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

  • View

  • Download

Embed Size (px)


  • 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 abn