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New Perspectives in Molecular Diagnosis of Neuromuscular Disorders
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New Perspectives in Molecular Diagnosis of Neuromuscular Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 24771

Special Issue Editor

Dr. Annalaura Torella

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Guest Editor
Department of Precision Medicine, Università degli Studi della Campania ‘Luigi Vanvitelli’, 80138 Naples, Italy
Interests: nerve; muscle; neuromuscular

Special Issue Information

Dear Colleagues,

Neuromuscular disorders (NMDs) affects the peripheral nervous system and muscle, consequently leading to a significant disability in children as well as in adults.

Over the past decade, research has expanded our understanding of the molecular bases of NMDs. However, the causes remain unknown for many patients, also with clear clinical and histological evidence of disease. The genetic and phenotypic heterogeneity and the lack of segregation data in sporadic cases complicate the detection of causative genetic variants in individual families. In addition, some NMD genes, such as TTN, NEB, RYR, and DMD, are the largest human genes with a wide mutational spectrum, including single base substitutions, small indel, and intragenic deletion/duplication of one or more exons. The identification of the pathogenic mutation and accurate diagnosis improve clinical management and genetic counseling in patients with NMDs and also pave the path forward for clinical trials.

In this Special Issue, we will publish reviews and original papers covering recent advances and perspectives in the molecular diagnosis of NMDs, in research and clinical practice and the latest developments that are underway in NGS.

Dr. Annalaura Torella
Guest Editor

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Keywords

  • NGS
  • exome
  • genome
  • nerve
  • muscle
  • neuromuscular

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Published Papers (5 papers)

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Research

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15 pages, 3649 KiB  
Article
Whole-Genome Sequencing Identified New Structural Variations in the DMD Gene That Cause Duchenne Muscular Dystrophy in Two Girls
by Natalie Pluta, Arpad von Moers, Astrid Pechmann, Werner Stenzel, Hans-Hilmar Goebel, David Atlan, Beat Wolf, Indrajit Nanda, Ann-Kathrin Zaum and Simone Rost
Int. J. Mol. Sci. 2023, 24(17), 13567; https://doi.org/10.3390/ijms241713567 - 1 Sep 2023
Cited by 3 | Viewed by 1746
Abstract
Dystrophinopathies are the most common muscle diseases, especially in men. In women, on the other hand, a manifestation of Duchenne muscular dystrophy is rare due to X-chromosomal inheritance. We present two young girls with severe muscle weakness, muscular dystrophies, and creatine kinase (CK) [...] Read more.
Dystrophinopathies are the most common muscle diseases, especially in men. In women, on the other hand, a manifestation of Duchenne muscular dystrophy is rare due to X-chromosomal inheritance. We present two young girls with severe muscle weakness, muscular dystrophies, and creatine kinase (CK) levels exceeding 10,000 U/L. In the skeletal muscle tissues, dystrophin staining reaction showed mosaicism. The almost entirely skewed X-inactivation in both cases supported the possibility of a dystrophinopathy. Despite standard molecular diagnostics (including multiplex ligation-dependent probe amplification (MLPA) and next generation sequencing (NGS) gene panel sequencing), the genetic cause of the girls’ conditions remained unknown. However, whole-genome sequencing revealed two reciprocal translocations between their X chromosomes and chromosome 5 and chromosome 19, respectively. In both cases, the breakpoints on the X chromosomes were located directly within the DMD gene (in introns 54 and 7, respectively) and were responsible for the patients’ phenotypes. Additional techniques such as Sanger sequencing, conventional karyotyping and fluorescence in situ hybridization (FISH) confirmed the disruption of DMD gene in both patients through translocations. These findings underscore the importance of accurate clinical data combined with histopathological analysis in pinpointing the suspected underlying genetic disorder. Moreover, our study illustrates the viability of whole-genome sequencing as a time-saving and highly effective method for identifying genetic factors responsible for complex genetic constellations in Duchenne muscular dystrophy (DMD). Full article
(This article belongs to the Special Issue New Perspectives in Molecular Diagnosis of Neuromuscular Disorders)
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9 pages, 3053 KiB  
Article
Alu-Mediated Insertions in the DMD Gene: A Difficult Puzzle to Interpret Clinically
by Annalaura Torella, Alberto Budillon, Mariateresa Zanobio, Francesca Del Vecchio Blanco, Esther Picillo, Luisa Politano, Vincenzo Nigro and Giulio Piluso
Int. J. Mol. Sci. 2023, 24(11), 9241; https://doi.org/10.3390/ijms24119241 - 25 May 2023
Cited by 1 | Viewed by 1341
Abstract
Disrupting variants in the DMD gene are associated with Duchenne or Becker muscular dystrophy (DMD/BMD) or with hyperCKemia, all of which present very different degrees of clinical severity. The clinical phenotypes of these disorders could not be distinguished in infancy or early childhood. [...] Read more.
Disrupting variants in the DMD gene are associated with Duchenne or Becker muscular dystrophy (DMD/BMD) or with hyperCKemia, all of which present very different degrees of clinical severity. The clinical phenotypes of these disorders could not be distinguished in infancy or early childhood. Accurate phenotype prediction based on DNA variants may therefore be required in addition to invasive tests, such as muscle biopsy. Transposon insertion is one of the rarest mutation types. Depending on their position and characteristics, transposon insertions may affect the quality and/or quantity of dystrophin mRNA, leading to unpredictable alterations in gene products. Here, we report the case of a three-year-old boy showing initial skeletal muscle involvement in whom we characterized a transposon insertion (Alu sequence) in exon 15 of the DMD gene. In similar cases, the generation of a null allele is predicted, resulting in a DMD phenotype. However, mRNA analysis of muscle biopsy tissue revealed skipping of exon 15, which restored the reading frame, thus predicting a milder phenotype. This case is similar to very few others already described in the literature. This case further enriches our knowledge of the mechanisms perturbing splicing and causing exon skipping in DMD, helping to properly guide clinical diagnosis. Full article
(This article belongs to the Special Issue New Perspectives in Molecular Diagnosis of Neuromuscular Disorders)
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Review

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13 pages, 774 KiB  
Review
Neuromuscular and Neuromuscular Junction Manifestations of the PURA-NDD: A Systematic Review of the Reported Symptoms and Potential Treatment Options
by Magdalena Mroczek and Stanley Iyadurai
Int. J. Mol. Sci. 2023, 24(3), 2260; https://doi.org/10.3390/ijms24032260 - 23 Jan 2023
Cited by 4 | Viewed by 3181
Abstract
PURA-related neurodevelopmental disorders (PURA-NDDs) are a rare genetic disease caused by pathogenic autosomal dominant variants in the PURA gene or a deletion encompassing the PURA gene. PURA-NDD is clinically characterized by neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements, and epilepsy. [...] Read more.
PURA-related neurodevelopmental disorders (PURA-NDDs) are a rare genetic disease caused by pathogenic autosomal dominant variants in the PURA gene or a deletion encompassing the PURA gene. PURA-NDD is clinically characterized by neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements, and epilepsy. It is generally considered to be central nervous system disorders, with generalized weakness, associated hypotonia, cognitive and development deficits in early development, and seizures in late stages. Although it is classified predominantly as a central nervous syndrome disorder, some phenotypic features, such as myopathic facies, respiratory insufficiency of muscle origin, and myopathic features on muscle biopsy and electrodiagnostic evaluation, point to a peripheral (neuromuscular) source of weakness. Patients with PURA-NDD have been increasingly identified in exome-sequenced cohorts of patients with neuromuscular- and congenital myasthenic syndrome-like phenotypes. Recently, fluctuating weakness noted in a PURA-NDD patient, accompanied by repetitive nerve stimulation abnormalities, suggested the disease to be a channelopathy and, more specifically, a neuromuscular junction disorder. Treatment with pyridostigmine or salbutamol led to clinical improvement of neuromuscular function in two reported cases. The goal of this systematic retrospective review is to highlight the motor symptoms of PURA-NDD, to further describe the neuromuscular phenotype, and to emphasize the role of potential treatment opportunities of the neuromuscular phenotype in the setting of the potential role of PURA protein in the neuromuscular junction and the muscles. Full article
(This article belongs to the Special Issue New Perspectives in Molecular Diagnosis of Neuromuscular Disorders)
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18 pages, 578 KiB  
Review
Application of Droplet Digital PCR Technology in Muscular Dystrophies Research
by Ioana Lambrescu, Alexandra Popa, Emilia Manole, Laura Cristina Ceafalan and Gisela Gaina
Int. J. Mol. Sci. 2022, 23(9), 4802; https://doi.org/10.3390/ijms23094802 - 27 Apr 2022
Cited by 4 | Viewed by 13183
Abstract
Although they are considered rare disorders, muscular dystrophies have a strong impact on people’s health. Increased disease severity with age, frequently accompanied by the loss of ability to walk in some people, and the lack of treatment, have directed the researchers towards the [...] Read more.
Although they are considered rare disorders, muscular dystrophies have a strong impact on people’s health. Increased disease severity with age, frequently accompanied by the loss of ability to walk in some people, and the lack of treatment, have directed the researchers towards the development of more effective therapeutic strategies aimed to improve the quality of life and life expectancy, slow down the progression, and delay the onset or convert a severe phenotype into a milder one. Improved understanding of the complex pathology of these diseases together with the tremendous advances in molecular biology technologies has led to personalized therapeutic procedures. Different approaches that are currently under extensive investigation require more efficient, sensitive, and less invasive methods. Due to its remarkable analytical sensitivity, droplet digital PCR has become a promising tool for accurate measurement of biomarkers that monitor disease progression and quantification of various therapeutic efficiency and can be considered a tool for non-invasive prenatal diagnosis and newborn screening. Here, we summarize the recent applications of droplet digital PCR in muscular dystrophy research and discuss the factors that should be considered to get the best performance with this technology. Full article
(This article belongs to the Special Issue New Perspectives in Molecular Diagnosis of Neuromuscular Disorders)
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15 pages, 2678 KiB  
Review
The Increasing Impact of Translational Research in the Molecular Diagnostics of Neuromuscular Diseases
by Dèlia Yubero, Daniel Natera-de Benito, Jordi Pijuan, Judith Armstrong, Loreto Martorell, Guerau Fernàndez, Joan Maynou, Cristina Jou, Mònica Roldan, Carlos Ortez, Andrés Nascimento, Janet Hoenicka and Francesc Palau
Int. J. Mol. Sci. 2021, 22(8), 4274; https://doi.org/10.3390/ijms22084274 - 20 Apr 2021
Cited by 10 | Viewed by 3962
Abstract
The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for establishing prognosis, [...] Read more.
The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for establishing prognosis, treatment and genetic counselling. Currently, the genetic approach includes both the gene-targeted analysis in specific clinically recognizable diseases, as well as genomic analysis based on next-generation sequencing, analyzing either the clinical exome/genome or the whole exome or genome. However, as of today, there are still many patients in whom the causative genetic variant cannot be definitely established and variants of uncertain significance are often found. In this review, we address these drawbacks by incorporating two additional biological omics approaches into the molecular diagnostic process of NMDs. First, functional genomics by introducing experimental cell and molecular biology to analyze and validate the variant for its biological effect in an in-house translational diagnostic program, and second, incorporating a multi-omics approach including RNA-seq, metabolomics, and proteomics in the molecular diagnosis of neuromuscular disease. Both translational diagnostics programs and omics are being implemented as part of the diagnostic process in academic centers and referral hospitals and, therefore, an increase in the proportion of neuromuscular patients with a molecular diagnosis is expected. This improvement in the process and diagnostic performance of patients will allow solving aspects of their health problems in a precise way and will allow them and their families to take a step forward in their lives. Full article
(This article belongs to the Special Issue New Perspectives in Molecular Diagnosis of Neuromuscular Disorders)
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