4dc66a60334c3208581a56d03431da16 292252.pdf 2a75e4ad0aa2eb6b73d4b10ddee8841f57c5ed95 292252.pdf a25efe8a939df50974dbb56989f26e020ab2b76f06500a87a6d7a6984b461228 292252.pdf Title: An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature Subject: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants. Keywords: TARDBP; TDP-43; juvenile amyotrophic lateral sclerosis; upper motor neuron predominant disorder Author: Daniel Sánchez-Tejerina, Juan Luis Restrepo-Vera, Eulalia Rovira-Moreno, Marta Codina-Sola, Arnau Llauradó, Javier Sotoca, Maria Salvado, Núria Raguer, Elena García-Arumí and Raúl Juntas-Morales Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Aug 25 03:37:18 2022 CEST ModDate: Thu Aug 25 03:40:55 2022 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 9 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 848576 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- LNTTSH+VnURWPalladioL Type 1 Custom yes yes no 10 0 POEDZW+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 MJFMGH+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 BUMYXK+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 ZDSWMD+URWPalladioL-BoldItal Type 1 Custom yes yes no 28 0 JCYIDT+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 KONDUX+EuphemiaUCAS-Bold Type 1C WinAnsi yes yes no 50 0 HIZBRM+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 53 0 FXXUVH+CMSY10 Type 1 Builtin yes yes no 90 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-05-28 02:40:45 CEST RepresentationInformation: 292252.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-05-27 13:30:41 CEST Size: 848576 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 251 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Patient and Method Destination: section.2 Children: Item: Title: Clinical Presentation Destination: subsection.2.1 Item: Title: Genetic Results Destination: subsection.2.2 Item: Title: Discussion Destination: section.3 Item: Title: Conclusions Destination: section.4 Item: Title: References Destination: section.4 Info: Title: An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature Author: Daniel Sánchez-Tejerina, Juan Luis Restrepo-Vera, Eulalia Rovira-Moreno, Marta Codina-Sola, Arnau Llauradó, Javier Sotoca, Maria Salvado, Núria Raguer, Elena García-Arumí and Raúl Juntas-Morales Subject: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants. 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