Article

Nemaline myopathy type 6: Clinical and myopathological features

Institute of Neuropathology, Pathology Department, IDIBELL-Hospital de Bellvitge and CIBERNED, Hospitalet de Llobregat, Feixa Llarga s/n, Hospitalet de Llobregat, Barcelona 08907, Spain.
Muscle & Nerve (Impact Factor: 2.31). 12/2010; 42(6):901-7. DOI: 10.1002/mus.21788
Source: PubMed

ABSTRACT Nemaline myopathy (NEM) is one of the most common congenital myopathies. A unique subtype, NEM6, maps to chromosome 15q21-q23 in two pedigrees, but the causative gene has not been determined. We conducted clinical examination and myopathological studies in a new NEM family. Genotyping and gene screening were accomplished by searching known and 18 new candidate genes. The disease started in childhood by affecting proximal and distal muscles and causing slowness of movements. Muscle biopsies showed numerous nemaline rods and core-like formations. Suggestive linkage to chromosome 15q22-q23 was established. Genes known to be mutated in NEM or core-rod myopathy were screened and excluded. No pathogenic mutations were identified in other candidate genes. The disease in this Spanish family was classified as NEM6. It is phenotypically similar and probably allelic to the two previously reported NEM6 pedigrees. Further studies of these families will lead to the identification of the NEM6 gene.

Download full-text

Full-text

Available from: Montse Olivé, Aug 14, 2015
0 Followers
 · 
134 Views
  • Source
    • "It has been increasingly recognized that the histological features observed within a muscle biopsy may represent manifestations along spectra of possible abnormalities, rather than discrete pathological entities (Sewry et al., 2008; Nance et al., 2012). For example central nuclei are classically associated with mutations in BIN1, DNM2, MTM1, and SPEG however, more recently, prominent central nuclei have been reported in cases resulting from mutations in CFL2 (Ockeloen et al., 2012), KBTBD13 (Olive et al., 2010), RYR1 (Wilmshurst et al., 2010) and TTN (Ceyhan-Birsoy et al., 2013; Palmio et al., 2014). On the flip side, although congenital myopathies have traditionally been classified purely by their defining histopathology , with the discovery of the underlying genetic cause for an increasing number of patients, the field has also begun in parallel to classify patients based on the causative disease gene, such that there is now, for instance, reference to ACTA1-related myopathies (Nowak et al., 2013), RYR1-related myopathies (Klein et al., 2012; Amburgey et al., 2013; Bharucha-Goebel et al., 2013) and SEPN1- related myopathies (Schara et al., 2008; Scoto et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The congenital myopathies are a diverse group of genetic skeletal muscle diseases, which typically present at birth or in early infancy. There are multiple modes of inheritance and degrees of severity (ranging from foetal akinesia, through lethality in the newborn period to milder early and later onset cases). Classically, the congenital myopathies are defined by skeletal muscle dysfunction and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. However, mutations in multiple different genes can cause the same pathology and mutations in the same gene can cause multiple different pathologies. This is becoming ever more apparent now that, with the increasing use of next generation sequencing, a genetic diagnosis is achieved for a greater number of patients. Thus, considerable genetic and pathological overlap is emerging, blurring the classically established boundaries. At the same time, some of the pathophysiological concepts underlying the congenital myopathies are moving into sharper focus. Here we explore whether our emerging understanding of disease pathogenesis and underlying pathophysiological mechanisms, rather than a strictly gene-centric approach, will provide grounds for a different and perhaps complementary grouping of the congenital myopathies, that at the same time could help instil the development of shared potential therapeutic approaches. Stemming from recent advances in the congenital myopathy field, five key pathophysiology themes have emerged: defects in (i) sarcolemmal and intracellular membrane remodelling and excitation-contraction coupling; (ii) mitochondrial distribution and function; (iii) myofibrillar force generation; (iv) atrophy; and (v) autophagy. Based on numerous emerging lines of evidence from recent studies in cell lines and patient tissues, mouse models and zebrafish highlighting these unifying pathophysiological themes, here we review the congenital myopathies in relation to these emerging pathophysiological concepts, highlighting both areas of overlap between established entities, as well as areas of distinction within single gene disorders. Published by Oxford University Press on behalf of the Guarantors of Brain 2014. This work is written by US Government employees and is in the public domain in the US.
    Brain 12/2014; 138(2). DOI:10.1093/brain/awu368 · 10.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We identified a member of the BTB/Kelch protein family that is mutated in nemaline myopathy type 6 (NEM6), an autosomal-dominant neuromuscular disorder characterized by the presence of nemaline rods and core lesions in the skeletal myofibers. Analysis of affected families allowed narrowing of the candidate region on chromosome 15q22.31, and mutation screening led to the identification of a previously uncharacterized gene, KBTBD13, coding for a hypothetical protein and containing missense mutations that perfectly cosegregate with nemaline myopathy in the studied families. KBTBD13 contains a BTB/POZ domain and five Kelch repeats and is expressed primarily in skeletal and cardiac muscle. The identified disease-associated mutations, C.742C>A (p.Arg248Ser), c.1170G>C (p.Lys390Asn), and c.1222C>T (p.Arg408Cys), located in conserved domains of Kelch repeats, are predicted to disrupt the molecule's beta-propeller blades. Previously identified BTB/POZ/Kelch-domain-containing proteins have been implicated in a broad variety of biological processes, including cytoskeleton modulation, regulation of gene transcription, ubiquitination, and myofibril assembly. The functional role of KBTBD13 in skeletal muscle and the pathogenesis of NEM6 are subjects for further studies.
    The American Journal of Human Genetics 12/2010; 87(6):842-7. DOI:10.1016/j.ajhg.2010.10.020 · 10.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Congenital myopathy is a clinicopathological concept of characteristic histopathological findings on muscle biopsy in a patient with early-onset weakness. Three main categories are recognized within the classical congenital myopathies: nemaline myopathy, core myopathy, and centronuclear myopathy. Recent evidence of overlapping clinical and histological features between the classical forms and their different genetic entities suggests that there may be shared pathomechanisms between the congenital myopathies. Animal models, especially mouse and zebrafish, have been especially helpful in elucidating such pathomechanisms associated with the congenital myopathies and provide models in which future therapies can be investigated.
    Current Neurology and Neuroscience Reports 03/2012; 12(2):165-74. DOI:10.1007/s11910-012-0255-x · 3.67 Impact Factor
Show more