Nemaline myopathy type 6: Clinical and myopathological features

Abstract

Introduction 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. Methods 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. Results The disease started in childhood by affecting proximal and distal muscles and causing slowness of movements. Muscle biopsies show 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. Discussion The disease in this Spanish family is 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.

Congenital Myopathies: An Update

“…The most recent genetic discovery in NM are mutations in KBTBD13 causing a dominant rod myopathy with cores [9••], referred to as NM type 6. This myopathy is characterized by childhood-onset of slowly progressive weakness of neck and proximal muscle groups, and a slowness of movement that is not common in other congenital myopathies [35]. This slowness of movement, together with core-like structures, may represent a sign of abnormal excitation-contraction coupling.…”

“…This slowness of movement, together with core-like structures, may represent a sign of abnormal excitation-contraction coupling. Muscle biopsies show softly defined core areas referred to as “pseudocores” [35], distinct from the sharply demarcated core structures observed in RYR1 mutations [36, 37] and NEB mutations [27••]. The exact role of KBTBD13 is unknown, but other BTB/Kelch family proteins are involved in regulation of cytoskeleton remodeling, gene transcription, and myofiber assembly [9••].…”

KBTBD13 interacts with Cullin 3 to form a functional ubiquitin ligase

“…We recently identified dominant mutations in an unknown gene, eventually designated as Kelch-repeat and BTB (POZ) domain containing 13 gene (KBTBD13) that are associated with a new form of Nemaline Myopathy type 6 (NEM6) [1,2]. NEM is a heterogeneous group of inherited myopathies that mostly affect infants and children.…”

“…NEM is a heterogeneous group of inherited myopathies that mostly affect infants and children. NEM is characterized by slowly progressive muscle weakness and the presence of thread- or rod-like so called nemaline bodies in affected muscle [2–4]. Mutations causing phenotypically distinct NEM variants have been identified in genes encoding components of skeletal muscle sarcomeric thin filaments or regulators of their assembly and as such NEM is considered a disease of muscle thin filament [3,4].…”

Congenital myopathies: not only a paediatric topic

“…NEM6 is characterized by a peculiar slowness of movements, and the development of slowly progressive muscle weakness affecting neck and proximal limb muscles. As in other adult-onset congenital myopathies, muscle weakness often manifests not until adolescence or adulthood, but all patients retrospectively report difficulties with sport in childhood [36,84]. The characteristic slowness is often perceived as clumsiness, with patients generally unable to sprint or to suddenly adapt their position to avoid falls.…”