fiber innervation, theyw disturbance of structural integrity and destruction ofmarily normal sarcomeres. It appears that proteins are notularly catabolized when intact structures of sarcomeresve been compromised. Progressive failure to maintainuctural integrity of abnormal sarcomeres seems to impairralysosomal proteolytic capacities in such sarcomeres andresult in extralysosomal aggregation of noncatabolizedteins. It is conceivable, although to our knowledge not yetcumented, that other such sarcomere-defective areas withinscle fibers, such as sarcoplasmic masses, may also show ag-gation of proteins.Morphologically, aggregates of proteins may be ill definedh as in ragged red fibers and core-targetoid lesions or maym distinct and well-described inclusion bodies, some-es patches or plaques. In the context of protein aggrega-n, certain inclusion bodies within muscle fibers have al-dy been shown to contain proteins such as nemalinedies, actin filament aggregates, cytoplasmic, and othersmin-containing bodies. Even if the entire spectrum ofteins composing individual inclusion bodies may not beown, certain inclusions within muscle fibers contain sev-l proteins, but not a single individual protein, only. Otherlusions have not successfully been analyzed such as re-cing bodies, cylindrical spirals, and others encountered inpsied muscle tissues of respective congenital myopathies.
yofibrillar Myopathiesofibrillar myopathies (MFMs)6 are the longest-knownd largest group of PAM, also designated as desmin-relatedopathies,7 because desmin, the intermediate filament ofiated and smooth muscle cells, is a consistent componenttheir protein aggregates. Hence, MFMs can be further sub-ided according to mutations in proteins (ie, desminopa-es,8 -B crystallinopathies,9 selenoproteinopathy,10 myo-nopathies,11 ZASPopathies,12 filaminopathy,13 and mostently also a form of laminopathy14 in which themajority oftients are adults) (Table 1). Because MFMs indicate a mor-ologically defined muscle lesion, namely derangement andtruction of sarcomeres, together with aggregation of proteinsong them desmin and other proteins, electron microscopi-ly either as inclusion bodies [eg, cytoplasmic bodies (Fig-1)], or granulofilamentous material, genetically not com-
tely identified forms seem to exist among MFM, fortance when related to gene loci 2q21,15 10q23,16 chromo-
Acmye 12,17 or, recently, 15q22.18 Although the majority oftients with MFM have an adult onset of muscle weakness,en more distally than proximally and not infrequently as-iated with cardiomyopathy, some MFMs commenced atious stages of childhood in several patients (Table 2).2
Selenoproteinopathy has often been observed in childrencause it originated from observations earlier designated asparticular form of congenital muscular dystrophy, thehsfeld type, by Goebel and coworkers19 or later as Mallorydy-like inclusion myopathy by Fidzianska and cowork-.20 These children have proximal or generalized muscleakness, scoliosis, and often severe respiratory failure lead-to premature death. Selenoproteinopathies are markedmutations in the selenoprotein N1 gene10 and may mor-ologically show accumulation of desmin and other pro-ns,20,21 thus, qualifying as a myofibrillar myopathy, al-ugh the aggregation of selenoprotein has not yet beenarly documented, perhaps because of lacking availabilitya suitable antibody. Other conditions occurring in child-od, originating from mutations in the selenoprotein N1,multiminicore disease, multiminicores also marked byumulation of diverse proteins,5,22 and a rigid spine syn-me.23 At another instance, Mallory body-like inclusionsre found in biopsied muscle tissue of 2 children, althought related to a mutation in the SEPN1 gene.24 This suggestedt heterogeneity of the descriptively labeledmyopathy withllory body-like inclusions was further confirmed by an-er study on 3 adolescents/young adults who had Mallorydy-like inclusions in their biopsied muscle specimens butmutations in the SEPN1 gene.25
Spheroid body myopathy, known for many years to affectarge kinship,26,27 has a wide clinical spectrum with child-od onset of muscle weakness in several patients. Presenceaggregated proteins, among them desmin in and aroundspheroid bodies27 as well as recently myotilin,28 promp-final recognition of a