Objective: To describe the case of two brothers affected by typical young-onset Parkinson’s disease (PD), carrying novel compound heterozygous variants in FBXO7.

Background: Bi-allelic mutations in the F-box protein 7 (FBXO7) are associated to a complex phenotype, known as parkinsonian-pyramidal syndrome [1, 2], that can variably include cognitive impairment, upward gaze palsy, dysarthria, dysphagia, and dystonia. However, very few cases of FBXO7-related disorder were described presenting with PD, completely lacking features considered atypical [3, 4].

Method: We collected detailed clinical information of the proband and his affected brother. Because of the likely genetic etiology, the proband underwent a clinical parkinsonism genetic panel including 29. Sanger sequencing was performed in both patients and their unaffected mother to confirm segregation and phasing.

Results: Both patients presented at the age of 45 with progressive asymmetric parkinsonism and moderate response to levodopa. They did not show signs of cognitive decline, oculomotor anomalies, autonomic dysfunction, dystonia, and pyramidal manifestations. The proband was found to harbor two heterozygous variants in FBXO7: a missense (c.992 G>T; p.G331V, NM_012179.3) and a frameshift (c.1268_1272dupCATTC; p.Y425HfsX56, NM_012179.3). Both variants were predicted to be deleterious, as demonstrated by a Combined Annotation Dependent Depletion (CADD) score of 26.6 and 24.8, respectively, and are unreported in the Genome Aggregation Database (https://gnomad.broadinstitute.org/). No other relevant variants were evidenced in parkinsonism-related genes. Sanger sequencing confirmed segregation and phasing within the family.

Conclusion: Our report describes two novel mutations causing FBXO7-related disease and highlights that typical PD can be part of the phenotype. Therefore, we strongly advocate including this gene in the genetic workup of PD, even in the absence of atypical features.

References: 1. Shojaee, S., et al., Genome-wide linkage analysis of a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays. Am J Hum Genet, 2008. 82(6): p. 1375-84.
2. Di Fonzo, A., et al., FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology, 2009. 72(3): p. 240-5.
3. Lohmann, E., et al., A new F-box protein 7 gene mutation causing typical Parkinson’s disease. Mov Disord, 2015. 30(8): p. 1130-3.
4. Lorenzo-Betancor, O., et al., Novel compound heterozygous FBXO7 mutations in a family with early onset Parkinson’s disease. Parkinsonism Relat Disord, 2020. 80: p. 142-
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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-bi-allelic-variants-in-fbxo7-in-a-family-with-young-onset-typical-parkinsons-disease/