Wladimir Bocca Vieira de Rezende Pinto1
Acary Souza Bulle Oliveira1
Alzira Alves de Siqueira Carvalho2
Hasan Orhan Akman3
Paulo Victor Sgobbi de Souza1*- 1Division of Neuromuscular Diseases, Neurometabolic Unit, Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
- 2Faculdade de Medicina do ABC, São Paulo, Brazil
- 3Columbia University Medical Center, New York, NY, United States
Editorial on the Research Topic
The expanding clinical and genetic basis of adult inherited neurometabolic disorders
The last decade of development of Neurogenetics has brought marked changes in knowledge regarding pathophysiological mechanisms, etiopathogenesis, targeted and untargeted metabolomics (and multi-omics), diagnosis of new rare genetic diseases, and the introduction of specific therapeutic approaches (1–4). The availability of genetic diagnostic methods in the clinical routine has enabled the expansion of diagnoses of rare neurogenetic diseases and significantly reduced the time required for the definitive diagnosis of rare and ultra-rare metabolic diseases (5). The classic diagnostic approach using different levels of complexity and at least two or three tiers during the biochemical evaluation has been updated (5–7). Metabolic biomarkers have emerged as important biochemical parameters during the reverse phenotyping process of complex neurological scenarios after deep phenotyping and data generated by genetic studies from next-generation sequencing-based multigene panels or whole-exome sequencing (8–11). In other cases, in the multi-omics era, transcriptomics with RNA sequencing has appeared, becoming an alternative diagnostic pathway (12). There has, therefore, been an evident change in the diagnostic work-up process of hereditary neurometabolic diseases and new guidelines and formal recommendations (13).
Adult-onset Inherited Neurometabolic Disorders represent a great challenge for clinicians due to several reasons (14, 15). First, clinical presentation, biochemical testing, and neuroimaging aspects frequently disclose atypical findings in the adult population compared to early childhood or infancy-onset forms. Thus, adult-onset phenotypes do not represent just a “childhood illness occurring in the adult population”. Furthermore, inherited metabolic diseases are commonly considered as a diagnostic hypothesis in adults only in patients with extensive diagnostic work-up which is not conclusive, and they are rarely included in the differential diagnosis of neurological presentations in acute emergency settings. Additionally, several inherited neurometabolic disorders represent potentially treatable diseases during the early stages of the disease course and with specific therapeutic approaches available, including diet therapies, enzyme replacement therapies, pharmacological chaperones, gene therapies, small interfering-RNA-based therapies, and hematopoietic stem cell transplantation (16–21).
The difficulty in diagnosing inborn errors of metabolism in adults with neurological presentation is very well demonstrated by Ferreira et al.. This systematic review article sought to assess the diagnostic complexity in such patients, analyzing the profile of types and diagnostic rates for the different genetic mechanisms from exome and genome sequencing data. The authors used this as a reference in their interpretation and conceptual definition of hereditary metabolic diseases according to the new International Classification of Inherited Metabolic Disorders (ICIMD), which markedly expanded the groups and pathophysiological mechanisms related to metabolic dysfunction in 2021 (22). The broad systematic review based on these current concepts showed an evident departure from the classic patterns of hereditary metabolic diseases: (i) there are several metabolic disorders without specific biochemical biomarkers, only with conclusive genetic diagnosis; (ii) several metabolic diseases are not directly related to enzymatic or membrane transporter defects; (iii) many neurological conditions previously thought to be primarily neuroinflammatory or neurodegenerative disorders show evidence of primary metabolic dysfunction in their pathogenesis (14, 23, 24). This manuscript represents a major representative publication related to the new ICIMD classification and the current concepts that the main researchers and clinicians have about inherited metabolic disorders.
Muthusamy et al. presented a narrative review article addressing adult-onset Leukodystrophies. This very complex issue involves a wide range of inherited metabolic diseases and the still poorly understood interface with neurodegenerative, neurometabolic, neuroinflammatory, and neurodevelopmental pathophysiological basis. It is one of the main groups of genetically determined neurological conditions in which the most current approaches related to large-scale sequencing with the use of whole-exome sequencing (and even whole-genome sequencing) have allowed in the last decades a frank expansion of the knowledge of new genetic diseases and mechanisms of etiopathogenesis. The authors present a detailed literature review covering the main clinical and neuroradiological aspects related to adult leukodystrophies, as well as an excellent diagnostic algorithm and high-quality neuroimaging studies. This is an unmissable review article for every neurologist and neuroradiologist.
Another key manuscript is presented by Nóbrega et al. with a narrative review describing the complex clinical scenario associated with Cerebrotendinous Xanthomatosis (CTX). This autosomal recessive inherited metabolic disorder represents a potentially treatable disease that frequently mimics several neurological and multisystemic conditions. Thus, it is not a surprise that CTX is commonly underdiagnosed or most frequently lately diagnosed, especially by neurologists dealing with complex neurological phenotypes. Clinical pleomorphism and marked expressivity variability are hallmarks of CTX. A detailed review of clinical, neuroradiological, and genetic aspects makes this manuscript a reference of real interest to clinicians who wish to review and stay up to date on CTX.
Huang et al. presented an original cross-sectional and longitudinal study describing the main aspects of 19 Chinese patients diagnosed with LAMA2-related Limb-Girdle Muscular Dystrophy (or LGMD R23). The diagnosis and recognition of this rare autosomal recessive LGMD represents a great challenge in clinical practice, especially regarding late-onset and atypical presentations, even for most neuromuscular disorder specialists. The authors demonstrated the presence of epilepsy and motor neuropathy in a high proportion of cases disclosing the complex task related to phenotype recognition and diagnostic approaches, especially in the presence of marked extra muscular involvement, a context in which metabolic myopathies and primary mitochondrial diseases are key differential diagnoses.
It is with huge satisfaction that all the Special Guest Editors of this edition invite researchers, geneticists, neurologists, neuropediatricians, and different scholars in the field of Neurosciences to seek out the up-to-date and high-quality content presented in this special edition dedicated to the emerging area of Adult Neurometabolic Diseases.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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.
Abbreviations
CTX, Cerebrotendinous xanthomatosis; ICIMD, International classification of inherited metabolic disorders; LGMD, Limb-girdle muscular dystrophy.
References
1. Coene KLM, Kluijtmans LAJ, van der Heeft E, Engelke U .F. Next-generation metabolic screening: targeted and untargeted metabolomics for the diagnosis of inborn errors of metabolism in individual patients. J Inherit Metab Dis. (2018) 41:337–53. doi: 10.1007/s10545-017-0131-6
2. Crowther LM, Porns M, Plecko B. Multiomics tools for the diagnosis and treatment of rare neurological disease. J Inherit Metab Dis. (2018) 41:425–34. doi: 10.1007/s10545-018-0154-7
3. Saudubray JM, Mochel F, Lamari F, Garcia-Cazorla A. Proposal for a simplified classification of IMD based on a pathophysiological approach: a practical guide for clinicians. J Inherit Metab Dis. (2019) 42:706–27. doi: 10.1002/jimd.12086
4. Stenton SL, Kremer LS, Kopajtich R, Ludwig C, Prokisch H. The diagnosis of inborn errors of metabolism by an integrative “multi-omics” approach: a perspective encompassing genomics, transcriptomics, and proteomics. J Inherit Metab Dis. (2020) 43:25–35. doi: 10.1002/jimd.12130
5. Fernández-Eulate G, Carreau C, Benoist JF, Lamari F, Rucheton B, Shor N, et al. Diagnostic approach in adult-onset neurometabolic diseases. J Neurol Neurosurg Psychiatry. (2022) 93:413–21. doi: 10.1136/jnnp-2021-328045
6. Tarailo-Graovac M, Wasserman WW, van Karnebeek CDM. Impact of next-generation sequencing on diagnosis and management of neurometabolic disorders: current advances and future perspectives. Expert Rev Mol Diagn. (2017) 17:307–9. doi: 10.1080/14737159.2017.1293527
7. Wanders RJA, Vaz FM, Ferdinandusse S, van Kuilenburg ABP, Kemp S, van Karnebeek CD, et al. Translational Metabolism: a multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era. J Inherit Metab Dis. (2019) 42:197–208. doi: 10.1002/jimd.12008
8. Reid ES, Papandreou A, Drury S, Boustred C, Yue WW, Wedatilake Y, et al. Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes. Brain. (2016) 139:2844–54. doi: 10.1093/brain/aww221
9. Evers C, Staufner C, Granzow M, Paramasivam N, Hinderhofer K, Kaufmann L, et al. Impact of clinical exomes in neurodevelopmental and neurometabolic disorders. Mol Genet Metab. (2017) 121:297–307. doi: 10.1016/j.ymgme.2017.06.014
10. Barbosa-Gouveia S, Vázquez-Mosquera ME, González-Vioque E, Álvarez JV, Chans R, Laranjeira F, et al. Utility of gene panels for the diagnosis of inborn errors of metabolism in a metabolic reference center. Genes). (2021) 12:1262. doi: 10.3390/genes12081262
11. Guéant JL, Feillet F. Inherited metabolic disorders beyond the new generation sequencing era: the need for in-depth cellular and molecular phenotyping. Hum Genet. (2022) 141:1235–7. doi: 10.1007/s00439-022-02467-4
12. Kremer LS, Wortmann SB, Prokisch H. “Transcriptomics”: molecular diagnosis of inborn errors of metabolism via RNA-sequencing. J Inherit Metab Dis. (2018) 41:525–32. doi: 10.1007/s10545-017-0133-4
13. Cassis L, Cortès-Saladelafont E, Molero-Luis M, Yubero D, González MJ, Ormazábal A, et al. Review and evaluation of the methodological quality of the existing guidelines and recommendations for inherited neurometabolic disorders. Orphanet J Rare Dis. (2015) 10:164. doi: 10.1186/s13023-015-0376-9
14. Morava E, Rahman S, Peters V, Baumgartner MR, Patterson M, Zschocke J, et al. Quo-vadis: the re-definition of “inborn metabolic diseases”. J Inherit Metab Dis. (2015) 38:1003–6. doi: 10.1007/s10545-015-9893-x
15. Wolf B. “Think metabolic” in adults with diagnostic challenges. Biotinidase deficiency as a paradigm disorder. Neurol Clin Pract. (2017) 7:518–22. doi: 10.1212/CPJ.0000000000000379
16. Prietsch V, Lindner M, Zschocke J, Nyhan WL, Hoffmann GF. Emergency management of inherited metabolic diseases. J Inherit Metab Dis. (2002) 25:531–46. doi: 10.1023/A:1022040422590
17. Lee PJ, Lachmann RH. Acute presentations of inherited metabolic disease in adulthood. Clin Med. (2008) 8:621–4. doi: 10.7861/clinmedicine.8-6-621
18. Gray R, Preece M, Green S, Whitehouse W, Winer J, Green A, et al. Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation. J Neurol Neurosurg Psychiatry. (2000) 69:5–12. doi: 10.1136/jnnp.69.1.5
19. Sirrs SM, Lehman A, Stockler S, van Karnebeek CDM. Treatable inborn errors of metabolism causing neurological symptoms in adults. Mol Genet Metab. (2013) 110:431–8. doi: 10.1016/j.ymgme.2013.10.002
20. Stockler-Ipsiroglu S, Potter BK, Yuskiv N, Tingley K, Patterson M, van Karnebeek C, et al. Developments in evidence creation for treatments of inborn errors of metabolism. J Inherit Metab Dis. (2021) 44:88–98. doi: 10.1002/jimd.12315
21. Sulaiman RA, Alali A, Hosaini S, Hussein M, Pasha F, Albogami M, et al. Emergency management of critically ill adult patients with inherited metabolic disorders. Am J Emerg Med. (2022) 55:138–42. doi: 10.1016/j.ajem.2022.02.053
22. Ferreira CR, Rahman S, Keller M, Zschocke J, ICIMD Advisory Group. An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis. (2021) 44:164–77. doi: 10.1002/jimd.12348
23. Ferreira CR, van Karnebeek CDM, Vockley J, Blau N. A proposed nosology of inborn errors of metabolism. Genet Med. (2019) 21:102–6. doi: 10.1038/s41436-018-0022-8
Keywords: inborn errors of metabolism, neurogenetics, inherited metabolic diseases, inherited neurometabolic disorders, next-generation sequencing, metabolomics, rare diseases
Citation: Pinto WBVdR, Oliveira ASB, Carvalho AAdS, Akman HO and Souza PVSd (2023) Editorial: The expanding clinical and genetic basis of adult inherited neurometabolic disorders. Front. Neurol. 14:1255513. doi: 10.3389/fneur.2023.1255513
Received: 08 July 2023; Accepted: 14 July 2023;
Published: 25 July 2023.
Edited and reviewed by: Daniele Orsucci, Unità di Neurologia, Azienda Usl Toscana Nord Ovest, Italy
Copyright © 2023 Pinto, Oliveira, Carvalho, Akman and Souza. 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: Paulo Victor Sgobbi de Souza, cGF1bG8uc2dvYmJpJiN4MDAwNDA7dW5pZmVzcC5icg==; cHZzZ29iYmkmI3gwMDA0MDtnbWFpbC5jb20=