Folia medica Cracoviensia · 2025
A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.
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Żur-Wyrozumska Kamila
Аннотация
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) represents a heterogeneous group of neurodegenerative disorders sharing a common ALS phenotype but arising from diverse genetic and molecular mechanisms. Among the genes implicated in ALS, SQSTM1, encoding the multifunctional protein p62, plays a pivotal role in maintaining neuronal homeostasis through the regulation of autophagy and the crosstalk between NF-κB and Nrf2 pathways. Disruption of these mechanisms contributes to oxidative stress, neuroinflammation, and protein aggregation in motor neurons.
MATERIAL AND METHODS: A comprehensive genetic analysis, including next-generation sequencing (NGS), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), was performed in a patient clinically diagnosed with ALS. Literature data regarding the role of SQSTM1, NF-κB/Nrf2 signaling, and autophagy modulation in ALS pathogenesis were reviewed to contextualize the findings.
CASE PRESENTATION: We describe a 49-year-old woman with a 12-month history of progressive - bulbar-onset ALS. Genetic testing revealed a heterozygous SQSTM1 c.1175C>T (p.Pro392Leu) variant inherited from her father, classified as likely pathogenic. The patient received dimethyl fumarate (Nrf2 activator), celecoxib (NF-κB inhibitor), and rapamycin (mTOR pathway modulator) as part of an individualized treatment strategy.
DISCUSSION: Mutations in SQSTM1 contribute to ALS pathogenesis through dysregulation of autophagy, impaired protein clearance, and excessive neuroinflammation mediated by NF-κB activation. The interplay between NF-κB and Nrf2 signaling pathways suggests that targeted therapeutic modulation may attenuate neurodegeneration. The patient's case illustrates the clinical and molecular heterogeneity of ALS and supports the concept of pathway-specific, precision medicine approaches.
CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.
MATERIAL AND METHODS: A comprehensive genetic analysis, including next-generation sequencing (NGS), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), was performed in a patient clinically diagnosed with ALS. Literature data regarding the role of SQSTM1, NF-κB/Nrf2 signaling, and autophagy modulation in ALS pathogenesis were reviewed to contextualize the findings.
CASE PRESENTATION: We describe a 49-year-old woman with a 12-month history of progressive - bulbar-onset ALS. Genetic testing revealed a heterozygous SQSTM1 c.1175C>T (p.Pro392Leu) variant inherited from her father, classified as likely pathogenic. The patient received dimethyl fumarate (Nrf2 activator), celecoxib (NF-κB inhibitor), and rapamycin (mTOR pathway modulator) as part of an individualized treatment strategy.
DISCUSSION: Mutations in SQSTM1 contribute to ALS pathogenesis through dysregulation of autophagy, impaired protein clearance, and excessive neuroinflammation mediated by NF-κB activation. The interplay between NF-κB and Nrf2 signaling pathways suggests that targeted therapeutic modulation may attenuate neurodegeneration. The patient's case illustrates the clinical and molecular heterogeneity of ALS and supports the concept of pathway-specific, precision medicine approaches.
CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.