FARS2 – SPG77-related Hereditary Spastic Paraplegia

FARS2 encodes the mitochondrial phenylalanyl-tRNA synthetase, essential for charging mt-tRNAPhe in mitochondrial translation. Autosomal recessive biallelic variants in FARS2 cause hereditary spastic paraplegia 77 (SPG77) characterized by progressive lower limb spasticity, motor delay, and corticospinal tract dysfunction. Clinical presentation often overlaps with epileptic mitochondrial encephalopathy but may manifest as pure or complicated spastic paraplegia.

A homozygous missense variant c.424G>T (p.Asp142Tyr) in a consanguineous Chinese family segregated with pure spastic paraplegia in the proband; aminoacylation assays demonstrated severe disruption of mtPheRS activity (PMID:26553276).

An 8-year-old patient with rapidly progressive, complicated spastic paraplegia harbored a novel intragenic deletion and a missense variant c.1082C>T (p.Pro361Leu), representing the first detailed molecular characterization of a FARS2 deletion in SPG77 (PMID:37152989).

A 9-year-old boy presented with pure spastic paraplegia and bilateral dentate lesions carrying a paternal nonsense variant c.646C>T (p.Gln216Ter) and a maternal missense c.407C>A (p.Pro136His); partial enzymatic activity of p.Pro136His was confirmed in vitro (PMID:30250868).

Across these reports, four probands from three unrelated families exhibit biallelic FARS2 variants (missense, nonsense, deletion) with autosomal recessive inheritance and no unaffected homozygotes reported, supporting pathogenicity in SPG77.

Functional studies demonstrate loss-of-function as the mechanism: in vitro aminoacylation assays show impaired mtPheRS activity for p.Asp142Tyr and p.Pro361Leu; a Drosophila model of p.Asp142Tyr recapitulates locomotor defects and developmental delay (PMID:34878141).

Together, genetic and experimental data support a Moderate clinical validity for FARS2-SPG77 association. Additional large-scale segregation and rescue studies could further strengthen the evidence. Key take-home: Biallelic FARS2 variants reliably cause autosomal recessive SPG77 and should be included in genetic testing panels for hereditary spastic paraplegia.

References

• Frontiers in Genetics • 2023 • Case report: A novel FARS2 deletion and a missense variant in a child with complicated, rapidly progressive spastic paraplegia. PMID:37152989
• Human Mutation • 2016 • A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia. PMID:26553276
• Annals of Clinical and Translational Neurology • 2018 • FARS2 mutations presenting with pure spastic paraplegia and lesions of the dentate nuclei. PMID:30250868
• Nucleic Acids Research • 2021 • FARS2 deficiency in Drosophila reveals the developmental delay and seizure manifested by aberrant mitochondrial tRNA metabolism. PMID:34878141

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