FBXO7 – parkinsonian-pyramidal syndrome

FBXO7, encoding an F-box protein component of SCF E3 ubiquitin ligase complexes, is associated with autosomal recessive parkinsonian-pyramidal syndrome (PMID:19038853). This rare juvenile-onset condition, designated PARK15 or parkinsonian-pyramidal syndrome, manifests with progressive parkinsonism accompanied by pyramidal tract signs. The disease has been mapped to FBXO7 through linkage in multiple families, establishing it as a clinically defined neurodegenerative entity (PMID:19038853).

Genetic studies across four unrelated families have identified at least six affected individuals harboring recessive FBXO7 variants (PMID:19038853; PMID:25169713; PMID:32274857). Inheritance is autosomal recessive, with homozygous truncating and compound heterozygous mutations segregating with disease in Italian, Dutch, Kurdish, and Chinese pedigrees. Segregation analysis confirmed carrier status in unaffected parents and extended relatives, supporting a Mendelian pattern.

The variant spectrum includes truncating, splice-site, and frameshift mutations. A recurrent pathogenic change is c.1492C>T (p.Arg498Ter), observed in multiple families and always in homozygous form (PMID:19038853; PMID:25169713). Additional alleles, such as c.402G>A (p.Trp134Ter) and various frameshift insertions, further define the mutational landscape. No dominant-acting or heterozygous variants have been implicated in this syndrome.

Clinically, affected individuals present in infancy or early childhood with bradykinesia, rigidity, spasticity, and exaggerated reflexes consistent with pyramidal involvement. Some families exhibit chorea and tics (PMID:25169713), while Chinese siblings demonstrate infantile onset of parkinsonian and pyramidal features (PMID:32274857). Common HPO features include HP:0002067 (Bradykinesia), HP:0007256 (Abnormal pyramidal sign), HP:0002072 (Chorea), HP:0100033 (Tics), and HP:0002172 (Postural instability).

Functional assays on patient-derived fibroblasts and neuronal cells reveal loss of FBXO7 isoform 1 in nuclei, impaired proteasome activity, and accumulation of poly-ubiquitinated proteins, consistent with reduced E3 ligase function (PMID:21347293). Mutant FBXO7 proteins exhibit decreased stability and mislocalization, supporting a loss-of-function mechanism. Animal and cellular models further corroborate proteasome and mitochondrial defects in FBXO7 deficiency.

Integration of genetic and experimental data supports a Strong ClinGen gene–disease association. Genetic evidence is capped by multiple segregating families with consistent recessive inheritance and clear phenotypic concordance. Functional evidence is Moderate, highlighting proteasomal and mitochondrial dysregulation as pathogenic mechanisms. Screening FBXO7 in early-onset parkinsonism with pyramidal signs is clinically recommended to improve diagnostic yield and guide genetic counseling.

References

• Neurology • 2009 • FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. PMID:19038853
• Parkinsonism & related disorders • 2014 • FBXO7-R498X mutation: phenotypic variability from chorea to early onset parkinsonism within a family. PMID:25169713
• Journal of clinical laboratory analysis • 2020 • Compound heterozygous variants of the FBXO7 gene resulting in infantile-onset Parkinsonian-pyramidal syndrome in siblings of a Chinese family. PMID:32274857
• PLoS one • 2011 • Loss of nuclear activity of the FBXO7 protein in patients with parkinsonian-pyramidal syndrome (PARK15). PMID:21347293

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