KLHL40-Related Myopathy: A Systematic Review and Insight into a Follow-up Biomarker Via a New Case Report

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2024 Feb 24

PMID 38397198

Authors

Bianca Buchignani

Gemma Marinella

Rosa Pasquariello

Giada Sgherri

Silvia Frosini

Filippo Maria Santorelli

Alessandro Orsini

Roberta Battini

Guja Astrea

Affiliations

Soon will be listed here.

Abstract

Background: Mutations in the gene are a common cause of severe or even lethal nemaline myopathy. Some cases with mild forms have been described, although the cases are still anecdotal. The aim of this paper was to systematically review the cases described in the literature and to describe a 12-year clinical and imaging follow-up in an Italian patient with KLHL40- related myopathy in order to suggest possible follow-up measurements.

Methods: Having searched through three electronic databases (PubMed, Scopus, and EBSCO), 18 articles describing 65 patients with homozygous or compound heterozygous mutations were selected. A patient with a homozygous mutation (c.1582G>A/p.E528K) was added and clinical and genetic data were collected.

Results: The most common mutation identified in our systematic review was the (c.1516A>C) followed by the (c.1582G>A). In our review, 60% percent of the patients died within the first 4 years of life. Clinical features were similar across the sample. Unfortunately, however, there is no record of the natural history data in the surviving patients. The 12-year follow-up of our patient revealed a slow improvement in her clinical course, identifying muscle MRI as the only possible marker of disease progression.

Conclusions: Due to its clinical and genotype homogeneity, KLHL40-related myopathy may be a condition that would greatly benefit from the development of new gene therapies; muscle MRI could be a good biomarker to monitor disease progression.

Citing Articles

Nemaline myopathy with scoliosis: a case report.

Huang J, Zhang C, Li J, Wang H, Cui X, Wang J Front Pediatr. 2024; 12:1413096.

PMID: 39474605 PMC: 11518715. DOI: 10.3389/fped.2024.1413096.

References

Huang R, Zhou H, Ma C, Fu F, Cheng K, Wang Y . Whole exome sequencing improves genetic diagnosis of fetal clubfoot. Hum Genet. 2022; 142(3):407-418. DOI: 10.1007/s00439-022-02516-y. View

Nance J, Dowling J, Gibbs E, Bonnemann C . Congenital myopathies: an update. Curr Neurol Neurosci Rep. 2012; 12(2):165-74. PMC: 4491488. DOI: 10.1007/s11910-012-0255-x. View

Marinella G, Astrea G, Buchignani B, Cassandrini D, Doccini S, Filosto M . A Schematic Approach to Defining the Prevalence of COL VI Variants in Five Years of Next-Generation Sequencing. Int J Mol Sci. 2022; 23(23). PMC: 9735635. DOI: 10.3390/ijms232314567. View

Lai T, Au L, Lau Y, Lo H, Chan K, Cheung K . Application of Prenatal Whole Exome Sequencing for Structural Congenital Anomalies-Experience from a Local Prenatal Diagnostic Laboratory. Healthcare (Basel). 2022; 10(12). PMC: 9778831. DOI: 10.3390/healthcare10122521. View

Seferian A, Malfatti E, Bosson C, Pelletier L, Taytard J, Forin V . Mild clinical presentation in KLHL40-related nemaline myopathy (NEM 8). Neuromuscul Disord. 2016; 26(10):712-716. DOI: 10.1016/j.nmd.2016.07.011. View

Liu D, Yu J, Wang X, Yang Y, Yu L, Zeng S . Case Report: Prenatal Diagnosis of Nemaline Myopathy. Front Pediatr. 2022; 10:937668. PMC: 9343628. DOI: 10.3389/fped.2022.937668. View

North K, Wang C, Clarke N, Jungbluth H, Vainzof M, Dowling J . Approach to the diagnosis of congenital myopathies. Neuromuscul Disord. 2014; 24(2):97-116. PMC: 5257342. DOI: 10.1016/j.nmd.2013.11.003. View

Nowak K, Davis M, Wallgren-Pettersson C, Lamont P, Laing N . Clinical utility gene card for: Nemaline myopathy - update 2015. Eur J Hum Genet. 2015; 23(11). PMC: 4613474. DOI: 10.1038/ejhg.2015.12. View

Boeckmann B, Bairoch A, Apweiler R, Blatter M, Estreicher A, Gasteiger E . The SWISS-PROT protein knowledgebase and its supplement TrEMBL in 2003. Nucleic Acids Res. 2003; 31(1):365-70. PMC: 165542. DOI: 10.1093/nar/gkg095. View

10.

Avasthi K, Agarwal S, Panigrahi I . Mutation Associated with Severe Nemaline Myopathy, Fetal Akinesia, and Cleft Palate. J Pediatr Neurosci. 2020; 14(4):222-224. PMC: 6935987. DOI: 10.4103/jpn.JPN_60_19. View

11.

Kawase K, Nishino I, Sugimoto M, Togawa T, Sugiura T, Kouwaki M . Nemaline myopathy with KLHL40 mutation presenting as congenital totally locked-in state. Brain Dev. 2015; 37(9):887-90. DOI: 10.1016/j.braindev.2015.02.002. View

12.

Anderson S, Ekstein J, Donnelly M, Keefe E, Toto N, LeVoci L . Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet. 2004; 115(3):185-90. DOI: 10.1007/s00439-004-1140-8. View

13.

Yeung K, Yu F, Fung C, Wong S, Lee H, Fung S . The KLHL40 c.1516A>C is a Chinese-specific founder mutation causing nemaline myopathy 8: Report of six patients with pre- and postnatal phenotypes. Mol Genet Genomic Med. 2020; 8(7):e1229. PMC: 7336759. DOI: 10.1002/mgg3.1229. View

14.

Burakiewicz J, Sinclair C, Fischer D, Walter G, Kan H, Hollingsworth K . Quantifying fat replacement of muscle by quantitative MRI in muscular dystrophy. J Neurol. 2017; 264(10):2053-2067. PMC: 5617883. DOI: 10.1007/s00415-017-8547-3. View

15.

Kopanos C, Tsiolkas V, Kouris A, Chapple C, Albarca Aguilera M, Meyer R . VarSome: the human genomic variant search engine. Bioinformatics. 2018; 35(11):1978-1980. PMC: 6546127. DOI: 10.1093/bioinformatics/bty897. View

16.

de Winter J, Ottenheijm C . Sarcomere Dysfunction in Nemaline Myopathy. J Neuromuscul Dis. 2017; 4(2):99-113. PMC: 5467716. DOI: 10.3233/JND-160200. View

17.

Gurgel-Giannetti J, Souza L, Yamamoto G, Belisario M, Lazar M, Campos W . Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization. Int J Mol Sci. 2022; 23(19). PMC: 9569467. DOI: 10.3390/ijms231911995. View

18.

Lammens M, Moerman P, Fryns J, Lemmens F, van de Kamp G, Goemans N . Fetal akinesia sequence caused by nemaline myopathy. Neuropediatrics. 1997; 28(2):116-9. DOI: 10.1055/s-2007-973683. View

19.

Liberati A, Altman D, Tetzlaff J, Mulrow C, Gotzsche P, Ioannidis J . The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009; 6(7):e1000100. PMC: 2707010. DOI: 10.1371/journal.pmed.1000100. View

20.

Yu Q, Zhen L, Lin X, Wen Y, Li D . Clinical and molecular analysis of nine fetal cases with clinically significant variants causing nemaline myopathy. Eur J Obstet Gynecol Reprod Biol. 2023; 292:263-266. DOI: 10.1016/j.ejogrb.2023.12.005. View