Objective: To perform clinical and genetic analysis of two large families with autosomal dominant hereditary spastic paraplegia (ADHSP).

Background: Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Among the various genetic causes of HSP, pathogenic variants in SPG4/SPAST are the most frequently identified, making them the leading molecular cause of ADHSP.

Method: Clinical assessments, Whole exome sequencing, Direct sequencing, Segregation study, Bioinformatic analysis, Minigene assay.

Results: In this study, we identified two novel intronic mutations with pathogenic effect in the SPAST gene in two large independent families, one of Brazilian origin and the other of Japanese origin. We also performed a functional characterization of these two variants. In addition, we also provided a detailed description of the affected individuals, highlighting the clinical presentation associated with these genetic changes. Notably, in both families, the identified variants co-segregate symptoms consistent with anorexia nervosa, suggesting a previously unrecognized association between SPAST mutations and disordered eating behaviors.

Conclusion: Our findings contribute to the expanding clinical spectrum of SPG4-associated HSP and highlight the importance of identifying intronic SPAST variants. The characterization of these intronic mutations enhances our understanding of their potential pathogenic mechanisms, which may have implications for both genetic diagnosis and the broader clinical management of HSP. Further studies are warranted to explore the underlying biological links between SPAST dysfunction and neuropsychiatric manifestations such as anorexia nervosa.

References: [1] Panza E, Meyyazhagan A, Orlacchio A: Hereditary spastic paraplegia: Genetic heterogeneity and common pathways. Experimental Neurology 2022, 357: 114203. [2] Martinello C, Panza E, Orlacchio A: Hereditary spastic paraplegias proteome: common pathways and pathogenetic mechanisms. Expert Review of Proteomics 2023, 20: 171-188. [3] Evangelisti C, Ramadan S, Orlacchio A, Panza E: Experimental cell models for investigating neurodegenerative diseases. International Journal of Molecular Sciences 2024, 25: 9747.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-identification-of-two-novel-intronic-variants-of-the-spg4-spast-gene-with-pathogenic-effect-reveals-a-novel-genotype-phenotype-correlation/