Genes

Research

Jump to: Review

18 pages, 1264 KiB

Open AccessArticle

NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia

by Federica Invernizzi, Rossella Izzo, Isabel Colangelo, Andrea Legati, Nadia Zanetti, Barbara Garavaglia, Eleonora Lamantea, Lorenzo Peverelli, Anna Ardissone, Isabella Moroni, Lorenzo Maggi, Silvia Bonanno, Laura Fiori, Daniele Velardo, Francesca Magri, Giacomo P. Comi, Dario Ronchi, Daniele Ghezzi and Costanza Lamperti

Genes 2023, 14(7), 1393; https://doi.org/10.3390/genes14071393 - 2 Jul 2023

Viewed by 1425

Abstract

Introduction/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose [...] Read more.

Introduction/Aims HyperCKemia is considered a hallmark of neuromuscular diseases. It can be either isolated or associated with cramps, myalgia, weakness, myoglobinuria, or rhabdomyolysis, suggesting a metabolic myopathy. The aim of this work was to investigate possible genetic causes in order to help diagnose patients with recurrent hyperCKemia or clinical suspicion of inherited metabolic myopathy. Methods A cohort of 139 patients (90 adults and 49 children) was analyzed using a custom panel containing 54 genes associated with hyperCKemia. Results A definite genetic diagnosis was obtained in 15.1% of cases, while candidate variants or variants of uncertain significance were found in a further 39.5%. Similar percentages were obtained in patients with infantile or adult onset, with some different causative genes. RYR1 was the gene most frequently identified, either with single or compound heterozygous variants, while ETFDH variants were the most common cause for recessive cases. In one patient, mRNA analysis allowed identifying a large LPIN1 deletion missed by DNA sequencing, leading to a certain diagnosis. Conclusion These data confirm the high genetic heterogeneity of hyperCKemia and metabolic myopathies. The reduced diagnostic yield suggests the existence of additional genes associated with this condition but also allows speculation that a significant number of cases presenting with hyperCKemia or muscle symptoms are due to extrinsic, not genetic, factors. Full article

(This article belongs to the Special Issue Neuromuscular Disorders: Clinical Treatment and Molecular Genetics)

► Show Figures

Figure 1

Review

Jump to: Research

17 pages, 305 KiB

Open AccessReview

The Current State of Charcot–Marie–Tooth Disease Treatment

by Yuji Okamoto and Hiroshi Takashima

Genes 2023, 14(7), 1391; https://doi.org/10.3390/genes14071391 - 1 Jul 2023

Cited by 6 | Viewed by 3149

Abstract

Charcot–Marie–Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments have not established. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and causes lifelong disability, presents a significant barrier to the development [...] Read more.

Charcot–Marie–Tooth disease (CMT) and associated neuropathies are the most predominant genetically transmitted neuromuscular conditions; however, effective pharmacological treatments have not established. The extensive genetic heterogeneity of CMT, which impacts the peripheral nerves and causes lifelong disability, presents a significant barrier to the development of comprehensive treatments. An estimated 100 loci within the human genome are linked to various forms of CMT and its related inherited neuropathies. This review delves into prospective therapeutic strategies used for the most frequently encountered CMT variants, namely CMT1A, CMT1B, CMTX1, and CMT2A. Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed. Furthermore, the progress in established gene therapy techniques, including gene replacement via viral vectors, exon skipping using antisense oligonucleotides, splicing modification, and gene knockdown, are appraised. Each of these gene therapies has the potential for substantial advancements in future research. Full article

(This article belongs to the Special Issue Neuromuscular Disorders: Clinical Treatment and Molecular Genetics)

25 pages, 1912 KiB

Open AccessReview

Metabolic Myopathies in the Era of Next-Generation Sequencing

by Jon Andoni Urtizberea, Gianmarco Severa and Edoardo Malfatti

Genes 2023, 14(5), 954; https://doi.org/10.3390/genes14050954 - 22 Apr 2023

Cited by 5 | Viewed by 3313

Abstract

Metabolic myopathies are rare inherited disorders that deserve more attention from neurologists and pediatricians. Pompe disease and McArdle disease represent some of the most common diseases in clinical practice; however, other less common diseases are now better-known. In general the pathophysiology of metabolic [...] Read more.

Metabolic myopathies are rare inherited disorders that deserve more attention from neurologists and pediatricians. Pompe disease and McArdle disease represent some of the most common diseases in clinical practice; however, other less common diseases are now better-known. In general the pathophysiology of metabolic myopathies needs to be better understood. Thanks to the advent of next-generation sequencing (NGS), genetic testing has replaced more invasive investigations and sophisticated enzymatic assays to reach a final diagnosis in many cases. The current diagnostic algorithms for metabolic myopathies have integrated this paradigm shift and restrict invasive investigations for complicated cases. Moreover, NGS contributes to the discovery of novel genes and proteins, providing new insights into muscle metabolism and pathophysiology. More importantly, a growing number of these conditions are amenable to therapeutic approaches such as diets of different kinds, exercise training protocols, and enzyme replacement therapy or gene therapy. Prevention and management—notably of rhabdomyolysis—are key to avoiding serious and potentially life-threatening complications and improving patients’ quality of life. Although not devoid of limitations, the newborn screening programs that are currently mushrooming across the globe show that early intervention in metabolic myopathies is a key factor for better therapeutic efficacy and long-term prognosis. As a whole NGS has largely increased the diagnostic yield of metabolic myopathies, but more invasive but classical investigations are still critical when the genetic diagnosis is unclear or when it comes to optimizing the follow-up and care of these muscular disorders. Full article

(This article belongs to the Special Issue Neuromuscular Disorders: Clinical Treatment and Molecular Genetics)

► Show Figures