FARS2 – Combined Oxidative Phosphorylation Deficiency Type 14

Biallelic pathogenic variants in FARS2, encoding the mitochondrial phenylalanyl-tRNA synthetase, underlie combined oxidative phosphorylation deficiency type 14 (COXPD14), a severe autosomal recessive disorder characterized by early-onset encephalopathy, hypotonia, global developmental delay and liver failure. Initial reports described fatal infantile Alpers-like presentations with compound heterozygous missense mutations (e.g., p.Ile329Thr, p.Asp391Val) disrupting aminoacylation activity ([PMID:22833457]). Subsequent case series identified two Chinese siblings with compound heterozygous c.925G>A (p.Gly309Ser) and c.943G>C (p.Gly315Arg), both in conserved domains and absent from controls, confirming segregation in a single family ([PMID:36155627]).

An adult‐onset status epilepticus phenotype was later reported in a patient harboring one recurrent missense variant (c.467C>T (p.Thr156Met)) and one novel frameshift (c.119_120del (p.Glu40ValfsTer87)), expanding the phenotypic spectrum and raising the total number of reported subjects to approximately 58 unrelated probands ([PMID:38166857]). Across all reports, FARS2 variants include predominantly missense changes, alongside nonsense, splice-site, frameshift and small indels, demonstrating a wide variant spectrum in COXPD14.

Functional studies have consistently shown that pathogenic FARS2 variants impair mt-PheRS catalytic activity and protein stability. In vitro assays revealed decreased ATP and tRNA binding for p.Ile329Thr and p.Asp391Val, and impaired aminoacylation for p.Asp325Tyr with subsequent rescue by lentiviral complementation ([PMID:24161539]). Structural and kinetic analyses of multiple mutants (e.g., p.Gly309Ser, p.Arg153Gly, p.Arg423Gln) further delineate domain-specific defects ([PMID:28419689]). A Drosophila model of FARS2 deficiency recapitulates developmental delay and seizure phenotypes, confirming loss-of-function as the primary mechanism ([PMID:34878141]).

No study has reported conflicting evidence or alternative phenotypes outside the mitochondrial translation deficiency spectrum. Taken together, ample genetic and experimental data establish a definitive autosomal recessive association between FARS2 and COXPD14, with broad phenotypic variability from neonatal lethal encephalopathy to juvenile-onset epilepsy and spastic paraplegia. Key Take-home: Genetic testing for FARS2 variants is essential for the diagnosis and management of COXPD14 and related mitochondrial disorders.

References

• European journal of medical research • 2022 • Two Chinese siblings of combined oxidative phosphorylation deficiency 14 caused by compound heterozygous variants in FARS2. PMID:36155627
• BMC neurology • 2024 • Adult-onset combined oxidative phosphorylation deficiency type 14 manifests as epileptic status: a new phenotype and literature review. PMID:38166857
• Human molecular genetics • 2012 • Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. PMID:22833457
• Protein science : a publication of the Protein Society • 2017 • Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2. PMID:28419689
• 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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