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Mutations in PTPN11 could lead to a congenital myasthenic syndrome phenotype: a Noonan syndrome case series

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Abstract

The RASopathies are a group of genetic rare diseases caused by mutations affecting genes involved in the RAS/MAPK (RAS–mitogen activated protein kinase) pathway. Among them, PTPN11 pathogenic variants are responsible for approximately 50% of Noonan syndrome (NS) cases and, albeit to a lesser extent, of Leopard syndrome (LPRD1), which present a few overlapping clinical features, such as facial dysmorphism, developmental delay, cardiac defects, and skeletal deformities. Motor impairment and decreased muscle strength have been recently reported. The etiology of the muscle involvement in these disorders is still not clear but probably multifactorial, considering the role of the RAS/MAPK pathway in skeletal muscle development and Acetylcholine Receptors (AChR) clustering at the neuromuscular junction (NMJ). We report, herein, four unrelated children carrying three different heterozygous mutations in the PTPN11 gene. Intriguingly, their phenotypic features first led to a clinical suspicion of congenital myasthenic syndrome (CMS), due to exercise-induced fatigability with a variable degree of muscle weakness, and serum proteomic profiling compatible with a NMJ defect. Moreover, muscle fatigue improved after treatment with CMS-specific medication. Although the link between PTPN11 gene and neuromuscular transmission is unconfirmed, an increasing number of patients with RASopathies are affected by muscle weakness and fatigability. Hence, NS or LPDR1 should be considered in children with suspected CMS but negative genetic workup for known CMS genes or additional symptoms indicative of NS, such as facial dysmorphism or intellectual disability.

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Data availability

Genomic and phenotypic data for patients 2, 3 and 4 is available to authorized users of the RD-Connect GPAP in non-identifiable pseudonymized form. Other data is available from the corresponding author upon reasonable request.

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Acknowledgements

HL receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). RT and KP are recipients of CIHR Postdoctoral fellowships. This research was also partly funded by the European Regional Development Fund (ERDF; project NME-GPS; grant to AR and USS) as well as the German Society for Muscular Diseases (DGM; grant to AR and USS). Moreover, the study was supported by the “Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen,” the “Regierenden Bürgermeister von Berlin—Senatskanzlei Wissenschaft und Forschung,” and the “Bundesministerium für Bildung und Forschung”.

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Authors and Affiliations

  1. IRCCS Centro Neurolesi “Bonino Pulejo”, Messina, Italy

    Alessia Pugliese

  2. Children’s Hospital of Eastern Ontario Research Institute, 401 Smyth Rd., Ottawa, ON, K1H 8L1, Canada

    Alessia Pugliese, Andreas Roos, Rachel Thompson, Kiran Polavarapu & Hanns Lochmüller

  3. Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45147, Essen, Germany

    Adela Della Marina, Andreas Roos & Ulrike Schara-Schmidt

  4. Department of Neurology, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil

    Eduardo de Paula Estephan & Edmar Zanoteli

  5. Department of Neurological Sciences, Psychiatry, and Medical Psychology, Sao Jose do Rio Preto State Medical School, Sao Jose do Rio Preto, São Paulo, Brazil

    Eduardo de Paula Estephan

  6. Department of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789, Bochum, Germany

    Andreas Roos

  7. Leibniz-Institut Für Analytische Wissenschaften-ISAS-e.V., 44227, Dortmund, Germany

    Andreas Roos & Andreas Hentschel

  8. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan

    Yoshiteru Azuma

  9. John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, University of Newcastle, Newcastle Upon Tyne, UK

    Ana Töpf

  10. Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada

    Hanns Lochmüller

  11. Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada

    Hanns Lochmüller

  12. Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany

    Hanns Lochmüller

  13. Centro Nacional de Análisis Genómico (CNAG), Barcelona, Catalonia, Spain

    Hanns Lochmüller

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  1. Alessia Pugliese
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Ethical approval statement

All patients provided their informed consent for the original genetic analysis that is now retrospectively summarized in this paper, and informed consent was obtained for the publication of patient images. Patient 1 was diagnosed within a standard clinical diagnostics process for which research ethics approval was not required. The RD-Connect GPAP, which was used for analysis of patients 2, 3 and 4, has received ethics approval from the Parc de Salut MAR Clinical Research Ethics Committee on 27 October 2015 under ref. no. 2015/6456/I.

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Pugliese, A., Della Marina, A., de Paula Estephan, E. et al. Mutations in PTPN11 could lead to a congenital myasthenic syndrome phenotype: a Noonan syndrome case series. J Neurol 271, 1331–1341 (2024). https://doi.org/10.1007/s00415-023-12070-w

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