Genotype variability in early-onset Hereditary Spastic Paraplegia: a single-center study

Area of Science:

• Genetics
• Neurology
• Rare Diseases

Background:

• Hereditary spastic paraplegias (HSPs) are heterogeneous, progressive neurological disorders affecting corticospinal tracts.
• Early-onset HSP (EO-HSP) mimics cerebral palsy, presenting diagnostic difficulties due to rarity and varied symptoms.

Purpose of the Study:

• To investigate the diagnostic yield and genetic variability in a cohort of early-onset hereditary spastic paraplegia (EO-HSP) patients.
• To identify novel genetic causes and expand the understanding of genotype-phenotype correlations in complex EO-HSP cases.

Main Methods:

• Analysis of a cohort of 104 consecutive HSP cases, focusing on early-onset phenotypes.
• Application of molecular analyses, including whole exome sequencing (WES), for genetic variant detection.
• Detailed genotype-phenotype correlation for affected patients.

Main Results:

• Whole exome sequencing identified 19 variants across 10 genes in 14 patients with complex EO-HSP.
• Many identified genes are not typically associated with HSP or listed in standard classifications (e.g., OMIM SPG).
• Highlighted genetic variability and identified novel gene variants contributing to EO-HSP.

Conclusions:

• Whole exome sequencing significantly improves diagnostic detection rates for challenging EO-HSP cases.
• The study expands the known genetic landscape of EO-HSP, implicating novel genes.
• Emphasizes the value of specialized translational approaches and genotype-phenotype correlations for diagnosing rare neurological disorders.