Current and future therapeutic approaches to the congenital myopathies

Abstract

a b s t r a c tThe congenital myopathies -including Central Core Disease (CCD), Multi-minicore Disease (MmD), Centronuclear Myopathy (CNM), Nemaline Myopathy (NM) and Congenital Fibre Type Disproportion (CFTD) -are a genetically heterogeneous group of early-onset neuromuscular conditions characterized by distinct histopathological features, and associated with a substantial individual and societal disease burden. Appropriate supportive management has substantially improved patient morbidity and mortality but there is currently no cure. Recent years have seen an exponential increase in the genetic and molecular understanding of these conditions, leading to the identification of underlying defects in proteins involved in calcium homeostasis and excitation-contraction coupling, thick/thin filament assembly and function, redox regulation, membrane trafficking and/or autophagic pathways. Based on these findings, specific therapies are currently being developed, or are already approaching the clinical trial stage. Despite undeniable progress, therapy development faces considerable challenges, considering the rarity and diversity of specific conditions, and the size and complexity of some of the genes and proteins involved.The present review will summarize the key genetic, histopathological and clinical features of specific congenital myopathies, and outline therapies already available or currently being developed in the context of known pathogenic mechanisms. The relevance of newly discovered molecular mechanisms and novel gene editing strategies for future therapy development will be discussed. © 2016 Elsevier Ltd. All rights reserved.

In vivo characterization of skeletal muscle function in nebulin‐deficient mice

“…So far, potential therapies seeking to restore or at least prevent muscle weakness are studied mainly on single muscle fibers or on isolated muscles . Our in vivo methodological approach may be used to evaluate whether and to what extent potential therapies such as increasing myofiber size, upregulating of protein expression, and targeting thin filaments and their interactions with specific pharmacological compounds or drugs may prevent the large force reduction and/or atrophy typically observed in Neb ‐cKO mice. This is particularly relevant when we consider that those mice surviving to adulthood displayed NEB levels close to those reported in severely affected patients with NEB mutations.…”

An Extended Targeted Copy Number Variation Detection Array Including 187 Genes for the Diagnostics of Neuromuscular Disorders

“…Specifically designed follow-up and specific putative future therapies can be administered only when the correct molecular diagnosis and the underlying causative mechanisms of the disorder have been determined [3, 4]. …”

Clinicopathologic Conference: A Newborn With Hypotonia, Cleft Palate, Micrognathia, and Bilateral Club Feet

“…CFTD is histopathologically defined by the presence of type 1 fibers of small cross sectional area (CSA) and typically found in predominance in comparison to type 2 fibers; because such features may be seen in a variety of congenital (structural) myopathies, this diagnosis is reserved for biopsies in which there are no other histopathologic features suggesting another specific diagnosis, such as nemaline myopathy or central core myopathy 4 . The definition of what constitutes disproportion is inexact; initially, classification as CFTD was based on type 1 fibers >12% smaller than type 2 fibers but this was later found to be relatively non-specific and the cutoff was raised to 25%, with an argument that the cutoff should be raised to >35–40% to heighten specificity 5 .…”