Journal of Neuromuscular Diseases - Volume 2, issue s2

Article Type: Editorial

DOI: 10.3233/JND-159904

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S1-S1, 2015

Authors: Walton, John

Article Type: Other

DOI: 10.3233/JND-159903

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S3-S4, 2015

Authors: Meadowcroft, Robert

Article Type: Other

DOI: 10.3233/JND-159902

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S5-S6, 2015

Authors: Murphy, Alexander Peter | Straub, Volker

Article Type: Review Article

Abstract: Over sixty years ago John Walton and Frederick Nattrass defined limb girdle muscular dystrophy (LGMD) as a separate entity from the X-linked dystrophinopathies such as Duchenne and Becker muscular dystrophies. LGMD is a highly heterogeneous group of very rare neuromuscular disorders whose common factor is their autosomal inheritance. Sixty years later, with the development of increasingly advanced molecular genetic investigations, a more precise classification and understanding of the pathogenesis is possible. To date, over 30 distinct subtypes of LGMD have been identified, most of them inherited in an autosomal recessive fashion. There are significant differences in the frequency of …subtypes of LGMD between different ethnic populations, providing evidence of founder mutations. Clinically there is phenotypic heterogeneity between subtypes of LGMD with varying severity and age of onset of symptoms. The first natural history studies into subtypes of LGMD are in process, but large scale longitudinal data have been lacking due to the rare nature of these diseases. Following natural history data collection, the next challenge is to develop more effective, disease specific treatments. Current management is focussed on symptomatic and supportive treatments. Advances in the application of new omics technologies and the generation of large-scale biomedical data will help to better understand disease mechanisms in LGMD and should ultimately help to accelerate the development of novel and more effective therapeutic approaches. Show more

Keywords: Limb-girdle muscular dystrophy, natural history, pathogenesis

DOI: 10.3233/JND-150105

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S7-S19, 2015

Authors: Evangelista, Teresinha | Hanna, Mike | Lochmüller, Hanns

Article Type: Research Article

Abstract: Congenital myasthenic syndromes are a heterogeneous group of genetically determined disorders characterized by impaired neuromuscular transmission. They usually present from birth to childhood and are characterised by exercise induced weakness and fatigability. Genotype-phenotype correlations are difficult. However, in some patients particular phenotypic aspects may point towards a specific genetic defect. The absence of ptosis and ophthalmoparesis in patients with limb-girdle weakness makes the diagnosis of a neuromuscular transmission defect particularly challenging (LG-CMS). This is illustrated by a well-documented case published by Walton in 1956. The diagnosis of LG-CMS is secured by demonstrating a neuromuscular transmission defect with single fibre …EMG or repetitive nerve stimulation, in the absence of auto-antibodies. Ultimately, a genetic test is required to identify the underlying cause and assure counselling and optimization of treatment. LG-CMS are inherited in autosomal recessive traits, and are often associated with mutations in DOK7 and GFPT1 , and less frequently with mutations in COLQ, ALG2, ALG14 and DPAGT . Genetic characterization of CMS is of the upmost importance when choosing the adequate treatment. Some of the currently used drugs can either ameliorate or aggravate the symptoms depending on the underlying genetic defect. The drug most frequently used for the treatment of CMS is pyridostigmine an acetylcholinesterase inhibitor. However, pyridostigmine is not effective or is even detrimental in DOK7 - and COLQ -related LG-CMS, while beta-adrenergic agonists (ephedrine, salbutamol) show some sustained benefit. Standard clinical trials may be difficult, but standardized follow-up of patients and international collaboration may help to improve the standards of care of these conditions. Show more

DOI: 10.3233/JND-150098

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S21-S29, 2015

Authors: Müller, Juliane S. | Giunta, Michele | Horvath, Rita

Article Type: Research Article

Abstract: Defects of RNA metabolism have been increasingly identified in various forms of inherited neurological diseases. Recently, abnormal RNA degradation due to mutations in human exosome subunit genes has been shown to cause complex childhood onset neurological presentations including spinal muscular atrophy, pontocerebellar hypoplasia and myelination deficiencies. This paper summarizes our current knowledge about the exosome in human neurological disease and provides some important insights into potential disease mechanisms.

Keywords: Exosome, RNA degradation, pontocerebellar hypoplasia, spinal muscular atrophy, hypomyelination

DOI: 10.3233/JND-150086

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S31-S37, 2015

Authors: Mazzeo, Anna | Russo, Massimo | Di Bella, Gianluca | Minutoli, Fabio | Stancanelli, Claudia | Gentile, Luca | Baldari, Sergio | Carerj, Scipione | Toscano, Antonio | Vita, Giuseppe

Article Type: Research Article

Abstract: Background: Familial amyloid polyneuropathy related to transthyretin gene (TTR-FAP) is a life-threatening disease transmitted as an autosomal dominant trait. Val30Met mutation accounts for the majority of the patients with large endemic foci especially in Portugal, Sweden and Japan. However, more than one hundred other mutations have been described worldwide. A great phenotypic variability among patients with late- and early-onset has been reported. Objective: To present a detailed report of TTR-FAP patients diagnosed in our tertiary neuromuscular center, in a 20-year period. Methods: Clinical informations were gathered through the database of our center. …Results: The study involved 76 individuals carrying a TTR-FAP mutation. Three phenotypes were identified, each corresponding to a different TTR variant, homogeneous within and heterogeneous between each other: i) Glu89Gln mutation, characterised by 5th – 6th decade onset, neuropathy as presenting symptoms, early heart dysfunction, cardiomyopathy as major cause of mortality followed by dysautonomia and cachexia; ii) Phe64Leu mutation, marked by familiarity reported in one-half of cases, late onset, severe peripheral neuropathy, moderate dysautonomia and mild cardiomyopathy, death for wasting syndrome; iii) Thr49Ala mutation, distinguished by onset in the 5th decade, autonomic disturbances as inaugural symptoms which may remain isolated for many years, moderate polyneuropathy, cachexia as major cause of mortality followed by cardiomyopathy. Conclusions: This survey highlighted a prevalence of 8.8/1,000,000 in Sicily Island. Good knowledge of the natural history of the disease according to different TTR mutations allow clinicians to optimise multiprofessional care for patients and to offer carriers a personalized follow-up to reveal first signs of the disease. Show more

Keywords: Familial amyloid polyneuropathy, FAP, transthyretin, TTR, amyloidosis, cardiomyopathy, dysautonomia, epidemiology, Italy

DOI: 10.3233/JND-150091

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S39-S48, 2015

Authors: Aartsma-Rus, Annemieke | Spitali, Pietro

Article Type: Review Article

Abstract: Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput – omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular …dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products. Show more

Keywords: Biological markers, biomarkers, Duchenne muscular dystrophy, gene expression, proteomics, metabolomics

DOI: 10.3233/JND-150102

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S49-S58, 2015

Authors: Meola, Giovanni | Cardani, Rosanna

Article Type: Research Article

Abstract: Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert’s disease) is caused by a (CTG)n expansion in DMPK , while myotonic dystrophy type 2 (DM2) is caused by a (CCTG)n expansion in CNBP . Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders. The pathogenesis of DM is explained by a common RNA gain-of-function mechanism in which the CUG and CCUG repeats alter cellular function, including alternative …splicing of various genes. However additional pathogenic mechanism like changes in gene expression, modifier genes, protein translation and micro-RNA metabolism may also contribute to disease pathology and to clarify the phenotypic differences between these two types of myotonic dystrophies. This review is an update on the latest findings specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology between the two forms of myotonic dystrophies. Show more

Keywords: Myotonic dystrophy type 1, myotonic dystrophy type 2, clinical findings, muscle biopsy, molecular mechanism, pathology

DOI: 10.3233/JND-150088

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S59-S71, 2015

Authors: Argov, Zohar | Mitrani Rosenbaum, Stella

Article Type: Research Article

Abstract: GNE myopathy (previous names: HIBM, DMRV, IBM2) is a unique distal myopathy with quadriceps sparing. This recessively inherited myopathy has been diagnosed in various regions of the world with more than 150 disease-causing mutations already identified. Several of those are proven or suspected to be founder mutations in certain regional clusters and are described in this review. The review also discusses some historical aspects that might be relevant to the mutational distribution.

Keywords: Distal myopathy, GNE mutations, Roma/Gypsy, hereditary inclusion body myopathy, distal myopathy with rimmed vacuoles, ethnic clusters

DOI: 10.3233/JND-150087

Citation: Journal of Neuromuscular Diseases, vol. 2, no. s2, pp. S73-S76, 2015