Sec. Diagnostic and Forensic Neuropathology
Volume 14 - 2023 | https://doi.org/10.3389/fneur.2023.1188037
Editorial: Diagnosis of neuromuscular disorders in the era of personalized genomic medicine
- 1Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
- 2Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Editorial on the Research Topic
Diagnosis of neuromuscular disorders in the era of personalized genomic medicine
In the last decade, the evolution of diagnostic technologies, such as next-generation sequencing (NGS), has drastically improved the diagnostic yield and changed how physicians approach and manage neuromuscular disorders. However, employing these modern techniques to diagnose and treat neuromuscular disorders is not without its challenges, e.g., the cost-benefit issue, difficulties in handling and interpreting the genetic data, and the gap between knowledge and action; they have all limited the utility of these novel tools in the care of patients with neuromuscular conditions. The articles in this Research Topic aimed to develop a systemic approach to guide physicians in efficiently utilizing personalized genomic medicine in the management of specific neuromuscular disorders, e.g., hereditary and idiopathic myopathies such as inclusion body myositis (IBM) and inherited neuropathies.
Ng et al. discussed the benefits and limitations of using genetic panels as first-tier investigations in the evaluation of neuromuscular disorders. This approach could shorten diagnostic delays and end the need for invasive tests, such as muscle or nerve biopsies (1). Early molecular diagnosis leads to a more specific treatment, which is essential in certain disorders, such as congenital myasthenic syndromes and Duchenne muscular dystrophy (DMD), in which certain medications can be harmful or ineffective (2). Compared with whole-genome sequencing (WGS), genetic panels are less likely to generate incidental findings that are not pertinent to the clinical presentation (3). Additionally, they have the capacity to evaluate large genes that cannot be reliably tested by WGS, e.g., TTN, NEB, and RYR1 (4). However, NGS-based gene panels are incapable of evaluating certain elements of the human genome, such as repeats (5), and have variable sensitivity in detecting deep intronic variants and copy number variations, as in some cases of DMD and PMP22-related Charcot–Marie–Tooth (CMT) disease, respectively (6, 7). Additionally, the authors argued against using genetic panels as first-tier tests in patients with dual pathology, e.g., neuromyopathies or diseases with poor genotype-phenotype correlation. Finally, the authors offered recommendations on how to efficiently and accurately utilize the genetic panels in the disease work-up to maximize the benefits.
A mini-review by Kazamel et al. reviewed the clinical presentation, pathophysiology, and management of acute hepatic porphyrias (AHPs). AHPs are a group of inherited disorders characterized by hepatic overproduction of the neurotoxic porphyrin precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) (8). Patients report severe abdominal pain during attacks (9) and recent studies reported neuropathic pain in many patients in between attacks (10). The authors recommended screening of any patient with recurrent severe acute abdominal pain with no obvious explanation for AHPs, especially if it is associated with neuropathic pain, autonomic manifestations, or encephalopathy. Checking spot urine PBG adjusted to creatinine during the attack can inform the diagnosis, which nevertheless needs to be confirmed by genetic testing (11). Autonomic neuropathy is likely responsible for most acute symptoms. The blood-nerve-barrier (BNB) is absent/less restrictive in the autonomic ganglia and gut small nerve fibers, rendering these sites more vulnerable to ALA neurotoxic effects (8). The observation that lower back pain often precedes limb pain suggests that nerve roots, where the BNB is also less restrictive, are a primary site of pathology. Potential mechanisms of chronic pain include chronic small fiber neuropathy due to ALA neurotoxicity in addition to peripheral and central sensitization elicited by hepatic proinflammatory mediators (12, 13). While pain during attacks is treated with opiates and hemin infusions, the authors recommended treating pain between attacks with gabapentinoids and certain antidepressants before opiates. A recently approved siRNA molecule, givosiran, reduces ALA and PBG levels and likely helps with chronic pain (14). Early diagnosis with biochemical and genetic testing and specific treatment are essential for preventing long-term neurologic morbidity.
An article by Naddaf provided a comprehensive review of IBM, the most common form of inflammatory myopathy in patients over the age of 40 years. The review discussed the unique characteristics of the disease, including clinical, radiological, electrodiagnostic, and pathological features. It also discussed the long-term outcomes as well as the challenges in establishing the diagnosis and treating the disease. Despite the fact that no pharmacological treatments are currently available for IBM, in the era of personalized medicine, individualized outcome measures and clinical trial designs offer an innovative approach for addressing this issue. The disease mechanism is not well-understood, possibly due to the lack of an appropriate animal model (15). However, based on human data, inflammation and abnormal protein aggregates, e.g., TDP-43, may both play a role in the pathogenesis of the disease (16, 17).
A review by Bumma et al. discussed a single tertiary center's experience with the multidisciplinary management of patients with amyloidosis in the era of precision medicine. Additionally, the authors briefly reviewed the pathophysiology and management of different types of amyloidosis. They recognized the lack of coordinated care for these patients, which has led to a delay in diagnosis and treatment, with 75% of cases taking 12 months to reach a definitive diagnosis (18). In their comprehensive amyloid clinic, different specialties work collaboratively to manage patients' symptoms, sustain the involved organs, and reduce the amyloid burden. A board-certified hematologist directs the clinic and works with specialists from other medical disciplines, including nephrology, neurology, cardiology, and physical therapy. The clinic workflow follows a one-stop design, in which patients are seen in the same room by rotating providers. The program's ultimate goal is to improve access and outcome for amyloidosis patients through the delivery of personalized medicine.
Lastly, Jiang et al. reported axonal motor-predominant neuropathy and myopathy with rimmed vacuoles in a young male and his brother. The patient and his brother both harbored a novel and likely pathogenic homozygous mutation p.I63N (c.188T>A) in the gene histidine triad nucleotide-binding protein 1 (HINT1). Recessive mutations in HINT1 have been associated with axonal motor-predominant CMT disease with neuromyotonia (19). The presence of rimmed vacuoles on the muscle biopsy raises the possibility that mutations in the HINT1 gene may also cause myopathy.
In summary, the articles in this Research Topic provide successful personalized medicine examples of certain neuromuscular disorders. The Research Topic described the use of genetic panels as first-tier tests for inherited neuromuscular diseases, which led to unnecessary tests and ineffective treatments for certain muscular dystrophies being avoided. Additionally, the Research Topic featured the recent FDA approval of specifically designed siRNA molecules for treating inherited neuropathies like those associated with AHPs and hereditary TTR amyloidosis, with a particular focus on the multidisciplinary mode of management for the latter. It indeed emphasized the need for individualized outcome measures and innovative clinical trial designs for potential IBM therapeutics. Ultimately, we hope that a better understanding of personalized genomic medicine will increase the use of molecular diagnostic tools, improve the diagnostic yield, and maximize the treatment benefit for more neuromuscular diseases.
MK and C-YH writing and editing the original draft. Both authors contributed to the article and approved the submitted version.
C-YH was supported by NIH/NINDS K08102468.
Conflict of interest
MK received consulting fees from Alnylam Pharmaceuticals.
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
1. Cordoba M, Rodriguez-Quiroga SA, Vega PA, Salinas V, Perez-Maturo J, Amartino H, et al. Whole exome sequencing in neurogenetic odysseys: an effective, cost- and time-saving diagnostic approach. PLoS ONE. (2018) 13:e0191228. doi: 10.1371/journal.pone.0191228
4. Gonzalez-Quereda L, Rodriguez MJ, Diaz-Manera J, Alonso-Perez J, Gallardo E, Nascimento A, et al. Targeted next-generation sequencing in a large cohort of genetically undiagnosed patients with neuromuscular disorders in Spain. Genes. (2020) 11:539. doi: 10.3390/genes11050539
5. Bean LJH, Funke B, Carlston CM, Gannon JL, Kantarci S, Krock BL, et al. Diagnostic gene sequencing panels: from design to report-a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet Med. (2020) 22:453dtic doi: 10.1038/s41436-019-0666-z
6. Wei X, Dai Y, Yu P, Qu N, Lan Z, Hong X, et al. Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study. Eur J Hum Genet. (2014) 22:110m G doi: 10.1038/ejhg.2013.82
7. MacDonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW. The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. (2014) 42(Database issue):D986–92. doi: 10.1093/nar/gkt958
10. Gouya L, Ventura P, Balwani M, Bissell DM, Rees DC, Stolzel U, et al. EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks. Hepatology. (2020) 71:1546–546 doi: 10.1002/hep.30936
12. Storjord E, Dahl JA, Landsem A, Fure H, Ludviksen JK, Goldbeck-Wood S, et al. Systemic inflammation in acute intermittent porphyria: a case-control study. Clin Exp Immunol. (2017) 187:466Immu doi: 10.1111/cei.12899
13. Poli A, Schmitt C, Moulouel B, Mirmiran A, Talbi N, Riviere S, et al. Givosiran in acute intermittent porphyria: a personalized medicine approach. Mol Genet Metab. (2022) 135:206 Met doi: 10.1016/j.ymgme.2022.01.002
14. Balwani M, Sardh E, Ventura P, Peiro PA, Rees DC, Stolzel U, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. (2020) 382:2289–2892 doi: 10.1056/NEJMoa1913147
15. Britson KA, Ling JP, Braunstein KE, Montagne JM, Kastenschmidt JM, Wilson A, et al. Loss of TDP-43 function and rimmed vacuoles persist after T cell depletion in a xenograft model of sporadic inclusion body myositis. Sci Transl Med. (2022) 14:eabi9196. doi: 10.1126/scitranslmed.abi9196
16. Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol. (1984) 16:209olyp doi: 10.1002/ana.410160207
17. Mendell JR, Sahenk Z, Gales T, Paul L. Amyloid filaments in inclusion body myositis. Novel findings provide insight into nature of filaments. Arch Neurol. (1991) 48:1229–229 doi: 10.1001/archneur.1991.00530240033013
Keywords: acute hepatic porphyria, amyloidosis, inclusion body myositis, precision medicine, whole exome sequencing
Citation: Kazamel M and Ho C-Y (2023) Editorial: Diagnosis of neuromuscular disorders in the era of personalized genomic medicine. Front. Neurol. 14:1188037. doi: 10.3389/fneur.2023.1188037
Received: 16 March 2023; Accepted: 11 May 2023;
Published: 24 May 2023.
Edited and reviewed by: Matthew E. R. Butchbach, Nemours Children's Health Delaware, United States
Copyright © 2023 Kazamel and Ho. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mohamed Kazamel, firstname.lastname@example.org