Early-Onset Cataracts as a Clinical Indicator of DJ-1-Related Parkinsonism
Article information
Dear Editor,
A 40-year-old male born to nonconsanguineous parents presented with involuntary forceful blinking of the eyes followed by bradykinesia and rigidity (right>left) for the last 4 years. Resting tremors in the bilateral upper limbs emerged within the previous year. There was no family history of similar symptoms. Birth and developmental history were noncontributory. The patient had no history of rapid eye movement sleep behavior disorder, falls, constipation, or bladder dysfunction. He had a relevant history of cataracts at age 13. He underwent intraocular lens implantation, which improved his vision. There was no preceding history of trauma or evidence of ocular infection or diabetes as the cause of the cataract. On examination, his Montreal Cognitive Assessment score was 26/30 (impairment in Trail-Making Test, abstraction and attention). Examination of the extraocular movements revealed broken pursuits and hypometric saccades (horizontal and vertical). Deep tendon reflexes were normal, with bilateral flexor plantar response. Striatal toe was present. His Unified Parkinson’s Disease Rating Scale III score decreased from 34 to 24 during the levodopa challenge test with a 250 mg dose; however, axial rigidity showed no response, and no levodopa-induced dyskinesias were reported (Supplementary Video 1 in the online-only Data Supplement). The patient continued on levodopa at a dosage of 125 mg three times a day and pramipexole (0.5 mg/day). Brain magnetic resonance imaging revealed no significant abnormalities. 18F-fluorodopa positron emission tomography scan (Figure 1) revealed severe reduction of tracer uptake in the bilateral striatum. Pure tone audiometry revealed mild bilateral sensorineural hearing loss. Clinical exome sequencing revealed likely pathogenic (very strong level of pathogenicity, moderate evidence of pathogenicity) compound heterozygous 5’ splice site variants in the PARK7 gene. One of the heterozygous variants was in intron 4 (c.253-1G>C; ENST00000338639.10), and the other variant was in intron 6 (c.410-1G>C; ENST00000338639.10). The in silico prediction tools MutationTaster2, SpliceAI, AdaBoost, and MaxEntScan indicated that both canonical variants had a damaging effect. The intron 4 splice site variant (ENST00000338639.10: c.253-1G>C) is novel and has not been reported in population or disease databases. The variant in intron 6 has been reported previously in one individual in a compound heterozygous state [1].
Structural and functional imaging of the brain. Brain MRI T2W (A) and FLAIR (B) images showing normal basal ganglia. FDOPA PET images showing severely reduced dopamine uptake in the striatum (C and D). MRI, magnetic resonance imaging; T2W, T2 weighted; FLAIR, fluid attenuated inversion recovery; FDOPA PET, 18F-fluorodopa positron emission tomography.
Mutations in the PARK7 gene, which encodes DJ-1, lead to a rare recessive form of Parkinson’s disease (PD) that manifests with not only the triad of tremors, rigidity, and bradykinesia but also anxiety, dystonia, and hyposmia as the primary clinical features [2]. The global burden of DJ-1 mutations is relatively rare, approximately 1%–2%. The prevalence of PARK7-related PD in Indian patients has been reported to be 3.9%.
A total of 46% of patients exhibit associated dystonia, which can involve the lower limbs, eyes, or craniocervical region. Cataracts and hearing loss are rare in patients with DJ-1 mutations, occurring in 14.3% and 6.1%, respectively [3,4]. Narendra et al. [4] reported a history of cataracts, sensorineural hearing loss, and eyelid apraxia in a 35-year-old PD patient with compound heterozygous DJ-1 mutations. The authors also demonstrated evidence of alpha-synuclein deposition in the sympathetic noradrenergic nerves. Two additional cases were documented by Namnah et al. [5], substantiating the occurrence of cataracts in patients with DJ-1 mutations. Other ocular manifestations reported in patients with DJ-1 parkinsonism include blepharospasm, oculogyric crisis, and retinitis pigmentosa [6-8]. DJ-1, an evolutionarily conserved protein encoded by PARK7, is a deglycase used to repair cellular damage caused by reactive aldehydes and oxidative stress, both of which are believed to play crucial roles in the development of cataracts, suggesting a plausible association. DJ-1 exerts antioxidant effects through various signaling pathways, such as the nuclear factor erythroid-2 related factor 2, phosphoinositide 3-kinase, and apoptosis signal-regulating kinase 1 pathways.
In conclusion, cataracts could be a clinical indicator of PARK7 mutations in patients with early-onset PD.
Supplementary Materials
The online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.25016.
Video 1. The video demonstrates Parkinsonian features of mask-like facies and bradykinesia affecting both upper and lower limbs (slightly more impaired on the right side). Eye movement examination shows broken pursuits and hypometric saccades (horizontal>vertical). The latter part of the video depicts hypokinetic dysarthria.
Notes
Ethics Statement
The authors confirm that the approval of an institutional review board was not required for this work. We also confirm that the patient’s guardian has given written informed consent for the publication of his video.
Conflicts of Interest
The authors have no financial conflicts of interest.
Funding Statement
None
Acknowledgments
None
Author Contributions
Conceptualization: Sahil Mehta. Data curation: Sahil Mehta, Jagdeep Singh, Saurabh Mishra. Formal analysis: Sahil Mehta. Investigation: Sahil Mehta, Saurabh Mishra. Methodology: Sahil Mehta. Project administration: Sahil Mehta. Supervision: Vivek Lal. Writing—original draft: Sahil Mehta. Writing—review & editing: Sahil Mehta, Vivek Lal.