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HOME > J Mov Disord > Early view > Article
Case Report Nearly Abolished Dopamine Transporter Uptake in a Patient With a Novel FBXO7 Mutation
Eun Young Kim1orcid, Seon Young Kim2orcid, Youngduk Seo3orcid, Chaewon Shin1,4orcid

DOI: https://doi.org/10.14802/jmd.22006
Published online: July 26, 2022
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1Department of Neurology, Chungnam National University Sejong Hospital, Sejong, Korea

2Department of Laboratory Medicine, Chungnam National University Hospital, Chungnam National University, Daejeon, Korea

3Department of Nuclear Medicine, Chungnam National University Sejong Hospital, Sejong, Korea

4Department of Neurology, Chungnam National University College of Medicine, Daejeon, Korea

Corresponding author: Chaewon Shin, MD, PhD Department of Neurology, Chungnam National University Sejong Hospital, 20 Bodeum 7-ro, Sejong 30099, Korea / Tel: +82-44-995-4751 / Fax: +82-44-995-5597 / E-mail: chw.shin@cnu.ac.kr
• Received: January 13, 2022   • Revised: March 14, 2022   • Accepted: April 26, 2022

Copyright © 2022 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • Mutations in the F-box only protein 7 (FBXO7) gene are the cause of autosomal recessive parkinsonian-pyramidal syndrome. Herein, we report a patient with a novel FBXO7 mutation with a unique clinical presentation. A 43-year-old male visited our hospital with complaints of progressing gait disturbance since a generalized tonic clonic seizure. There were no past neurological symptoms or familial disorders. Neurological examination revealed bradykinesia, masked face, stooped posture, parkinsonian gait, and postural instability. The bilateral uptake by dopamine transporters was nearly abolished, as determined by N-(3-[18F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography (18F-FP-CIT PET). Next-generation sequencing revealed a heterozygous c.1066_1069delTCTG (p.Ser356ArgfsTer56) frameshift variant and a heterozygous c.80G>A (p.Arg27His) missense variant of the FBXO7 gene. The patient’s specific clinical features, medication-refractory parkinsonism and seizures further broaden the spectrum of FBXO7 mutations. The nearly abolished dopamine transporter uptake identified by 18F-FP-CIT PET is frequently found in patients with FBXO7 mutations, which is different from the usual rostrocaudal gradient that is observed in patients with Parkinson’s disease.
Mutations in the F-box only protein 7 (FBXO7) gene are the cause of autosomal recessive parkinsonian-pyramidal syndrome (PARK15, OMIM 260300). These gene mutations were first reported in 2008, and only 35 cases in 17 families have been reported [1]. Clinically, medication-responsive young-onset parkinsonism with pyramidal signs is predominant, and various clinical symptoms, such as dystonia, chorea, perioral myoclonus, slow saccade, upgaze palsy, cognitive decline, and hallucination, have been reported (Supplementary Table 1 in the online-only Data Supplement).
Herein, we report a patient with a novel FBXO7 mutation with a unique clinical presentation. We summarize the updated clinical characteristics of the mutation and discuss the nearly complete loss of dopamine transporter uptake, identified by a functional neuroimaging, in FBXO7 mutations.
A 43-year-old male patient presented with a gait disturbance that had progressed for 10 months before the first visit. The patient grew up without any problems after having 5 to 6 afebrile seizure events before 2 years of age. He had exotropia, which developed in childhood. After graduating from university, he completed his Korean military duty service without any problems. Ten months before the visit to our hospital, he experienced a generalized tonic clonic seizure for approximately 20 minutes. Due to this seizure, he was sent to the emergency room of another hospital and was admitted for treatment of status epilepticus. Electroencephalography (EEG) did not show any abnormal findings, but he was prescribed levetiracetam 1,000 mg and lacosamide 50 mg two times per day. After discharge, the patient started to show abnormal behaviors such as stubborn personality, reduced communication, and new hobbies, such as fishing, which he had not done before. He also showed gait disturbance. At the next outpatient visit to that hospital, he was suspected to have parkinsonism and started anti-parkinsonian medications. The treatments were not effective, and he came to our outpatient clinic. The patient had a brother and sister who were normal. The parents said that the patient was normal before this seizure event but developed the problems since then. He had mild constipation but did not have other autonomic dysfunctions, hyposmia or rapid eye movement sleep behavior disorder.
Neurological examination revealed that the patient had exotropia, bradykinesia, masked face, stooped posture, parkinsonian gait, and postural instability (Supplementary Video 1 in the online-only Data Supplement). There was no rigidity or resting tremor, and the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III score was 14 points. The patient had no pyramidal signs or dystonia. The cognitive function test showed mild cognitive decline with a Mini-Mental Status Exam (MMSE) score of 28, a Montreal Cognitive Assessment score of 21, and a Clinical Dementia Rating (CDR) of 0.5 (sum-of-box 1.5). In brain magnetic resonance imaging (MRI), bilateral hypointensities in both globus palliduses were found in the susceptibility weighted imaging (SWI) sequence (Figure 1A and B). The bilateral dopamine transporter uptake was nearly eliminated, as determined by an N-(3-[18F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography (18F-FP-CIT PET) scan (Figure 1C). EEG and laboratory tests, including screening for Wilson disease, were normal.
Next-generation sequencing was performed on 340 target genes to identify the genetic cause of his young-onset parkinsonism. These genes included ATP13A2, CHMP2B, COQ2, C9orf72, DCTN1, DNAJC6, EIF4G1, GBA, GIGYF2, GRN, HTRA2, LRRK2, MAPT, PARK2, PARK7, PDE8E, PDGFB, PINK1, PLA2G6, POLG, SLC6A3, SLC20A2, SLC30A10, SMPD1, SNCA, SOD1 SPG11, TH, UCHL1, VPS35, and FBXO7. A heterozygous c.1066_1069delTCTG (p.Ser356ArgfsTer56) frameshift variant and a heterozygous c.80G>A (p.Arg27His) missense variant of the FBXO7 gene were found. Segregation analysis showed that the FBXO7 p.Ser356ArgfsTer56 frameshift variant and the p.Arg27His missense variant were inherited from the mother and father, respectively (Figure 1D). p.Ser356ArgfsTer56 was not reported in the Asian population, and it was identified as a pathogenic variant as PM2 and PM3 in PVS1 according to the American College of Medical Genetics and Genomics guidelines. The p.Arg27His missense variant was reported previously in a Korean patient with FBXO7 mutations [2]. The minor allele frequency in the Asian population was 0.009% (gnomAD East Asian). It was predicted to be tolerated by SIFT and probably damaging by Polyphen-2 in in silico analyses. The p.Arg27His missense variant was classified as likely pathogenic (PS1, PM2, and PM3). These compound heterozygous variants are thought to be the genetic cause of the condition in this patient.
The patient received levodopa 150 mg three times a day, pramipexole extended release form 0.75 mg and amantadine 100 mg two times a day, but there was no improvement in his symptoms. However, he showed complications such as aggressive behavior, somnolence, and impulse control disorder to gaming and shopping. Therefore, we could not increase the doses of antiparkinsonian medications. One year later, the patient’s gait abnormality had worsened, and his cognitive function deteriorated, making him more stubborn and forgetful. In the follow-up cognitive function test, there was marked dysfunction in visuospatial function, memory, and frontal/executive function on the Seoul Neuropsychological Screening Battery with MMSE 29, CDR 0.5 (sum-of-box 4.5).
The patient was diagnosed with young-onset parkinsonism with a p.Ser356ArgfsTer56 novel frameshift and a p.Arg27His missense variant in the FBXO7 gene. Interestingly, the nearly complete loss of dopamine transporter uptake that was identified by 18F-FP-CIT PET in this case has been reported in previous case reports, and all but one of these cases harbored a FBXO7 mutation [2-5]. The only case with normal uptake showed divergent clinical characteristics, such as infantile onset, epilepsy, cerebellar degeneration, spastic paraplegia and parkinsonism [5]. This phenotypic heterogeneity might be based on differences in gene expression and brain dysfunction, which explains the normal dopamine transporter uptake.
In patients with Parkinson’s disease (PD), the signals of dopamine receptor uptake are maintained to some extent in the striatum, such as the anterior portion of the putamen and caudate, regardless of the severity of symptoms [6]. This rostrocaudal gradient pattern is also found in genetic parkinsonism caused by LRRK2, SNCA, GBA, VPS35, and ATP1A3 mutations [7]. In contrast, patients with PINK1 and DCTN1 mutations or spinocerebellar ataxia types 2 and 3 may show a homogeneously decreased pattern similar to our case [7,8]. This pattern suggests a more widespread dopaminergic denervation and different pathophysiologic progress in patients with these genetic mutations [9]. Therefore, the loss of dopamine uptake in this case is a characteristic finding of FBXO7 mutations and several other genetic causes of parkinsonism, which is different from the usual rostrocaudal gradient that is observed in patients with idiopathic PD.
This patient also had unique clinical characteristics that are different from those of previous reports. 1) There was a seizure event at the onset of symptoms. 2) There was a poor medication effect. 3) Brain MRI showed globus pallidus hypointensity on SWI.
Seizures have only been reported in one case thus far [5]. FBXO7 protein is distributed widely in the frontal, temporal, and occipital cerebral cortex, hippocampus, globus pallidus, substantia nigra, and cerebellar cortex of the brain [10]. This topographic distribution can explain seizures with the severe loss of function of the FBXO7 gene. However, further studies are needed to determine its association with and pathophysiological role in seizures.
In previous studies, the levodopa response was reported in all cases (Supplementary Table 1 in the online-only Data Supplement), except one in a low-dose trial of 100 mg/day [5]. In that case, there were hypointensities in the globus pallidus in the gradient recall echo sequence, which is similar to the present case. These results suggest that severe cases of FBXO7 mutations present with clinical findings of neurodegeneration with brain iron accumulation (NBIA) spectrum disorder, and levodopa unresponsiveness might result from postsynaptic dysfunction.
In conclusion, this case was a patient with parkinsonism with a unique course due to a novel FBXO7 mutation. The patient’s specific clinical features, medication-refractory parkinsonism and seizures further broadened the spectrum of FBXO7 mutations. The pallidal hypointensity suggests that the disease exists in the form of an NBIA-related disorder. Finally, the nearly abolished dopamine transporter uptake that was identified by 18F-FP-CIT PET is frequently found in patients with FBXO7 mutations, and this is different from the usual rostrocaudal gradient that is observed in patients with PD.

Ethics Statement

Informed consent was obtained from the patient for using his case and video for publication purpose.

Video 1.

The patient shows stooped posture, slightly shuffling gait, masked face, and bilateral hand hypokinesia that were not responsive to levodopa treatment.
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.22006.

Supplementary Table 1.

Summary of previous reports with FBXO7 mutation
jmd-22006-suppl.pdf

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This study was partly supported by Chungnam National University Sejong Hospital Research Fund 2021 (2021-S4-003).

Author Contributions

Conceptualization: Chaewon Shin. Data curation: Eun Young Kim, Chaewon Shin. Formal analysis: all authors. Funding acquisition: Chaewon Shin. Investigation: Chaewon Shin. Methodology: Eun Young Kim, Chaewon Shin. Project administration: Chaewon Shin. Resources: Seon Young Kim, Youngduk Seo, Chaewon Shin. Software: Chaewon Shin. Supervision: Chaewon Shin. Validation: Eun Young Kim, Chaewon Shin. Visualization: Eun Young Kim, Youngduk Seo, Chaewon Shin. Writing—original draft: Eun Young Kim, Chaewon Shin. Writing—review & editing: all authors.

Figure 1.
Neuroimaging findings and pedigree of the index patient. A: FLAIR sequence of the brain MRI showing no abnormal findings. B: Bilateral hypointensities were found in both pallidum in the SWI sequence. C: 18F-FP-CIT PET shows the loss of dopamine transporters in the whole striatum. D: The pedigree shows that the FBXO7 frameshift and missense variants were inherited in trans. FLAIR, fluid attenuated inversion recovery; MRI, magnetic resonance imaging; SWI, susceptibility weighted imaging; 18F-FP-CIT, N-(3-[18F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane; PET, positron emission tomography; FBXO7, F-box only protein 7.
jmd-22006f1.jpg
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