review article nemaline myopathy: current concepts · knnorth,nglaing,cwallgren-pettersson,...

JMed Genet 1997;34:705-713

Review article

Nemaline myopathy: current concepts

K N North, N G Laing, C Wallgren-Pettersson, and the ENMC International Consortiumon Nemaline Myopathy*

NeurogeneticsResearch Unit,Clinical SciencesBuilding, RoyalAlexandra Hospital forChildren, PO Box3515, Parramatta,NSW 2124, Sydney,AustraliaK N North

AustralianNeuromuscularResearch Institute,QEII Medical Centre,Nedlands, WesternAustraliaN G Laing

Department ofMedical Genetics,University ofHelsinki,The FolkhfilsanDepartment ofMedical Genetics,Helsinki, FinlandC Wallgren-Pettersson

Correspondence to:Dr North.

*ENMC InternationalConsortium on NemalineMyopathy: Dr AnthonyAkkari, USA; Prof RichardBarohn, USA; Prof PeterBarth, The Netherlands; DrAlan Beggs, USA; ProfAlbert de la Chapelle,Finland; Prof Marianne deVisser, The Netherlands;Prof Victor Dubowitz, UK;Dr Marc Fiszman, France;Prof Hans Goebel, Germany;Prof Susan lannaccone,USA; Dr Bharat Jasani, UK;Dr Siegfried Labeit,Germany; Dr Nigel Laing,Australia; Dr MartinLammens, Belgium; DrCarmen Navarro, Spain; DrGeoffrey Newman, UK; DrKathryn North, Australia; DrKatrina Pelin, Finland; DrNorma Romero, France; DrCaroline Sewry, UK; DrAvril Sloane, Canada; DrCarina Wallgren-Pettersson,Finland.

DefinitionNemaline (rod) myopathy, first described in1963 by Shy et al' and Conen et al,' is assignedto the group of congenital myopathies. Thesemuscle disorders are defined on the basis ofstructural abnormalities of the muscle fibres,visible after staining of muscle biopsy sectionswith histochemical methods. The histologicaldefinition of nemaline myopathy is based onthe presence of thread- or rod-like bodies, thenemaline (rod) bodies in the muscle fibres ofpatients.(7Med Genet 1997;34:705-713)

Keywords: nemaline myopathy; congenital myopathy;tropomyosin; a-actinin

Nemaline myopathy, first described in 1963,' 2

is a neuromuscular disorder characterised bymuscle weakness and the presence of rodshaped structures (synonym: rods) in the mus-cle fibres. The term nemaline was applied byShy et at' because of the thread-like appearanceof the rod bodies (Greek nema=thread). This isa rare form of congenital myopathy with an esti-mated incidence of 0.02 per 1000 live births.'

IncidenceTo our knowledge, the only published inci-dence figure, based on ascertainment through a

number of sources in a small geographical areain Finland, gives an estimate ofthe incidence ofcongenital nemaline myopathy of 1 per500 000.3

ClassificationClassification of nemaline myopathy into sub-types has been attempted on the basis of clini-cal features such as the pattern ofweakness andage of onset. Three subtypes have beensuggested: severe neonatal onset, a milder con-genital, non-progressive or slowly progressivenemaline myopathy, and a slowly progressivelate or adult onset form"6; however, there ismarked overlap between each of these groups.The large kindred described by Laing et af doesnot fall into any of these subtypes and probablywarrants the inclusion of an additional "child-hood onset" group. With the recent confirma-tion of both autosomal dominant and recessiveforms of nemaline myopathy, and the discoveryof two genetic loci for the disorder (see below),further molecular studies may eventually resultin a meaningful classification which permits

prediction of prognosis or determination of themode of inheritance in singleton cases. Thediagnostic criteria for nemaline myopathy aresummarised in table 1.The severe neonatal form presents at birth

with severe hypotonia and muscle weakness,little spontaneous movement, difficulties withsucking and swallowing, gastro-oesophagealreflux, and respiratory insufficiency. Decreasedfetal movements and rarely polyhydramniosmay complicate the pregnancy.8 Dilated car-diomyopathy and arthrogryposis occurinfrequently.9 '" Death from respiratory insuffi-ciency or recurrent pneumonia is commonduring the first weeks or months of life.8 How-ever, even patients with severe floppiness andlack of spontaneous respiration at birth havebeen known to survive, some of them with lit-tle residual disability."-13The mild congenital or "classic" form of

nemaline myopathy usually presents at birth orduring the first year of life with hypotonia,weakness, and feeding difficulties; however, theseverity of muscle involvement is often lessmarked than in the severe neonatal form. Somecases present later with delayed attainment ofmotor milestones, a waddling gait, or speechabnormalities. There is commonly distal in-volvement in addition to the proximal muscleweakness, and some patients have initially beenthought to have peroneal paresis because oftheir foot drop. The respiratory muscles arealways involved although hypoventilation maynot be clinically obvious; cardiac involvement israre. The course of the disease is often static oronly very slowly progressive and most patientswill be able to lead an active life. Others mayexperience deterioration during the prepuber-tal period of rapid growth and some will startusing a wheelchair at this time.'4The childhood onset form of nemaline

myopathy occurred in a large Australiankindred described by Laing et al,7 in whichinheritance was autosomal dominant. Onset ofweakness occurred late in the first or early inthe second decade and was slowly progressive.Early motor development was normal with thedevelopment of symmetrical weakness of ankledorsiflexion in the late first or early seconddecade. Weakness was slowly progressive witheventual involvement of all ankle movementsand more proximal limb musculature. Twoolder family members were wheelchair bound

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Table 1 Criteria for diagnosis of nemaline myopathy

DefinitionNeuromuscular disorder producing weakness and associated with nemaline bodies in the absence of other known conditions

sometimes associated with nemaline bodies (see exclusion criteria).Features(A) Clinicalfeatures

(1) Patterns of weakness:(a) Predominantly proximal limb/neck muscles (including diaphragm)(b) Diffuse (proximal and distal muscles equally weak)(c) Selective patterns: scapuloperoneal, scapulohumeral, distal(d) Facial with a, b, or c

(e) Note: extraocular muscles usually not involved(2) Onset

(a) Infantile: birth or within first year(b) Childhood(c) Adult

(3) Inheritance(a) AR, NEM2, and other(b) AD, NEM1, and other

(B) Laboratoryfindings(1) CK normal or mildly raised(2) EMG:

(a) Early: normal or "myopathic"(b) Late: can be "neuropathic" in distal muscles

(3) Nerve conduction studies:(a) Normal motor and sensory conduction velocities and latencies(b) Normal sensory amplitudes(c) Distal compound muscle action potential amplitudes can be decreased when distal atrophy is present

(C) Muscle histology(1) Light microscopy:Nemaline bodies visible with Gomori trichrome in subsarcolemmal or sarcoplasmic regions, rarely intranuclearOther common features: type 1 predominance, poor fibre type differentiation, fibre type disproportion(2) Electron microscopy:Nemaline bodies in cytoplasm resemble Z disc with periodic lattice pattern(3) Immunohistochemistry:Nemaline bodies positive for a-actinin

Exclusion criteria(A) Sensory symptoms or signs(B) Other known conditions sometimes associated with nemaline bodies, eg mitochondrial myopathy, HIV infection,inflammatory myopathy, central core disease, toxic myopathies

Table compiled by Dr Richard Barohn, Dallas, Texas, USA.

by 40 years of age. Cardiac muscle was spared,although the proband had achalasia andchronic intestinal pseudo-obstruction.The late onset or adult onset form ofnemaline

myopathy is heterogeneous in terms of clinicalpresentation and disease progression. In patientswith a true isolated adult onset form of nemaline

myopathy, there is no family history and no pre-ceding symptoms and onset of proximal anddistal weakness is in the third to sixth decade.15In some patients there is minimal skeletal mus-cle involvement and presentation is with acardiomyopathy'6 17 or as part of the investiga-tion of other family members."8 19 Respiratoryand cardiac involvement occurs in the minorityof cases, but in these patients the disease oftenfollows a clearly progressive course.20.27 A fewpatients have shown monoclonal gammopa-thy20 28 29 and others have had muscle pain,22 30

paraesthesias,20 or inflammation.20 31

Clinical featuresThe cardinal features of nemaline myopathyare weakness and hypotonia. Muscle weaknessis usually most severe in the face, the neck flex-ors, and the proximal limb muscles. In some U -

patients there is an additional distal involve-ment. The extraocular muscles are spared.Rarely, the muscle weakness in sporadic cases Figure 1 A brother and sister (aged 3 and 7years,has shown a scapulohumeral distribution, with respectively) with classical congenital onset nemalinecc 32myopathy. Both sibs had dysphagia and respiratory distress"terracing" of the shoulders.2 at birth (note gastrostomy scar and pectus excavatum in theIn congenital onset forms of nemaline male sib); age at walking was 13 months in the male and

myopathy, the face is often elongated and 24 months in the female. Note proximal muscle wasting andexpressionless, the mouth tent shaped, and the facial diplegia ("myopathic facies") in both children.

t(Photograph reproduced with permission, courtesy ofDrpalate high arched (a myopathic facies, fig 1). Susan Iannaccone, Dallas, Texas, USA.)

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i necessarily reflect the degree of respiratory^ :t muscle involvement. Although symptom free,

most patients will show restriction of their res-. piratory capacity on testing. The patients run a0 6 great risk of insidious nocturnal hypoxia even

in the absence of morning symptoms, and sev-^fi;aM eral patients have experienced sudden respira-\; tory failure."2 402 While infants with the

congenital onset form of nemaline myopathycommonly have feeding difficulties, older

^ patients may present with isolated swallowingdifficulties.

t\ Cardiac contractility is usually normal in;i. S s congenital nemaline myopathy.43 However,

cardiac involvement, particularly dilated car-se* diomyopathy, may occur.9 1744 The central

0 ^! nervous system is not usually affected in nema-line myopathy and intelligence is usually

-s normal.'2 However, Sewry and Dubowitz"reported two infants with arthrogryposis and ahistological diagnosis of nemaline myopathywho were unresponsive to external stimuli frombirth. Absence of fetal movements, polyhy-

'V-t dramnios, and the development of seizureswere suggestive of clinical involvement of thecentral nervous system.

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Figure 2 Light microscopy in nemaline myopathy (Gomori trichrome stain). Sections formuscle biopsies of two patients showing variability in the number of nemaline bodies (rods)that may be present. In muscle from patient 1 (A) rods were present and multiple in almos;allfibres. Note aggregation of rods under the sarcolemmal membrane. In muscle frompatient 2 (B) rods are only present in occasionalfibres (arrow).

There may be retrognathia and later jaw lociThe patients commonly have a nasal voice c

even dysarthria, the palatal reflex is usuallabsent, the tongue is often small and furrowecand most patients are unable to lift their headin the supine position.The gait is usually waddling. The build i

slender but muscle bulk is not necessarilreduced, especially in young children. Thspine is hyperlordotic and sometimerigid.'2 33-36 In some patients, chest deformity ievident at birth. Tendon reflexes are weakabsent. Gross motor activity is slow whereafine motor activity is normal. Many patienthave hypermobility of joints, and contractureand deformities of the joints commonldevelop with time. Severe arthrogryposis is nc

a characteristic feature of the mainstream fornof nemaline myopathy, but there have beenfew descriptions of patients with congenitaarthrogryposis and nemaline bodies in theimuscle fibres.'0 37-39

Respiratory problems are a common featuriof congenital nemaline myopathy, not only i]the neonatal period but throughout life. Thldegree of skeletal muscle weakness does no

InvestigationsLaboratory examinations are of little help inmaking the diagnosis of nemaline myopathy.Serum concentrations of creatine kinase aremostly normal or slightly raised (up to five

I times higher than normal). Electromyographymay be normal in young patients and mildcases, but usually shows polyphasic motor unitpotentials with small amplitude, a full interfer-ence pattern during weak effort, and normalfibre density.45 46 In addition to these "myo-pathic" features, electromyographic signs ofteninterpreted as neurogenic (large motor unitpotentials with discrete pattern on full effort,abnormal jitter, and increased fibre density)may develop with time, especially in distal

k muscles.4"' Although a variety of abnormali-ties interpreted as neurogenic have been

r reported,49 50 most patients will have normali findings on examination of peripheral nerves,

including normal conduction velocities.Ls Ultrasonography often shows abnormally

high echogenicity in affected muscles, com-puted tomography will show low density of

ly muscles with preservation ofvolume, and mag-Le netic resonance imaging will commonly show-s fatty infiltration of the muscle tissue.5'-

)r Muscle pathologyS N1EMALNE BODIES (RODS)Ls The pathological changes of nemaline myopa-s thy are much the same irrespective of theIy severity of the clinical manifestations or the ageAt of onset.54 Nemaline bodies or rods are then pathological hallmark of the disorder. The rodsa are only readily visible after staining with theAl Gomori trichrome method and appear red orir purple against the blue-green myofibrillar

background55 56 (fig 2). The distribution ofrodse within myofibres may be random, but theyn show a tendency to cluster under the sarco-e lemma and around nuclei. The proportion ofit fibres containing rods varies from case to case

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Figure 3 Electron microscopy of nemaline bodies. Note that nemaline bodies appear t

in structural continuity with the Z disk (A) and the lattice pattern of the rod ultrastruat higher magnification (B).

and from muscle to muscle; in many patthey are present in every extrafusal fibre. I

ever, in some patients the rods occur on

type I fibres (which are usually smaller) an

the minority of patients, rods occur in oi

small proportion of fibres. Some patientsnemaline myopathy have shown nemalineies only in their second muscle biopsy,'whereas fibre type disproportion was evialready in the first biopsy.On electron microscopy, nemaline bodie

electron dense and measure 1-7 ztm in leand 0.3-2 ,um in width (fig 3). For severalsons they are considered to be derived frorlateral expansion of Z disks. On EM,nemaline bodies are in structural contijwith Z disks, their ultrastructure resemblelattice pattern of the Z disk,"9 60 and the,penetrated by thin filaments which run pato their long axis and which behave likefilaments." a-actinin, the main componendisks (see below), is also a major componenemaline bodies,62 63 and desmin, the struc

component of muscle specific interme

filaments, is accumulated at the periphery of Zdiscs and of nemaline bodies.62

It is important to note that nemaline bodiesare not specific to congenital nemaline myopa-thy, but have been described in a number ofprobably unrelated conditions, such as intenotomised rat muscle,64 haemodialysis,6' and

= HIV infection.66 Combinations of histologicalabnormalities characteristic for different con-genital myopathies, particularly cores, havebeen encountered within families, sometimeseven in the same patient.30 67 70 Nemalinebodies may also occur in the setting of a mito-chondrial myopathy.7 72 It is not justified,therefore, to make the diagnosis of hereditarynemaline myopathy in the absence of a typicalclinical picture.

OTHER HISTOLOGICAL FEATURESOn staining with H&E (haematoxylin andeosin) the changes characterising the disorderare difficult to detect. Replacement of musclefibres by fat and fibrous tissue may be seen inadvanced cases, but necrotic and regeneratingfibres are uncommon. Inflammation is not afeature. There may be internal nuclei andoccasional fibre splitting."7 There is often focaldisruption of the myofibrillar pattern on EM.Goebel et af3 described necropsy findings in

i one case of the severe neonatal form of nema-line myopathy and in one boy with the milderform. They found large areas in both dia-phragm and skeletal muscle where contractilematerial was deficient and there was excessformation of thin filaments, suggesting thatdisorganisation of the sarcomere may be part ofthe pathogenesis of the disorder. In olderpatients, there is usually an abnormal variabil-ity in fibre size, reflecting the presence of onepopulation of small fibres and one of largefibres. Follow up biopsies of 1 1 out of 13

to be patients showed increase in internal nuclei,tcture fibrosis, or fibre splitting which is suggestive of

a continuing disease process.48

:lents FIBRE TYPINGSow- Predominance of type I fibres is a commonly in feature of nemaline myopathy and someid, in patients show exclusively type I fibres or poornly a fibre type differentiation. In many biopsies, thewith mean diameter of the type I fibres is smallerbod- than that of the type II fibres. Fibre type I pre-8 57 58 dominance and atrophy tend to become moreident prominent with age and there is often a

complete deficiency of type IIB (fast glycolytic)!s are fibres and an increase in undifferentiated type-ngth IIC fibres.48 74 Volpe et afl4 showed a lack ofirea myosin light fast chains in muscle from threee patients with nemaline myopathy, reflecting a

n the depletion of type II (fast) fibres. They sug-, the gested that there was delayed muscle fibre typenuity differentiation in the severe neonatal form ofSs the nemaline myopathies and that, in other forms,y are there was active transformation of type II (fast)rallel to type I (slow) fibres as part of the diseaseactin process. This hypothesis has been supported bytofZ the morphometric studies of Miike et af' who!nt of suggested the following sequence of events: (1):tural atrophy of type I fibres, (2) transformation ofdiate IIB to IIA fibres resulting in deficiency of IIB

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Nemaline myopathy: current concepts I vy

,.,:..i..-. fibres, (3) type I predominance and IIA hyper-t-̂fs;R-E;l,j6; jZ ;z^ v fis d" -1 trophy, (4) transformation of IIA to type I

'(1 98 .te.i,5,;fibres resulting in marked type I fibre predomi-nance. It is not known whether this progressive

" > - q|,,2;ii;ii;{-I', type I fibre predominance is part of the primarydisease process or a compensatory mechanism.Intrafusal muscle fibres are normally differenti-ated even when there is a marked type I fibrepredominance.

INTRANUGLECAR RODSkyvi'ts.ffi^ ~ ¢ Whereas nemaline bodies typically occur in theNMtp ..._Z,4k' ,2,*-...................sarcoplasmof the muscle fibre, intranuclear

nemaline bodies (fig 4) have been observed inmuscle biopsies from patients with severe neo-natal myopathy"8 76 and in some adult onset%;>7>*,S_1ztt -e'sa w- -cases, with a progressive course.77 Nuclear rodstend to be larger than sarcoplasmic rods, areusually solitary, may be formed in the absenceof sarcoplasmic rods, and have a crystallineappearance with an ultrastructural pattern

B * typical of Z discs.73 By immunocytochemistry,B _ they consist mainly of a-actinin (see below).

Intranuclear rods have generally been con-sidered to be associated with more severe mus-cle involvement and a worse prognosis.3876Goebel et a?" reported clinical and pathologicalfindings in four patients with intranuclear rodsand summarised eight of nine published cases

for whom clinical data were available. Onset ofsymptoms was at birth in 8/12 cases, inchildhood in one case, and in adulthood(fourth to sixth decade) in three cases. Seven ofthe 12 patients developed respiratory insuffi-ciency (including two with adult onset disease)and two of the infantile onset patients had car-diac involvement. Mortality was high at all ages_|;,

* > 1ofonset; 6/8 patients with onset at birth died inthe first year of life and 2/3 adult onset patientsdied four years and seven years after onset,respectively.

Figure 4 (A) Electron micrograph showing intranuclear rods in two nuclei (straight CLINICOPATHOLOGICAL CORRELATESarrows). Intranuclear rods are at least 10 times larger than cytoplasmic rods (curved To date, no histological means of distinguish-arrows) which are present in areas of myofibrillar disarray. (B) Higher magnification of ing between the various forms of nemalineintranuclear rod. Note lattice pattern of rod ultrastructure. (Courtesy of Dr Richard myopathy has been found. Shimomura andBarohn, Dallas, Texas, USA.) Nonaka" performed comparative muscle histo-

chemistry in the severe neonatal (n=6), moder-ate congenital (n= 13), and adult onset (n=3)forms of nemaline myopathy. Although thenumber of rods appeared to increase with age,there was no correlation between the numberof rods and the severity or age of onset of themyopathy.

Wallgren-Pettersson et at8 performed repeatbiopsies in 13 patients with the moderatechildhood form of nemaline myopathy (time offollow up biopsy five to 18 years after the firstbiopsy); 10/12 patients (for whom clinical datawere available) had become weaker with time.Type I fibre predominance (>55%) was evidentin 12/13 follow up biopsies and eight patientshad exclusively type I fibres. Type I fibres weresmall and numerous; type II fibres, wherepresent, were large. Compared to earlier biop-sies, the following changes were noted at followup: there was an increase in mean fibre

Figure S Immunocytochemistry of muscle biopsy shown infig 2A, using antibody to diameter, a decrease in the number of type IIa-actinin-2. With antibody to a-actinin-2 all muscle fibres show positive staining fi(a-actinin is localised in the Z disk of the sarcomere). Nemaline bodies (rods) show strongly fibres, and an increase in number of nemalinepositive staining. bodies. Again, there was no correlation be-

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tween the number of rods and the severity ofdisease. Fibrosis was evident in some biopsies,suggestive of a continuing pathological process,but there was no evidence of necrosis or regen-eration. In two patients, fibre type distributionwas normal, raising the possibility that theserepresent a genetically distinct form of nema-line myopathy.

IMMUNOCYTOCHEMISTRYa-actinin is the main constituent of thenemaline bodies (fig 5); rods also contain actinand are surrounded by an outer layer ofdesmin.623 a-actinin-2 is present in rods in allfibres, but the other skeletal muscle isoforma-actinin-3, which is specific for type II fibres,is only present in rods in type II muscle fibres(North and Beggs, unpublished observations).Although rods contain actin and may containtropomyosin, staining with antibodies to theseproteins did not show any increase in fluores-cence at the site of rods.62 Yamaguchi et alt'suggested that the antibodies to these proteinsdo not sufficiently penetrate the electron densematerial (presumably a-actinin).Sewry and Dubowitz39 found that rods were

negative for titin (Novocastra) and nebulin(Sigma) but otherwise staining with antibodiesto these proteins showed no difference betweencontrol muscle and muscle from patients withnemaline myopathy. Desmin (Amersham) wasnot present in rods but staining with anantibody to this protein showed disruption ofmyofibrillar pattern. Expression of the sarco-lemmal proteins dystrophin, dystroglycan, andthe extracellular matrix protein a2-laminin wasnormal. Fibre type I predominance in nema-line myopathy was associated with abnormallyhigh expression of fetal myosin (usually notexpressed after 6 months of age) and coexpres-sion of fast and slow myosin in some musclefibres.

Pathological studies of other tissuesInvolvement of cardiac muscle is unusual innemaline myopathy.9 78 In the majority ofnecropsy studies, nemaline bodies are notpresent in heart muscle.49 58 59 80-85 However,one case of congenital nemaline myopathy,with onset of cardiac symptoms in childhood,had dilated cardiomyopathy with nemalinebodies verified histologically.9 In two atypicalcases, rods have been observed in both the dia-phragm and cardiac muscle86 and there are alsoreports of cases with cardiac involvement butno muscle weakness.'6 87The central nervous system appears normal

in necropsy studies of congenital nemalinemyopathy. Two studies have identified adecrease in size or number of motor neuronesin the spinal cord but it is not known whetherthis represents a primary or secondaryphenomenon.49 50 There is no evidence forabnormalities of smooth muscle88 or of thecontractile elements (especially actin andct-actinin) in non-muscle cells, for example,fibroblasts, axons, Schwann cells, and whiteblood cells.89

InheritanceNemaline myopathy is genetically heterogene-ous with both autosomal dominant (MIM* 1618009°) and autosomal recessive (MIM*2560309°) forms now identified. In a review byKondo and Yuasa,9' it was concluded thatnemaline myopathy was an autosomal domi-nant condition with reduced penetrance, butreanalysis of the 44 pedigrees included in thereview indicated that most of them were com-patible with a recessive mode of inheritance.92There have been further reports of familialcases with probable autosomal recessiveinheritance.54 9295 A segregation analysis per-formed on a further 46 families presented atthe ENMC Workshop on Nemaline Myopathyin The Netherlands (2-4 February 1996) andanalysed by Alan Emery gave a segregationratio of p=0.23 + 0.05, consistent withautosomal recessive inheritance. Moreover, thehigh proportion (5/43) of consanguinity amongparents of patients with congenital nemalinemyopathy also supports a recessive mode ofinheritance.96 Only one pedigree with histologi-cally verified male to male transmission ofnemaline myopathy has been described,7 al-though a number of reported families areclearly compatible with autosomal dominantinheritance...8 80 .. The proportion ofnew muta-tions and the incidence of germline mosaicismis as yet uncertain.The autosomal dominant and autosomal

recessive forms are clinically and histologicallysimilar, although the family reported by Lainget af had onset of muscle weakness inchildhood, rather than the congenital onsetseen in many families with verified autosomalrecessive inheritance. It remains to be deter-mined whether adult onset cases represent auniform disease entity, and whether they aregenetic in origin.When only one person in a family is affected

by nemaline myopathy, determining the modeof inheritance can be a problem. Clinicalevaluation of both parents is necessary to ruleout minor muscle weakness. Muscle biopsy ofparents may be useful, but interpretation ofabnormal findings can be difficult. In somefamilies both clinically healthy parents haveshown abnormalities on muscle biopsy, sug-gesting a manifesting heterozygote state for arecessive gene." 92 This means that if only oneparent undergoes muscle biopsy and showsabnormalities, these are not in themselves defi-nite proof of the person manifesting a domi-nant gene. If one parent shows overt diseaseclinically and typical histological abnormalitieson muscle biopsy, while the other parent ishealthy and shows normal findings on musclebiopsy, the likely mode of inheritance isautosomal dominant. If both parents are clini-cally healthy and show no abnormality onmuscle biopsy, dominant transmission fromone of the parents is unlikely, leaving thepossibility of a new dominant mutation (theproportion ofwhich remains to be determined)in the child, germline mosaicism in one of theparents (the role of which has also yet to bedetermined), or recessive inheritance with a25% recurrence risk. As the molecular genetics

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of the disorder are clarified (see below), someof these diagnostic issues may be resolved.

Molecular geneticsTo date, two genetic loci for nemaline myopa-thy have been identified. Laing et ar foundlinkage to chromosome 1 (NEMI at 1q22-q23) in the large Australian kindred withchildhood onset autosomal dominant nemalinemyopathy. Wallgren-Pettersson and et at8 sub-sequently discovered the locus for a congenitalonset autosomal recessive form of nemalinemyopathy (NEM2 at 2q21 .2-2q22) using sam-ples from seven European multiplex families. Acandidate gene in this region is the gene for thethin filament protein nebulin. The autosomalrecessive form of the disease may be geneticallyheterogeneous and other loci may be found.Laing et al9 have recently identifiedu-tropomyosinSLI,. (TPM3) as the disease geneon chromosome 1 causing an autosomal domi-nant form of nemaline myopathy.a-tropomyosin is a component of thin fila-ments of the sarcomere; the two muscle specificisoforms (a-TmSLOW and a-TmFAST dependingon the muscle fibre type, and f3-Tm) form ana-helical dimer, bind head to tail, and lie in themajor groove of filamentous actin with eachtropomyosin molecule binding to seven actinmolecules. The mutation described in TPM3 isa point mutation (Met9Arg) close to theN-terminal end of the protein. This region maybe important for assembly of dimers and actinbinding. It is not yet known how the mutationin TPM3 results in rod formation or muscleweakness. Interestingly a-tropomyosin SLOW isspecific for type I (slow) fibres and nemalinebodies in patients with the TPM3 mutationoccur preferentially in type I fibres (K NNorth, unpublished observations).The TPM3 gene has been screened for

mutations in 45 other nemaline myopathypatients and a mutation has been identified inone additional case, in which inheritanceappears to be autosomal recessive (N G Laing,unpublished observations). The other threehuman tropomyosin genes, TPM1 at 15q22,'00TPM2 at 9pl3,'1' and TPM4 at l9pl3.1,'02must all be considered as candidate genes forother forms of nemaline myopathy. However,the majority of the recessive cases of nemalinemyopathy studied to date appear to localise tochromosome 2q (see above), thus excludingthe tropomyosin genes. In one family notshowing evidence of linkage to chromosome2q, linkage to TPM1 and TPM2 has beenruled out, but definite exclusion ofTPM3 andTPM4 is not currently possible as their locali-sation on the genetic maps remains imprecise(C Wallgren-Pettersson, unpublished observa-tions). TPM1 mutations have been identifiedin patients with familial hypertrophiccardiomyopathy,'03 104 indicating that mutationsin other tropomyosin genes may produce acompletely different phenotype.

ManagementNo curative treatment is currently available forthe congenital myopathies. However, a multi-disciplinary approach to management can offer

much to the individual patient in terms ofquality of life (reviewed in Wallgren-Petterssonand Clarke'4). The main factors influencingprognosis seem to be respiratory capacity andthe development of scoliosis" 4 4; the monitor-ing of respiratory function and of the spine areessential elements in the ongoing care of thesepatients.The need for intermittent or permanent use

of a mechanical ventilator should be evaluatedat an early stage because of the risk of insidiousnocturnal hypoxia and sudden respiratoryfailure.4 105 Follow up care should include theassessment of cardiac status because of the riskof cardiomyopathy or cor pulmonale4' andinvolvement, as needed, of physiotherapy,speech therapy, and orthopaedics. Malignanthyperthermia has not been clearly associatedwith nemaline myopathy, although one reportdescribes three children with nemaline myopa-thy in whom the heart rate decreased duringinduction of anaesthesia for cardiac surgery,and body temperature increased during or aftersurgery.06 If surgery is planned, the anaesthet-ist should be aware of the patient'sdiagnosis.'07 108

Future prospectsThe pathogenesis of nemaline myopathy, interms of the clinical and histopathological phe-notype, is not well understood. Questions arisein three main areas. (1) What is the mechanismof rod formation in nemaline myopathy? (2)What is the mechanism of suggested type Ifibre predominance in nemaline myopathy? Isprogressive type I fibre predominance part ofthe primary disease process or a compensatorymechanism? (3) What is the mechanism ofweakness in nemaline myopathy apart fromtype I predominance, and what factors influ-ence the severity of phenotype (age of onset,rate of progression, and severity of muscleweakness)?The identification of two genetic loci for

nemaline myopathy, and the recent identifica-tion of a mutation in a-tropomyosinSLOW inchildhood onset nemaline myopathy are thefirst steps towards understanding the patho-genesis of this disorder.

1 Shy GM, Engel WK, Somers JE, Wanko T. Nemalinemyopathy. A new congenital myopathy. Brain 1963;86:793-810.

2 Conen PE, Murphy EG, Donohue WL. Light and electronmicroscopic studies of 'myogranules' in a child with hypo-tonia and muscle weakness. Can MedAssocJ7 1963;89:983-6.

3 Wallgren-Pettersson C. Congenital nemaline myopathy: a lon-gitudinal study. Academic Dissertation, University ofHelsinki, Commentationes Physico-Mathematicae 111/1990, Dissertationes 1990;30:102.

4 Banker BQ. The congenital myopathies. In: Engel AG,Banker BQ, eds. Myology, basic and clinical. New York:McGraw-Hill, 1986:1536.

5 Brooke MH. A clinician's view of neuromuscular diseases. 2nded. Baltimore: Williams & Wilkins, 1986:362-5.

6 Martinez BA, Lake BD. Childhood nemaline myopathy: areview of clinical presentation in relation to prognosis. DevMed Child Neurol 1987;29:815-20.

7 Laing NG, Majda BT, Akkari PA, et al. Assignment of a gene(NEM1) for autosomal dominant nemaline myopathy tochromosome 1. Am J Hum Genet 1992;50:576-83.

8 Romero N, Fardeau M. Congenital onset nemaline myopathy.Case presentation at the 33rd ENMC International Work-shop on Nemaline Myopathy, Naarden, The Netherlands,1996.

9 Ishibashi-Ueda H, Imakita M, Yutani C. Congenital nema-line myopathy with dilated cardiomyopathy: an autopsystudy. Hum Pathol 1990;21:77-82.

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North et al

10 Schmalbruch H, Kamienecka Z, Arroe M. Early fatal nema-line myopathy: case report and review. Dev Med Child Neu-rol 1987;29:784.

11 Roig M, Hernandez MA, Salcedo S. Survival from sympto-matic nemaline myopathy in the newborn period. PediatNeurosci 1987;13:95-7.

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56 Nienhuis AW, Coleman RF, Brown WJ, Munsat TL,Pearson CM. Nemaline myopathy. A histopathologic andhistochemical study. Am 7 Clin Pathol 1967;48: 1-13.

57 Dubowitz V. Muscle biopsy: a practical approach. 2nd ed.London; Balliere-Tindall, 1985, 20-40, 82-128, 432-4.

58 Karpati G, Carpenter S, Andermann F. A new concept ofchildhood nemaline myopathy. Arch Neurol 1971;24:291-304.

59 Engel AG, Gomez MR. Nemaline (Z disk) myopathy:observations on the origin, structure, and solubility proper-ties of the nemaline structures. _7 Neuropathol Exp Neurol1967;26:601-19.

60 Yamaguchi M, Robson R, Stromer MH, Dahl DS, Oda T.Nemaline myopathy rod bodies. Structure and composi-tion. 7 Neurol Sci 1982;56:35-56.

61 Yamaguchi M, Robson R, Stromer MH, Dahl DS. Actinfilaments form the backbone of nemaline myopathy rods.Nature 1978;271:265-7.

62 Jockusch BM, Veldman H, Griffiths G, van Oost, JennekensFGI. Immunofluorescence microscopy of a myopathy.a-actinin is a major constituent of nemaline rods. Exp CellRes 1980;127:409-20.

63 Wallgren-Pettersson C, Jasani B, Newman GR, et al.a-actinin in nemaline bodies in congenital nemalinemyopathy: immunological confirmation by light andelectron microscopy. Neuromusc Disord 1995;5:93-104.

64 Karpati G, Carpenter S, Eisen AA. Experimental core-likelesions and nemaline rods. A correlative morphological andphysiological study. Arch Neurol 1972;27:237-5 1.

65 Savica V, Bellinghieri G, Di Stefano C. Plasma and musclecarnitine levels in haemodialysis patients withmorphological-ultrastructural examination of muscle sam-

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67 Afifi A K, Smith J W, Zellweger H. Congenital nonprogres-sive myopathy. Central core and nemaline myopathy in onefamily. Neurology 1965;15:371-81.

68 Bethlem J, Arts WF, Dingemans KP. Common origin ofrods, cores, miniature cores, and focal loss of cross-

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70 Fitzsimons RB, McLeod JG. Myopathy with pathologicalfeatures of both centronuclear myopathy and multicoredisease. _f Neurol Sci 1982;57:395-405.

71 Kornfeld M. Mixed nemaline-mitochondrial "myopathy".Acta Neuropathol (Berl) 1980;51:185-9.

72 Fukunaga H, Osame M, Igata A. A case of nemalinemyopathy with ophthalmoplegia and mitochondrial abnor-malities. _7 Neurol Sci 1 980;46:169-77.

73 Goebel HH, Piirsoo A, Warlo I, Schofer 0, Kehr S, GaudeM. Infantile intranuclear rod myopathy. _7 Child Neurol1996;11: 1-9.

74 Volpe P, Damiani E, Margreth A. Fast to slow change ofmyosin of nemaline myopathy: electrophoretic and immu-nologic evidence. Neurology 1982;32:37-41.

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75 Miike T, Ohtani Y, Tamari H, Ishitsu T, Une Y Muscle fibertype transformationin nemaline myopathy and congenitalfiber type disproportion. Brain Dev 1986;8:526-32.

76 Barohn RJ, Jackson CE, Kagan-Hallet KS. Neonatal nema-line myopathy with abundant intranuclear rods. NeuromuscDisord 1994;4:513-20.

77 Otsuji Y, Osame M, Tei C. Cardiac involvement in congeni-tal myopathy. IntrJ Cardiol 1985,9:311-22.

78 Paulus W, Peiffer J, Becker I, Roggendorf W, Schumm F.Adult-onset rod disease with abundant intranuclear rods. .7Neurol 1988;235:343-7.

79 Van Antwerpen CL, Gospe SM Jr, Dentinger MP. Nemalinemyopathy associated with hypertrophic cardiomyopathy.Pediatr Neurol 1988;4:306-8.

80 Hopkins U, Lindsey JR, Ford FR. Nemaline myopathy. Along-term clinicopathologic study of affected mother anddaughter. Brain 1966;89:299-311.

81 Shafiq SA, Gorycki MA, Asiedu SA, Milhorat AT.Tenotomy. Effects on the fine structure of the soleus of therat. Arch Neurol 1969;20:625-33.

82 Neustein HB. Nemaline myopathy. A family study withthree autopsied cases. Arch Pathol 1973;96:192-5.

83 McComb RD, Markesbery WR, O'Connor WN. Fatal neo-natal nemaline myopathy with multiple congenital anoma-lies. _7 Pediatr 1979;94:47-5 1.

84 McMenamin JB, Curry B, Taylor GP, Becker LE, MurphyEG. Fatal nemaline myopathy in infancy. Can 7 Neurol Sci1984,11:305-9.

85 Iwami H, Inoue F, Takeuchi Y, et al. A case of congenitalnemaline myopathy presenting as pulmonary hypertension.Brain Dev 1986;8:227.

86 Bergmann M, Kamarampaka M, Kuchelmeister K, KleinH, Koch H. Nemaline myopathy: two autopsy reports.Childs Nerv Syst 1995;11:610-15.

87 Jones JG, Factor SM. Familial congestive cardiomyopathywith nemaline rods in heart and skeletal muscle. VirchowsArch 1985;408:307-12.

88 Matsuo T, Tashiro T, Ikeda T, Tsujihata M, Shimomura C.Fatal neonatal nemaline myopathy. Acta Pathol Japonica1982;32:907-1 6.

89 Jennekens FGI, Roord JJ, Veldman H, Willemse J, JockuschBM. Congenital nemaline myopathy. I. Defectiveorganisation of ca-actinin is restricted to muscle. MuscleNerve 1983;6:61-8.

90 McKusick VA. Mendelian inheritance in man. Catalogs ofautosomial dominant, autosomal recessive and X-linked pheno-types. 11th ed. Baltimore: The Johns Hopkins UniversityPress, 1994:1000-1, 2057-8.

91 Kondo K, Yuasa T. Genetics of nemaline myopathy. MuscleNerve 1980;3:308-15.

92 Wallgren-Pettersson C, Kaariainen H, Rapola J, Salmi T,Jaaskelainen J, Donner M. Genetics of congenital nemalinemyopathy: a study of 10 families. JMed Genet 1990;27:480-7.

93 Perez-Briceno R, Lopez-Habib G, Lisker R, Velazquez-Forero F. Miopatia nemalinica. Informe de una familiasugestiva de herencia recesiva. Rev Invest Clin 1974;26:373-82.

94 Shahar E, Tervo RC, Murphy EG. Heterogeneity of nema-line myopathy. A follow-up study of 13 cases. Pediatr Neu-rosci 1988;14:236-40.

95 Cartwright JD, Castle DJ, Duffield MG, Reef I. Nemalinemyopathy: a report of two siblings as evidence of autosomalrecessive inheritance of the infantile type. Postgrad Med J1990;66:962-4.

96 ArtsW F, de Groot C J. Congenital nemaline myopathy: twopatients with consanguineous parents, one with a progres-sive course. _7 Neurol 1983;230:123-30.

97 Spiro AJ, Kennedy C. Hereditary occurrence of nemalinemyopathy. Arch Neurol 1965;13:155-9.

98 Wallgren-Pettersson C, Avela K, Marchand S, et al. A genefor autosomal recessive nemaline myopathy assigned tochromosome 2q by linkage analysis. Neuromusc Disord1995;5:441-3.

99 Laing NG, Wilton SD, Akkari PA, et al. A mutation in thealpha-tropomyosin gene TPM3 associated with autosomaldominant nemaline myopathy NEML. Nat Genet 1995;9:75-9.

100 Eyre H, Akkari PA, Wilton SD, Callen DC, Baker E, LaingNG. Assignment of the human skeletal musclect-tropomyosin gene TPM1 to band 15q22 by fluorescencein situ hybridisation. Cytogenet Cell Genet 1995;69:15-17.

101 Hunt CCJ, Eyre HJ, Akkari PA, et al. Assignment of thehuman beta tropomyosin gene TPM2 to 9p13 byfluorescence in situ hybridisation. Cytogenet Cell Genet1995;71:94-5.

102 Wilton SD, Lim L, Dorosz S, et al. Assignment of thehuman a-tropomyosin gene TPM4 to 19pl 3.1 by fluores-cence in situ hybridisation. Cytogenet Cell Genet 1996;72:294-6.

103 Thierfelder L, Watkins H, MacRae C, et al. at-tropomyosinand cardiac troponin T mutations cause familial hyper-trophic cardiomyopathy: a disease of the sarcomere. Cell1994;77:701-12.

104 Watkins H, McKenna WJ, Thierfelder L, et al. Mutationsin the genes for cardiac troponin T and a-tropomyosin inhypertrophic cardiomyopathy. N Engl 7 Med 1995;332:1058-64.

105 Heckmatt JZ, Loh L, Dubowitz V. Night-time nasal venti-lation in neuromuscular disease. Lancet 1990;335:579-82.

106 Asai T, Fujise K, Uchida M. Anaesthesia for cardiacsurgery in children with nemaline myopathy. Anaesthesia1992;47:405-8.

107 Cunliffe M, Burrows FA. Anaesthetic implications ofnemaline rod myopathy. Can Anaesth Soc _r 1985;32:543-7.

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Letters, Book reviews, Correction

concluded that the best answer to all theseproblems, or questions, is that Mendel wasright.

This work on Pisum is, naturally enough,the centrepiece and cornerstone of Orel'sbook. However, there is a great deal more ofinterest. Thus, Mendel's other scientific workis described in detail, including his failure torepeat his results in Pisum during extensiveexperiments with several other species ofplants. He also worked with great skill in thefields of meteorology and of apiculture,including attempts, ultimately unsuccessful,to acclimatise a species of bee indigenous toBrazil, Trigona lineata, which had migrated toBrunn by accident in the hollow of a trunkincluded in a consignment ofwood importedfrom that country.

Orel's book examines in great detail thefascinating question of how it came aboutthat a man who did not form part of the sci-entific establishment was able to make a con-

tribution to science of such majesty and ofsuch magnitude. While he was born in 1822in humble circumstances as the only son of a

peasant farmer, of mixed Czech and Germanorigin, in Moravian Silesia, a province of theAustro-Hungarian Empire, Mendel was veryfar from being a self-taught prodigy, as was,for example, Srinivasa Ramanujan, the In-dian mathematician of similarly humbleorigin. Thus, he showed great talent at schooland his parents, who had enormous respectfor learning, endured great financial priva-tions to support him during his education.From an early age, Mendel had to augment

the necessarily meagre allowance provided byhis parents through private tutoring. Hewrote ofhimself in 1850 in the third person inhis curriculum vitae: "His sorrowful youthtaught him early the serious aspects of life,and it also taught him to work... It wasimpossible for him to endure such exertionfurther. Therefore, having finished his philo-sophical studies, he felt himself compelled toenter a station in life that would free him fromthe bitter struggle for existence. His circum-stances decided his vocational choice. Herequested and received in the year 1843admission to the Augustinian monastery of StThomas in Brno."Mendel then led a charmed life for a quar-

ter of a century. He was able to study naturalsciences, especially physics, at the Universityof Vienna, and, on his return to themonastery, as long as he fulfilled his duties asa priest and a secondary school teacher, hewas free to devote himself to private study,surrounded by a group of gifted colleagues,and able to play a full part in the active intel-lectual life of a thriving provincial city of theAustro-Hungarian Empire.A major change occurred in Mendel's

circumstances when he was elected Abbot in1868, a post which he was to fill for 16 years

until his death in 1884. He had to bid farewellto his beloved teaching and he soon had togive up his botanical researches. Even though

his way of life necessarily became moreworldly as he was loaded with honours and asimportant functions were thrust upon him,his essential humility, compassion, and kind-liness remained unaltered. Much has beenmade of his longstanding dispute with theauthorities over the taxation of the monas-tery. Mendel remained steadfast in his refusalto agree to payment and he stubbornlydeclined to consider the compromisewhereby this matter was resolved soon afterhis death, because he firmly believed that hewas in the right. However, he did not allowhimself to become embittered by the disputeto the extent of abandoning his manyintellectual interests. He continued until hislast days to pursue his scientific enquiriesvigorously, mainly in the fields of apicultureand meteorology, and, as an extremely skilfulpractical gardener, he remained active inbreeding varieties of fruits, vegetables, andflowers. He also played chess, especially withhis nephews who visited him frequently, andhe took great delight in composing chessproblems.

This gentle and unpretentious man, whoalways remained faithful to his family and tohis peasant origins, became, as "the firstgeneticist", one of the tiny band of thoseresponsible for substantial advances alongMan's difficult road towards knowledge ofhimself and of his environment. This is not a

road on which the lengths of advances can beexactly measured. We can say, nevertheless,that the advance along this road which weowe to Mendel is among the greatest whichhas ever been achieved by a single person.Our century, which began with the rediscov-ery of Mendel's work, is now ending in an

unprecedented explosion of science andtechnology. It is impossible to think of themany components of this explosion which arerelated to genetics without thinking also ofthis unassuming monk tending his peas in thepeaceful garden of his monastery.

This book represents a full and perceptiveaccount of the life of a man to whom thereaders of this journal, in common with thereaders of hundreds of other joumals, owetheir profession. In return, we should strive tocontinue to pursue our work in directions ofwhich Mendel, the first geneticist, would haveapproved.

In this context, Mendel wrote some versesin his youth in memory of Gutenberg; thesesentiments can now be fittingly applied tohimself.May the might of destiny grant meThe supreme ecstasy of earthly joy,The highest goal of earthly ecstasy,That of seeing, when I risefrom the tomb,My art thriving peacefullyAmong those who are to come after me.To go far back in time to the 6th century

BC, to the fragments which survive of thewritings of Xenophanes on the limitations ofhuman knowledge:

OYTOI An APXHX nANTA EEOI ENHTOIXYHEAEI_AN,

AAAA XPONQ ZHTOYNTEZ E4'EYPIEKOYEINAMEINON.

The gods did not reveal all things to mortals inthe beginning, but in long searching man findsthat which is better.Mendel's contribution, even though it

occupied only a few brief years of his life, ismaking this searching less long than it wouldhave been otherwise. All who consider them-selves to be geneticists would do well to studythis book and to learn from it about the life ofthe founder of their science, and about themanner of its founding.

GEORGE R FRASER

Essential Medical Genetics. 5th edition.M Connor, M Ferguson-Smith. (,C18.50.)Oxford: Blackwell Science. 1997. ISBN0-86542-666-X.

This latest edition of a very charming, short,and efficient introduction to medical geneticstries to give both medical students and busyclinicians a rapid and reliable overview ofmodern genetics and its clinical ramifica-tions. Brevity, simplicity, and clarity remainconstant features of this book that continuesto be updated every four years.There are a few points to consider in future

editions. Information on various causes ofone disease could be more easy to find, likeincluding maternal gonadal mosaicism as animportant cause of new cases of Duchennemuscular dystrophy (p 18). Differences couldbe clarified between CK assay for carriertesting for Duchenne muscular dystrophy(with major influences from lyonisation) andDNA analysis, which is independent of Xinactivation status. Legends to figures couldbe more informative, both in the colour platesand clinical examples (to explain dysmor-phology). The quality of the grey tone figuresis poor, another example of the continuoustrend to reduce the quality ofblack and whitereproductions. The explanation of the fragileX syndrome could be improved: this mightinclude clarification of figure 14.5 (transmis-sion through a normale male?). Chapter 16(genetics of common diseases) could makereference to genes now identified in diabetes,deafness, epilepsy, etc, to show how the"multifactorial" hypothesis became vali-dated. The role of dysmorphology, the trans-lation of mutations in human developmentalgenes into clinical studies of patients withmalformations, and the implications andhandling of presymptomatic genetic testingmight be areas to emphasise in daily clinicalgenetics.

Still, this "short essential" is extremelycomprehensive and a fine starting text formedical students, genetic assistants, paedia-tricians, and other clinicians needing "work-ing" knowledge of everyday genetics.

MARTINUS F NIERMEIJER

CorrectionIn the Review article "Nemaline myopathy: current concepts" by North et al (_7Med Genet 1997;34:705-713), the correct incidence figure fornemaline myopathy should be 0.02 per 1000 livebirths (Wallgren-Pettersson C. Congenital nemaline myopathy: a longitudinal study. AcademicDissertation, University of Helsinki, Commentationes Physico-Mathematicae 111/1990. Dissertationes 1990;30:102).

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review article nemaline myopathy: current concepts · knnorth,nglaing,cwallgren-pettersson,...

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