Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

Area of Science:

• Genetics and Neurology
• Neuroimmunology
• Genomic Medicine

Background:

• Primary progressive multiple sclerosis (PPMS) is characterized by progressive neurological disability without typical relapsing-remitting episodes.
• The influence of genetic variations on the disease course of PPMS remains largely undetermined.
• Investigating genetic links to disorders with MS-like features may elucidate PPMS pathogenesis.

Purpose of the Study:

• To determine if mutations causing neurological disorders with MS-like features contribute to the risk of developing PPMS.
• To analyze whole-genome sequencing data for pathogenic variants in PPMS patients.
• To assess the burden of rare mutations in hereditary spastic paraplegia (HSP) genes in progressive MS forms.

Main Methods:

• Whole-genome sequencing (WGS) was performed on 38 PPMS patients and 81 healthy controls.
• Pathogenic variants found exclusively in PPMS patients were selected for replication genotyping in larger cohorts.
• The burden of rare mutations in 41 HSP genes was examined in PPMS, SPMS, RMS, and healthy subjects.

Main Results:

• Three pathogenic variants (KIF5A, MLC1, REEP1) were identified in PPMS patients, associated with disorders sharing MS features.
• A significant enrichment of HSP-related mutations was observed in PPMS (RR=1.95) and SPMS (RR=1.57) patients compared to controls.
• This enrichment of HSP mutations was not found in relapsing multiple sclerosis (RMS) patients.

Conclusions:

• The study provides evidence that rare Mendelian genetic variants contribute to the risk of developing progressive forms of multiple sclerosis.
• Genetic factors, particularly those associated with hereditary spastic paraplegias, play a role in the pathogenesis of PPMS and SPMS.
• Findings differentiate genetic risk factors for progressive MS from relapsing forms.