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Multi-minicore disease–searching for boundaries: Phenotype analysis of 38 cases

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  • Multi-Minicore DiseaseSearching forBoundaries: Phenotype Analysis of 38 Cases

    Ana Ferreiro, MD,* Brigitte Estournet, MD, Danielle Chateau, MSci,* Norma B. Romero, MD, PhD,*Cecile Laroche, MD, Sylvie Odent, MD, Annick Toutain, MD,i Ana Cabello, MD, PhD,##Daniel Fontan, MD,# Helosa G. dos Santos, MD, PhD,** Charles-Antoine Haenggeli, MD,

    Enrico Bertini, MD, Jon-Andoni Urtizberea, MD,* Pascale Guicheney, PhD,* and Michel Fardeau, MD*

    Multi-minicore disease (MmD) is a congenital myopathy morphologically defined by the presence of multiple smallzones of sarcomeric disorganization and lack of oxidative activity (minicores) in muscle fibers. The clinical expressionof MmD is considered to be greatly variable, and the morphological lesions are nonspecific; therefore, its boundaries arepoorly defined, and its molecular bases are not known. To better define the phenotypic characteristics of MmD, weanalyzed a large series of 38 patients with multiple minicores in muscle fibers in the absence of any other potential cause.According to clinical features, 4 subgroups were identified. Most patients (30 cases) shared a common highly consistentphenotype marked by the axial predominance of muscle weakness and a high occurrence of severe respiratory insuffi-ciency and scoliosis (classical form). Other forms were characterized by pharyngolaryngeal involvement and total lackof head control (2 cases), antenatal onset with arthrogryposis (3 cases), and slowly progressive weakness with markedhand amyotrophy (3 cases). Type 1 fiber predominance and hypotrophy as well as centrally located nuclei were found inevery subgroup. MmD is thus phenotypically heterogeneous, but a typical recognizable phenotype does exist. This pheno-type classification should be helpful when undertaking research into the molecular defects that cause MmD.

    Ferreiro A, Estournet B, Chateau D, Romero NB, Laroche C, Odent S, Toutain A, Cabello A, Fontan D,dos Santos HG, Haenggeli C-A, Bertini E, Urtizberea J-A, Guicheney P, Fardeau M. Multi-minicore disease

    searching for boundaries: phenotype analysis of 38 cases. Ann Neurol 2000;48:745757

    Multi-minicore disease (MmD) is a congenital myop-athy defined by the presence of multiple small zones ofsarcomeric disorganization and diminished mitochon-drial oxidative activity (minicores) in muscle fibers.Minicores differ from cores, which are characteristic ofcentral core disease (CCD), by their nonselectivity fora particular fiber type and their smaller size; minicoresnever extend through the entire fiber length. The clin-ical features of MmD have not been sufficiently char-acterized but generally are thought to be common tothose of other congenital myopathies, including a dif-fuse slenderness and weakness of skeletal muscles. There-fore, the diagnosis of MmD is not possible on clinicalgrounds alone and always requires a muscle biopsy.

    MmD was first described as multicore disease byEngel and his colleagues,1,2 who emphasized the con-genital, benign, and nonprogressive character of this

    condition. Since then, at least 70 other cases havebeen reported with names such as multicore disease,327

    focal loss of cross striations,28,29 minicore myop-athy,3035 myopathy with multiple minicore,36 pleo-core disease,37 and multi-minicore disease.38,39 Most ofthese reports confirm the characteristics outlined previ-ously, but some describe cases with late onset,4,9,18,26

    major skeletal,8,21,27 ventilatory,26 or cardiac involve-ment,1820,24,25 occasionally leading to death or progres-sive weakness.29 Ophthalmoplegia has been reported insome cases.3,10,29,34,40

    Although it is generally agreed that MmD consti-tutes a distinct nosologic entity, its boundaries remainundefined. As stated previously, the clinical expressionof MmD is not specific and has been considered to begreatly variable. MmD is thus a morphologically de-fined disorder, but the significance of morphological

    From the *INSERM U523/Institut de Myologie, Groupe Hospi-talier Pitie-Salpetrie`re, Paris, Service de Neuropediatrie-Reani-mation Infantile, Hpital R. Poincare, Garches, Service de Pedia-trie, CHU Dupuytren, Limoges, Service de Genetique Medicale,CHU Pontchaillou, Rennes, iService de Genetique, Hpital Breton-neau, Tours, and #Service de Pediatrie, Hpital des Enfants, Bor-deaux, France; ##Departamento de Neuropatologia, Hospital 12de Octubre, Madrid, Spain; **Servico de Genetica, Hospital SantaMaria, Lisbon, Portugal; Departement de Neuropediatrie, Hpi-tal des Enfants, Geneva, Switzerland; and Unit of MolecularMedicine, Department of Neurosciences, Bambino Gesus HospitalIRCCS, Rome, Italy.

    Received Feb 9, 2000, and in revised form Jun 1. Accepted forpublication Jun 5, 2000.

    Address correspondence to Dr Ferreiro, INSERM U523/Institut deMyologie, Groupe Hospitalier Pitie-Salpetrie`re, 47 Boulevard delHpital, 75651 Paris, France.

    Copyright 2000 by the American Neurological Association 745

  • changes in MmD is still uncertain. They are not pa-thognomonic; small foci of sarcomeric disorganization(usually with an absence or paucity of mitochondria)occur in different pathological and experimental condi-tions such as inflammatory myopathies,41 metabolicdiseases,42,43 endocrinopathies,44 denervation atro-phy,45 several types of muscular dystrophy,46 ankylos-ing spondylitis,47 emetine myopathy,48 glucocorticoidtreatment in rats,49 tenotomy,50 and experimental tet-anus51 or even in healthy young people.52 Further-more, minicores can be associated with structuralchanges also found in other congenital myopathiessuch as cores and rods,32,53,54 mitochondrial abnormal-ities,8,55 or centrally located nuclei.11,12,56 Finally, themorphological pattern may vary with age in any givenpatient.54 Molecular genetic studies have never beenundertaken in MmD due to the previously mentioneddifficulties for defining homogeneous groups as well asbecause of the fact that MmD is a relatively rare con-dition for which an autosomal recessive pattern of in-heritance is generally postulated, but dominant formshave also been described.7,13,18,33,57

    Up to the present, only isolated cases or small seriesof MmD patients have been described. We report theretrospective clinical and morphological analysis of alarge series of 38 patients collected through a multi-center collaboration. The aims of this study were tofurther characterize the clinical and morphologicalboundaries of MmD and to try to identify phenotypi-cally homogeneous subgroups that could serve as a ba-sis for the genetic approach.

    Subjects and MethodsSubjectsWe reviewed all the muscle biopsies analyzed in our labora-tory from 1975 to 1998 that showed multiple minicores asthe main abnormality both by means of light and electronmicroscopy. The clinical data from these patients were sys-tematically retrieved according to a standardized form. Noadult-onset case was found. The diagnosis of MmD wasmade only when a clinical picture highly suggestive of a con-genital myopathy coexisted with stereotyped structuralchanges in a high proportion of fibers in the absence of anyother potential cause (Table 1); 25 cases were thus retained.Thirteen additional cases were collected from other referencecenters in Europe; 2 of them (Patients 5 and 6) had beenpreviously reported.36

    Morphological MethodsMuscle biopsies were taken from deltoid (18), quadriceps (4),peronaeus lateralis (2), biceps brachialis (1), and gastrocnemiusmuscles; the site of biopsy was unknown in 10 cases. Speci-mens for light microscopy analysis were immediately frozenand processed using standard histological and histochemicaltechniques according to previously described procedures.58

    Histometric and morphometric analysis of at least 200 ad-jacent fibers was performed in 20 cases using myosin aden-

    osine triphosphatase (ATPase) pH 9.4 transversal sections.The mean and SD of type 1 and 2 fiber diameters werecalculated for each biopsy and for the sum of all 20 cases(global means).

    Immunohistochemical studies were performed using thestandard indirect immunofluorescence technique. Mousemonoclonal antibodies against alpha-actinin (NCL-alpha-ACT; Novocastra, Newcastle upon Tyne, England), actin (N350; Amersham, International, Amersham Bucks, England),titin (NCL-TITIN; Novocastra), and desmin (D33; Dako,Glostrup, Denmark) were used in 4 cases. None of the re-activity patterns was observed after omission of the primaryantibodies.

    Muscle fragments for ultrastructural studies were fixedwith glutaraldehyde at 2.5% and embedded in epoxy resinafter standard postfixation and dehydration. Longitudinallyand transversely oriented semithin sections of every specimenwere stained with toluidine blue. Ultrathin sections were ob-served under a Philips CM120 electron microscope (PhilipsElectronics NV, Eindhoven, The Netherlands).

    ResultsClinical ResultsThe disease similarly affected female (20 cases) andmale (18 cases) patients. The first manifestations of thedisease were noted most often at birth (20 cases[52.6%]) or during infancy between 3 and 18 months(8 cases [21.1%]).

    The 38 cases were identified in a total of 29 families.All the pedigrees were compatible with an autosomalrecessive mode of transmission, which was highly prob-able in 12 families (21 patients): 6 families (9 patients)were consanguineous, and 6 others were multiplexfamilies with 2 affected siblings each. The remaining17 families were represented by sporadic cases. Parentswere systematically examined and clinically determinedto be normal. A muscle biopsy was performed in only1 case (mother of Patient 1) because of the presence of

    Table 1. Inclusion and Exclusion Criteria

    Inclusion Criteria Exclusion Criteria

    Early-onset globalweakness

    Endocrinopathy or chronicintake of drugs

    Creatine kinaselevel #3 timesnormal

    Electromyographic evidence ofperipheral nerve abnormali-ties

    Multiple minicoresin a significantproportion ofmuscle fibersboth by lightand electronmicroscopy

    Morphological evidence ofnecrosis or regeneration,glycogen or lipid abnormal-ities, inflammatory infil-trates, grouping, atrophicangulated fibers, or diffusedesmin accumulation

    Creatine kinase levels and electromyographic pattern were part ofthe inclusion and exclusion criteria; thus, only the patients fromwhom both tests were available (in at least 1 affected case in mul-tiplex families) were considered for inclusion.

    746 Annals of Neurology Vol 48 No 5 November 2000

  • mild electromyographic abnormalities; her deltoidmuscle showed no alterations.

    The electromyographic studies performed in 36 casesdisclosed either no abnormalities or a myopathic pat-tern (ie, brief, low-amplitude, polyphasic motor unitpotentials). Spontaneous activity was never found. Se-rum creatine kinase levels were normal or close to nor-mal in 36 patients; only in 2 cases (Patients 21 and 29)did they reach up to three times the upper normalvalue. Cardiac test results were available for 31 cases(electrocardiogram in 26 cases, echocardiogram in 21cases, and/or Holter recording in 4 cases); no majorabnormalities were found.

    There was no evidence of intellectual impairment inany of our cases; a brain computed tomography scanwas performed on 3 patients, with normal results.

    A total of 19 surgical procedures with general anes-thesia were performed in 16 patients; no episode ofmalignant hyperthermia or other adverse reactions toanesthesia occurred. No family history of anesthesia-related death was retrieved.

    According to clinical features, 4 homogeneous sub-groups were identified.

    CLASSICAL FORM. Thirty patients shared a constantpattern of muscular involvement marked by the pre-dominant weakness of axial muscles and a remarkablyhigh frequency of severe scoliosis and major respiratoryinvolvement (Tables 2 and 3). The clinical picture washighly consistent among patients belonging to the samefamily, although a slight interfamilial variability wasobserved (see Table 2).

    Early onset of the disease was common (Table 3).Severe neonatal hypotonia was present in 6 cases (Pa-tients 1, 710, and 14); Patients 1 and 14 needed tubefeeding until they were 6 months and 2 years of age,respectively. Delayed motor development was the mostconstant early sign. Autonomous gait was acquired byall but 1 patient, in most cases before the age of 2years. Most patients have never been able to run. Theability to rise up from the floor was frequently themost retarded milestone. Head control was also mark-edly delayed and has been only partially acquired in 4cases (Patients 7, 8, 19, and 23). In the 4 cases with alater onset (Patients 22 and 2830), the first abnor-mality was remarked between 1 and 6 years of age andconsisted of poor motor performance manifested byfrequent falls and excessive fatigability.

    Regardless of the age and form of onset, most pa-tients showed generalized muscle weakness and amyot-rophy, which clearly predominated in axial muscles.Global slenderness was sometimes extreme (Fig 1).Trunk and particularly neck flexors were the most se-verely affected groups; neck flexor power scored from 0to 4 according to the Medical Research Council(MRC) scale, being generally between 2 and 3. Sterno-

    cleidomastoideus bulk was often extremely reduced.Scaleni, trapezius, and intercostal muscles and, to alesser extent, trunk and neck extensors were also in-volved. Muscle power scores in pelvic and shoulder gir-dle groups ranged in general from 3 to 4. Distal muscleswere either normal or only moderately involved (scorerange, 31 to 5), except for intrinsic hand muscles,which were weaker than other proximal and distalgroups in 4 cases (Patients 3, 16, 19, and 26). In mostcases, there was no significant difference in severity be-tween upper and lower limb involvement. Facial muscleswere most often spared or mildly weak. External eyemovements were normal in all patients.

    Neck extensors and trunk muscles were frequentlyretracted; pectoralis major and intercostal muscle con-tractures led to severe thorax deformities. In contrast,limb joint contractures were neither frequent nor se-vere; when present, they involved mainly hips, knees,and elbows. Two cases (Patients 14 and 15) showed amarked joint hyperlaxity. Deep tendon reflexes couldbe hypoactive or absent but were frequently preserved.

    The most striking finding in this group was the highfrequency of severe scoliosis and major respiratory in-volvement. Early-onset scoliosis was present in 22 cas-es; 9 of these patients had a quickly evolving and ex-tremely marked deformity (up to 50 degrees) thatsometimes worsened dramatically in only a few weeksduring the pubescent period. A high cervicodorsal pre-dominance was common. Scoliosis was progressiveeven in those cases showing stable or improving generalweakness. Early intensive orthopedic treatment slowedevolution until the end of the growth period but didnot succeed in correcting scoliosis or preventing pro-gression; extensive arthrodesis was required in 8 cases.

    Respiratory involvement was detected in 18 cases; in12 of them, a severe hypercapnic respiratory insuffi-ciency, mainly or purely restrictive (28.3% mean vitalcapacity [VC]), required precocious respiratory assis-tance. This respiratory involvement was always dispro-portionate to the severity of scoliosis and to the degreeof general weakness (all the patients requiring ventila-tion remained ambulant); its major determinants werethe involvement of accessory respiratory muscles andthe intensity of thorax deformities, with patients whohad a flat thoracic cage with a dorsal hollow back beingat high risk. Nevertheless, VC was always better whenmeasured sitting or standing than in the supine position(up to 14.6% of the predicted value), thus reflectingsome degree of diaphragm involvement. Polysomno-graphic studies were performed in 3 cases, disclosingnocturnal desaturations and short apnea periods.

    Mild cardiac abnormalities were detected in only 7cases (Table 3); asymptomatic mitral prolapsus was themost common finding (Patients 2, 3, 13, 19, and 21).

    Other manifestations of the disease were rare, withthe exception of the dysmorphic features reflected in

    Ferreiro et al: Multi-Minicore Disease: Phenotype Analysis 747

  • Table 2. Classical Form

    Family Case First Referral Signs Walked at AgeFacial Weakness(1 to 111)

    Scoliosis(1 to 111)

    RespiratoryInvolvement(1 to 111) Dysmorphic Features, Others

    1 1 NH, feeding and respiratorydifficulties

    NA 111 111 11 Hip dysplasia, diaphragmherniationFrom 6 months

    2 2 DMM, respiratory insuffi-ciency

    24 mo 111 111 Flat thorax, microretrognathia

    Tr3 Congenital cervical scoliosis 14 mo 111 111 Flat thorax, flat feet

    3 4 DMM, PMP 15 mo 1 1 HAP, prognathism, hip dys-plasia, pes varus

    4 5 NH 12 mo 1 1 Polythelia6 DMM NA 1 1 Flat feet

    HL5 7 NH 14 mo 11 111 111 Flat thorax, hollow rigid back

    8 NH 14 mo 111 11 111 Flat thorax, hollow rigid back6 9 NH, respiratory difficulties 13 mo 1 11 111 Flat thorax, hypogenitalism

    Tr10 NH, respiratory difficulties 15 mo 11 111 111 Flat thorax, HAP

    Tr7 11 Congenital ptosis 13 mo 11 11 HAP, malocclusion, pes cavus

    12 Congenital ptosis 13 mo 111 111 111 Flat thorax, HAP, malocclu-sionFrom 1 year

    8 13 DMM 22 mo Hip dysplasia, pes cavus9 14 NH, feeding and respiratory

    difficulties9 yr (few steps) 1 1 111 Clock-like thorax, overweight,

    pectus excavatum, pes val-gusKyphosis Tr (from 11

    months)15 DMM 4 yr 1 1 Clock-like thorax, overweight,

    pes and genu valgum10 16 NH 24 mo 11 1 HAP, malocclusion

    HL11 17 RRI, DMM 21 mo 111 111 Flat thorax, failure to thrive

    Tr12 18 Respiratory difficulties,

    DMM26 mo 111 111 Flat thorax, diaphragmatic

    palsy13 19 DMM, poor head control 15 mo 11 111 Flat thorax, microretrognathia

    Tr14 20 Congenital club feet, DMM,

    PMP18 mo 111 111 Flat thorax, failure to thrive

    15 21 DMM, scoliosis 18 mo 1 11 11 HAP, pes cavus, spinal rigid-ity

    16 22 PMP, scoliosis NA 1 11 Flat feet17 23 NH, poor head control Not yet at 5 yr 1 1 HAP, flat feet18 24 NH 24 mo 1 1 Genu valgum, flat feet,

    P. colli19 25 NA NA 1 11

    Kyphosis 1120 26 DMM, PMP, FF 15 mo NA 11 Spinal rigidity21 27 DMM, PMP, FF 18 mo

    HL22 28 PMP, FF 12 mo Pes equinus23 29 PMP NA 24 30 PMP 12 mo

    In families 1, 3, 8, 9, and 10, parents are consanguineous. The phenotype was almost identical among affected siblings; note a mild interfamilial heterogeneity.

    NH 5 neonatal hypotonia; DMM 5 delayed motor milestones; PMP 5 poor motor performance; RRI 5 repeated respiratory infections; FF 5 frequent falls;HL 5 hyperlordosis; HAP 5 high arched palate; P. colli 5 pterygium colli; NA 5 data not available; Tr 5 tracheotomy.

    Respiratory involvement: vital capacity 6579% 5 1; 5064% 5 11; 1749% 5 111.

    748 Annals of Neurology Vol 48 No 5 November 2000

  • Tables 2 and 3. A marfanoid habitus was quite com-mon, but other typical features of Marfans syndromewere never found.

    The follow-up of this group spanned a period be-tween 10 months and 20 years in a total of 29 patients.In 20 patients (69%), limb muscle weakness remainedstable; 6 patients (20.7%) showed a mild progressionof their motor difficulties, sometimes beginning inadulthood (Patient 4). In 3 patients, functional capac-ities improved slowly during childhood; this could rep-resent developmental maturation rather than a real im-

    provement. All the patients who acquired gait are stillable to walk, at least for short distances. The oldestpatient (Case 17) is now aged 42 years; she has beenventilated for more than 20 years, and can still walkwith help. Onset of signs during childhood seems to beassociated with a better functional prognosis than earlieronset. The severity of the disease was determined by therespiratory function. One individual (Patient 20) withsevere respiratory insufficiency died at 14 years of agedue to a respiratory infection. The other patients withsevere respiratory involvement are effectively controlledwith intermittent positive-pressure, mainly nocturnal,ventilation.


    MENT AND LACK OF HEAD CONTROL. Two nonrelatedindividuals (Patients 31 and 32), currently aged 14 and15 years, with neonatal hypotonia, failure to thrive, ahigh-pitched nasal voice, and permanent and total lackof head control associated with severe scoliosis, flatthorax, and marked pectoralis major retractions. VCwas reduced to 15% and 17% of the predicted values;both patients have been ventilated through a tracheot-omy from the ages of 6 and 11 years. Weakness distri-bution was similar to that described for the previousgroup and remained stable; spinal fusion was requiredin both cases.

    Because pharyngolaryngeal involvement was notfound in any other severe case, these patients were ten-tatively considered to form a particular subgroup.

    ANTENATAL-ONSET FORM: ARTHROGRYPOSIS. In 3 chil-dren (Patients 3335), 2 of them siblings, congenitalgeneralized arthrogryposis was the manifestation of asevere antenatal akinesia. All 3 had dolichocephaly, aprominent nasal root, oblique palpebral fissures, a higharched palate, low-set ears, and a short neck with mild

    Table 3. Classic Form: Summarized Main Clinical Findings

    Number ofCases (%)

    First signsa

    Neonatal manifestations 14 (46.7%)Hypotonia 10Respiratory difficulties 4Feeding difficulties 2Congenital ptosis 2Dysmorphic features (thorax deformi-

    ties, hip dysplasia, congenital cervicalkyphoscoliosis, congenital club feet,polythelia)


    Delayed motor milestones 22 (73.3%)Mean age at acquisition of autono-

    mous gait: 23.1 moPoor motor performance in childhood 4 (13.3%)

    Facial muscle weakness 17 (56.7%)Mild 10Moderate 4Facial diplegia 3

    Limb joint contractures 10 (33.3%)Mild/moderate 10Severe 0

    Spinal abnormalitiesa 26 (86.7%)Scoliosis 22 (73.3%)

    Mild 6Moderate 7Severe 9(Mean age at diagnosis, 7.1 yr)

    Dorsal kyphosis 2Isolated hyperlordosis 3Spinal rigidity 4

    Respiratory involvement 18 (60%)Mild (VC $ 65%) 3Moderate (VC 5 5064%) 3Severe (VC 5 1749%) 12Tracheotomy 6(Mean age at diagnosis, 9.9 yr)Ventilatory assistance, mean age, 10.3 yr

    Cardiac abnormalities 7 (23.3%)MP 4MP 1 UBRBB 1 bradycardia 1MP 1 mild RVF 1Mild RVF 1

    aTwo or more of these signs concurred in some patients.

    VC 5 vital capacity; MP 5 mitral prolapsus; UBRBB 5 unifas-cicular block of the right bundle branch; RVF 5 right ventriclefailure.

    Fig 1. Classical form. Patient 19 at 15 years of age. Musclebulk is globally reduced; note marked sternocleidomastoideusamyotrophy, severe scoliosis, flat thorax with intercostal retrac-tions, and dorsal hollow back. In this case, mild elbow con-tractures are also present.

    Ferreiro et al: Multi-Minicore Disease: Phenotype Analysis 749

  • pterygium colli. The 2 brothers (Patients 33 and 34)also had a bell-shaped thorax, clinodactyly, bilateralcryptorchidism, and a single palmar crease.

    A mild to moderate muscle weakness, predominantlyaxial, was present in these 3 cases. The 2 siblings ac-quired autonomous gait at 18 and 26 months of age.Both had early, severe, and progressive scoliosis, whichrequired surgical correction in the elder boy at 4 yearsof age. VC was mildly to moderately reduced. Thethird child can only stand with help at 3 years. Heshowed from birth a severe nonprogressive dorsal ky-phosis; VC was reduced to 32% of the expected value.

    In these 3 cases, the joint contractures improvedwith precocious physiotherapy, and the muscle powerremained stable.

    PROGRESSIVE FORM WITH HAND AMYOTROPHY. Threesisters born of consanguineous Algerian parents (Pa-tients 3638) showed a particular clinical picture char-acterized by prominent hand amyotrophy and slowprogression.

    All 3 were moderately hypotonic at birth; 2 pre-sented with congenital club feet. Autonomous gait wasacquired between 15 months and 2 years of age. Theyhave never been able to run. A global muscle weaknessbecame evident during childhood, predominating inaxial (trunk flexors) and proximal groups (MRC scorerange, 31 to 4) and including facial muscles. The dis-tal lower limbs were almost normal; in contrast, amarked distal weakness was present in the upper limbs,with uniform amyotrophy of intrinsic hand muscles.Myotonia, lingual fasciculations, or signs of peripheralnerve involvement were absent. No marked scoliosis,respiratory insufficiency, or cardiac involvement wasdetected (normal electrocardiogram and echocardio-gram). Deep tendon reflexes were weak in the upperlimbs and knees, with normal ankle jerks. The 3 girlshad mild heel contractures despite a generalized jointhyperlaxity; 1 required surgery because of repeated pa-tellar and knee luxations.

    Genetic tests for spinal muscular atrophy and myo-tonic dystrophy enabled survival of motor neuron(SMN) gene abnormalities and CTG triplet expansionto be excluded.

    Muscle weakness was slowly progressive. The eldestsister (23 years old), who is the most severely affectedof the 3, can hardly walk without help.

    Morphological ResultsA total of 36 biopsies from 34 patients were reviewed(at least 1 biopsy per family in multiplex families).Ages at the time of the diagnostic biopsy ranged from2 months to 42 years (mean, 12.1 years). Only in theyoungest patient (2-month-old Patient 1) did the lightmicroscopy analysis fail to reveal any abnormality.

    Typical lesions were found only after electron micro-scope examination.

    The main morphological findings in this series (sum-marized in Table 4) were common to all the biopsiesand consisted of the association of type 1 predomi-nance and hypotrophy, centrally located nuclei, andmultiple minicores in both type 1 and 2 fibers. Therewas no clear correlation between the intensity of themorphological abnormalities and the severity of theclinical involvement.

    In hematoxylin-eosin and Gomoris trichromestained sections, the most constant findings were anincreased variability in fiber size and an elevated num-ber of centrally located nuclei. The endomysial andperimysial connective tissue was either normal orslightly increased in most cases (Fig 2).

    The myofibrillar ATPase reaction revealed type I fi-ber predominance in almost every case regardless of thesite of biopsy. Type 1 uniformity was observed in 7cases. When present, type 2 fibers were never grouped.A constant finding was the relative hypotrophy of type1 fibers; their mean diameter was smaller than that oftype 2 fibers in most biopsies, and the same was truefor the global means (see Table 4; Fig 3). Among type2 fibers, type 2A was always predominant, althoughtype 2B and 2C fibers were generally present. Poorly

    Table 4. Morphological Findings

    Fiber type distribution and size (seeFig 3)

    Cases with type 1 uniformity (% ofbiopsies)

    7 (19%)

    Cases with type 1 predominance(% of biopsies)

    28 (78%)

    Mean % of type 1 fibers 74.3%Mean fiber diameter (6SD)

    Type 1 43.8 (6 12.2)Type 2 56.8 (6 26.9)

    Oxidative abnormalitiesMinicore lesions (in fiber

    transversal sections)Mean % of affected fibers 69%Type of affected fibers BothSmaller diameter: mean (range) 8.4 (2.133.3)Number per fiber: mean (range) 2.8 (112)

    Central positive zonesMean % of affected fibers 32%

    Centrally located nucleiCases with increased number (% of

    biopsies)31 (86%)

    Mean % of affected fibers 12.4%Mean endomysial fibrosis degree


    Other lesionsCases with splitting in fibers

    (,6.5%)4 (11%)

    Cases with mildly lobulated fibers(,5%)

    5 (14%)

    750 Annals of Neurology Vol 48 No 5 November 2000

  • defined zones of decreased myofibrillar ATPase activitywere observed in both fiber types.

    When processed for demonstration of oxidative en-zyme activity, muscle sections showed multiple smallfocal lesions in which oxidative activity was reduced or

    absent (see Fig 2). These clear zones were more definiteon NADH-TRstained sections but larger and oftenmore numerous on succinate dehydrogenase sections.When observed in transversal sections, they were gen-erally round, small, multiple, and randomly distribut-ed; nevertheless, some fibers contained large unique le-sions, which were either central or eccentric. Lesionboundaries were poorly defined and without perile-sional enhancement of oxidative activity. In contrast, in9 cases, small areas showing increased oxidative activitywere observed in the center of some type 1 fibers.When the two fiber types were present, usually bothdemonstrated minicores, although the lesions in type 2fibers seemed to be larger, less frequent, and less defi-nite than those in type 1 fibers.

    In every case, semithin sections disclosed multiplesmall areas of sarcomere disorganization. Their mainaxis was either transversal or, less frequently, parallel tothe fiber longitudinal axis. Longitudinal semithin sec-tions proved to be the most adequate technique for es-timation of lesion length; minicores never spannedmore than 15 to 20 contiguous sarcomeres (Fig 4).

    Ultrastructural examination disclosed multiple re-

    Fig 2. Histological and histochemical findings; serial transverse cryostat sections (Patient 7). (a) Hematoxylin-eosin stain demonstrat-ing fiber size variability and centrally located nuclei (arrows). (b) Myosin adenosine triphosphatase (pH 9.4). Type 1 fiber predom-inance and relative hypotrophy. (c) NADH-TR (tetrazolium reductase). Multiple focal areas lacking oxidative activity are present inmost type 1 and 2 fibers (arrows). (d) Succinate dehydrogenase. The zones showing a decrease in oxidative enzyme activity seem tobe larger, less frequent, and less definite, especially in type 2 fibers (arrows). Bar 5 40 mm in a and b; bar 5 25 mm in c andd.

    Fig 3. Graphic representation of relative hypotrophy of type 1fibers compared with type 2 fibers. This graphic was obtainedfrom the megahistogram of 10 deltoid biopsies (2,211 fibers)from the classic group; ages at biopsy ranged from 5 to 27years. Fiber diameters are expressed in micrometers.

    Ferreiro et al: Multi-Minicore Disease: Phenotype Analysis 751

  • gions showing Z-line streaming and lack of mitochon-dria. There were several stages of lesion severity (Fig 5);myofibrillar disorganization could be detected in pre-sumably early lesions as a loss of myofilament align-ment causing the sarcomeres to appear out of register.No abnormal mitochondria or vesicular nuclei wereever found.

    The immunohistochemical studies performed in 4classical cases (Patients 24, 26, 27, and 30) disclosedincreased reactivity for desmin limited to the core le-sions (Fig 6); no isolated perilesional rims were found.Anti-titin antibodies revealed disorganization of thenormal striated pattern in the regions corresponding tominicore lesions. Antibodies against alpha-actinin andactin failed to reveal any particular abnormality.

    Although the basic morphological alterations thatdefine MmD were present in all cases, some particularnoteworthy observations were found in each clinicalgroup.

    CLASSICAL FORM. Centrally located nuclei were ob-served in more than 50% of the fibers in 3 cases (Pa-tients 16, 20, and 29). They were often multiple andnever accompanied by radial distribution of the oxida-tive activity as seen in centronuclear myopathy. In 1 ofthese cases (Patient 16), the predominant type 1 fiberswere either hypotrophic or hypertrophic, although alltype 2 fibers had large diameters. Several arrays ofT-tubules and lateral vesicles forming pentads or hep-tads were found within the ultrastructural lesions.

    Increase of endomysial connective and fatty tissuewas marked in the muscle biopsy of 2 siblings (Patients14 and 15) affected by a severe clinical form of thedisease. Merosin, dystrophin, sarcoglycans, and dystro-

    glycan staining were normal. Typical minicores werepresent in all muscle fibers.


    MENT AND LACK OF HEAD CONTROL. The ultrastruc-tural analysis of these two biopsies showed electron-dense images within some of the minicore lesions,suggesting accumulation of desmin filaments. Therewas no accumulation of abnormal material outside thelesions.

    ANTENATAL FORM: ARTHROGRYPOSIS. Patient 33 wasbiopsied at 16 months and 3.5 years of age. The mor-phological aspect of both biopsies was similar; amarked endomysial fibrosis and a slight increase in thenumber of minicores in the second biopsy were themost remarkable findings.

    DISTAL PROGRESSIVE FORM. Patient 37 had two biop-sies at 4 and 20 years of age. Both showed type 1 uni-formity. In the first biopsy, there were multiple minuteoxidative-negative foci; in the second one, these areaswere bigger and less frequent, and some centraloxidative-positive zones were found. Her sisters biopsy(Patient 36), performed at 4 years, revealed only type 1uniformity, without focal lesions.

    DiscussionSince the first description of multicore myopathy byEngel and colleagues2 in 1971, some 70 additionalcases have been reported. The clinical and morpholog-ical features described are not always consistent in dif-ferent reports, which probably reflects both the diffi-culty of establishing an accurate diagnosis and a realphenotypic heterogeneity. The analysis of a series of 38patients led us to encounter most of the unansweredquestions raised by MmD up to now.

    Clinical Definition and Heterogeneity of MmDThe first main problem is the clinical definition andheterogeneity of MmD. The identification of 4 differ-ent clinical groups among our patients, all carefully se-lected on morphological grounds, seems to confirmthat the spectrum of clinical manifestations of MmD isbroad. MmD is thus a clinically heterogeneous entity.

    Nevertheless, most of the patients in our series (30of 38) shared a consistent recognizable pattern of mus-cle involvement marked by the predominance of axialmuscle weakness, high occurrence of scoliosis and ma-jor respiratory involvement, and absence of markedlimb contractures. External eye movements were nor-mal in our series, in contrast with findings in previousreports.3,10,29,34,40 From this clinical picture alone,MmD cannot be differentiated from other congenitalmyopathies, but its consistency seems to validate our

    Fig 4. Longitudinal semithin section of epoxy-embedded mate-rial stained with toluidine blue (Patient 20). Multiple smallareas show disruption of the normal sarcomeric pattern in twoadjacent fibers. The lesions are often perpendicular to themain axis of the fibers; the abnormal Z-lines look pulledapart, curving away the contiguous normal sarcomeres. Bar 510 mm.

    752 Annals of Neurology Vol 48 No 5 November 2000

  • morphological criteria and to corroborate the nosologicentity of MmD.

    Clinical features were almost identical in all the af-fected siblings from the same family. In contrast, someinterfamilial differences were detected, especially con-cerning the facial involvement, severity of the disease,and importance of certain morphological abnormali-ties. This could suggest that a certain degree of geneticheterogeneity cannot be totally excluded.

    Axial Weakness and Respiratory InvolvementAxial muscle weakness is not rare in congenital myop-athies; however, the preferential and severe involve-ment of axial groups seems to be a significant featurein MmD and could be related to the fact that the em-bryonic origin of axial muscles and the regulatory fac-

    tors controlling their development are not identical tothose implicated in the genesis and migration of limbmuscle groups.59

    According to the present study, scoliosis is more fre-quent and severe in MmD than in any other congen-ital myopathy and shows steady evolution even whenlimb weakness remains stable. As previously reported,8,27

    scoliosis can be the form of presentation of the disease,and aggravation can be rapid during the adolescencerapid-growth period. Appropriate surgical procedurescan prevent loss of ambulation in patients with fairlygood limb power and contribute to stabilize respiratoryfunction.

    Respiratory involvement is also frequent and severein MmD. Its origins are multifactorial, including respi-ratory muscle weakness and retractions, thoracic wall

    Fig 5. Electron micrograph stages in lesionseverity. (a) Longitudinal section (Patient 21).In this early stage, the sarcomeres seem to beout of register. (b) Longitudinal section (Pa-tient 25). Z-line streaming is limited to onesarcomere in length and three to four myofi-brils in width; the longitudinal myofilamentarray is still recognizable. (c) Transverse sec-tion (Patient 25). Electron-dense material ofZ-line origin forms irregular zones. (d) Longi-tudinal section (Patient 27). Severe focal dis-organization of the myofibrillar structure. Inall cases, mitochondria (and reticular compo-nents) are virtually absent from the lesionsbut are normally present in the adjacentzones. Bars 5 1 mm.

    Ferreiro et al: Multi-Minicore Disease: Phenotype Analysis 753

  • deformities, scoliosis, and diaphragm involvement. Inmost cases, the severity of respiratory insufficiency isdisproportionate to the degree of mechanical abnor-malities and global muscle weakness; actually, respira-tory symptoms can be the first detected manifestationof the disease.26 The episodes of nocturnal hypoventila-tion found in some of our cases are relatively commoneven in patients with good motor function,35 probablyreflecting a central hypoventilation component.

    The severity of MmD is mainly determined by therespiratory involvement. Close monitoring and preco-cious treatment of the factors leading to it, includingscoliosis correction and ventilation, are thus highly rec-ommended. In this sense, most of our patients benefitedfrom early preventive treatment by face mask intermit-tent positive-pressure ventilation (Bird, Sebac, Pantin,France). As previously reported by Barois and Estour-net,60 its efficacy for favoring good thoracic and alveolardevelopment as well as for improving the long-term vitaland functional prognosis probably makes it the most ef-fective symptomatic measure for MmD patients.

    Cardiac Involvement in MmDOne of the original patients described by Engel andco-workers2 had atrial and ventricular septal defects.Since then, 9 other patients have been reported to haveboth minicore lesions in skeletal muscle and cardiacfailure secondary to patent foramen ovale14 or cardio-myopathy.9,1820,24,25 In addition, the patient reportedby Taratuto and colleagues6 died from an acute cardiacproblem in his teens (A. L. Taratuto, unpublisheddata). However, a differential diagnosis with centralcore disease18,19,22 or desmin-related myopathies20,25

    can be proposed for some of these cases, notably forthose with dominant transmission.

    In the present MmD series, the most common car-diac abnormality was subclinical mitral prolapsus(MP), which has been described in several other my-opathies. Some authors have suggested that in progres-sive muscular dystrophies, this abnormality could bemore closely linked to thorax and thoracic spine defor-mities than to the myocardial involvement itself, withthe lordotic or straight spine and flattened thorax beingthe major factors in the occurrence of MP.61 Because 5of our 6 patients with MP demonstrated this kind ofthoracic abnormality, this mechanical factor could alsoplay a role in MmD. Similarly, other abnormalitiesfound in our patients (ie, right bundle branch partialblock, nocturnal bradycardia, mild right ventricle failure)probably do not reflect primary cardiac involvement.

    Significance and Origin of the Morphological LesionsAs stated previously, core or core-like lesions can befound in a wide variety of conditions; this lack of spec-ificity suggests that they may represent the final com-mon expression of diverse pathogenic mechanisms.

    There are morphological similarities among the le-sions in MmD, the core formations in CCD, and thetarget formations in reinnervated muscles. Neverthe-less, central cores have been reported to extend the en-tire length of the fiber in the biopsy sample2,62,63; tar-get formations usually do not extend so far but arelonger than MmD lesions.2,40 The multi-minicore le-sions also differ from target and core formations intheir poorly defined limits, their varying orientationwith respect to the fiber axis, and their average numberin the affected fibers. In addition, both fiber types areusually affected in MmD, while target and core forma-tions are generally restricted to type 1 fibers. The def-inition of MmD thus rests on the presence of the same

    Fig 6. Immunohistochemical labeling for desmin (a) and titin (b); serial transverse cryostat sections (Patient 27). Multiple smallzones present increased desmin reactivity (a) and disarray of the normal titin striated pattern (b). The longest lesions can be identi-fied in several successive sections (arrows). Bar 5 25 mm.

    754 Annals of Neurology Vol 48 No 5 November 2000

  • stereotyped morphological change affecting a high pro-portion of the muscle fibers in the absence of any caus-ative agent and coexisting with other abnormalitiessuggestive of a congenital myopathy. In this sense, cen-trally located nuclei and, above all, type 1 fiber pre-dominance and hypotrophy have been constant find-ings in our study and could strongly support thediagnosis of MmD.

    The coexistence of MmD lesions with cores,32,53,54

    rods,64 or centrally located nuclei11,12,65 underlines thedifficulties of establishing morphological boundarieswithin the group of congenital myopathies. In our se-ries, the main diagnostic difficulty came from the 3cases demonstrating central nuclei in more than 50%of the fibers together with multiple zones of sarcomeredisorganization and absence of mitochondria. A similarcase was described by Fitzsimons and McLeod.12 Inone of these cases (Patient 16), the histochemical pat-tern was reminiscent of the so-called centronuclearmyopathy with type 1 hypotrophy65; arrays of T tu-bules and lateral vesicles were found within the ultra-structural lesions as previously reported.4,40

    A differential diagnosis with congenital musculardystrophy was considered in 3 of our patients (Patients14, 15, and 33) because of the presence of moderateendomysial fibrosis. The identification of typical multi-minicore lesions in more than 80% of the muscle fibersled to the diagnosis of MmD; however, because thesecases demonstrated unusual phenotypes, they couldrepresent variant forms.

    In some of our cases, there were moderate abnormal-ities in desmin distribution. This finding has been de-scribed in other congenital myopathies66,67; its possiblepathogenetic role remains undetermined. No previousimmunohistochemical studies on MmD have been re-ported. Although an enhancement in desmin immuno-histochemical staining is observed mainly around thecores in CCD,68 in our observations, desmin seemedto accumulate within the lesions and not around them.Ultrastructural analysis showed some evidence of desminaccumulation (restricted to the minicore lesions) in the 2patients presenting with a severe form with laryngeal in-volvement. Analysis of more cases is required to confirmthese preliminary findings and their possible diagnosticimplications. Potential relations between MmD anddesmin-related myopathies probably constitute one in-teresting field that deserves further investigation.

    Areas of focal loss of cross-striations may occur inadjacent zones of several muscle fibers. It has been pos-tulated that this distribution of lesions might be due totheir proximity to small blood vessels,32 but it mightequally well be explained by local stresses within themuscle.10 Foci of Z-disk disintegration with unequalnumbers of sarcomeres on both sides have been seen inhuman muscle fibers damaged by eccentric contrac-tions.69 It is conceivable that repeated eccentric con-

    traction of a defective muscle could be the origin ofmany of these zones, which would eventually evolvedue to an abnormal sarcomeric constitution. Minicorescould thus be the secondary morphological manifesta-tion of a primary lesion causing diminished resistanceof sarcomeres to tension. Their presence would be in-dependent of the nature of the primary abnormality,which could explain the lack of specificity of MmDlesions. As previously described,54 slight modificationsin the number and size of minicores were observed af-ter 2 and 16 years of evolution in 2 of our patients.Sequential changes are, however, not exceptional incongenital myopathies.

    Whether the primary abnormality causing minicoresconsists of a mitochondrial lesion or a defect directlyinvolving sarcomeric or cytoskeletal proteins remainsan unsolved question. Engel and colleagues2 suggestedthat the basic MmD process begins in mitochondria.This was based on their observation that the numberand mean area of mitochondria-lacking zones werelarger than those of myofibrillar lesions and disorga-nized sarcomeres. Later reports did not substantiatethese findings.4,5 However, in a recently reported caseof short-chain acyl-coenzyme A dehydrogenase defi-ciency presenting with ophthalmoplegia and congenitalprogressive weakness, small core lesions were found inskeletal muscle.43 Further studies are needed to deter-mine whether a physiopathologic link between mito-chondrial dysfunction and sarcomere lesions does exist.

    This phenotype analysis should be helpful in the di-agnosis, management, and follow-up of MmD patientsand should facilitate the identification of homogeneousgroups, thus allowing future molecular genetic studies.Knowledge of the genetic basis underlying MmD andsubsequent phenotype reevaluation should contributeto shed further light on the complex field of congenitalmyopathies.

    This study was supported in part by the Association Francaise con-tre les Myopathies. Dr Ferreiro received grants from the EuropeanCommission BIOMED program (Marie Curie BMH4-CT98-5091)and the Association Francaise contre les Myopathies.

    We thank Mrs Collin, Mr Bozin, and Mrs Rouche for technicalassistance. We also thank Dr Taratuto (National Pediatric Hospital,Buenos Aires), Dr Merlini (Istituto Rizzoli, Bologna), and Dr Ferrus(Instituto Cajal, Madrid) for useful discussions. We acknowledge allthe patients and families who participated in this study.

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