Adult‐Onset BPAN: An Atypical Presentation Mimicking Early‐Onset Parkinson's Disease

Early-onset Parkinson's disease (EOPD) is defined by the onset of motor symptoms before the age of 50 and is often associated with a genetic etiology.1 Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked form of neurodegeneration with brain iron accumulation (NBIA) caused by pathogenic variants in the WDR45. BPAN typically presents with neurodevelopmental abnormalities in early life with later development of severe parkinsonism, dystonia, and cognitive decline during adolescence or early adulthood.2 Herein, we report a unique case of a patient with a pathogenic WDR45 variant presenting with levodopa-responsive parkinsonism without major cognitive decline or other atypical features, mimicking EOPD. The proband is a 48-year-old female who initially presented with 6 months of left arm loss of dexterity and progressive gait unsteadiness. She reported a history of static mild intellectual disability (ID) since childhood. She was able to graduate from high school, she held various jobs throughout her life and performed her instrumental and daily living activities without difficulties. On examination at age 48, she exhibited asymmetric parkinsonism characterized by hypomimia, left-sided bradykinesia and rigidity, reduced left arm swing, and narrow-based gait with shortened stride length and pace. Her symptoms responded well to levodopa. Approximately 3 years after the diagnosis, when she was receiving carbidopa/levodopa 25/100 mg two tablets five times daily, she developed motor fluctuations and dyskinesias (see Video 1). She also had hyposmia and constipation. She had not experienced any further cognitive decline and continued to perform well in her daily activities. She had no history of developmental regression, seizures, psychiatric comorbidities, sleep disturbances or autonomic dysfunction. Her past medical history was also significant for a left ankle sprain at age 47, complicated by foot drop and progressive ankle deformity which ultimately resulted in an acquired equinovarus. EMG revealed a left common peroneal neuropathy, which was complicated by progressive left leg muscle atrophy. She subsequently underwent major orthopedic surgery to correct the deformity. Moreover, she had a history of bilateral hearing loss, beginning in her late 20s. Her family history was non-contributory, and she is of Slovakian and Irish descent. Genetic analysis with clinical exome sequencing identified a previously reported pathogenic heterozygous STOP-gain variant in WDR45 (NM_007075.4: c.400C>T; p.Arg134*). No other pathogenic variants were identified in other parkinsonism-related genes. Brain MRI, performed after identification of the WDR45 variant, revealed characteristic findings of BPAN, including marked hypointensity in the globus pallidus and substantia nigra on axial T2-weighted images, along with substantia nigra hyperintensity with a central band of hypointensity on T1-weighted images (Fig. 1A). (123)I-Ioflupane single-photon emission computed tomography (SPECT) done after 1 year of symptom onset showed bilateral decreased radiotracer uptake, slightly more pronounced in the right putamen (Fig. 1B). Most BPAN cases typically follow a biphasic course. In the first phase, occurring in infancy or childhood, most individuals present with global developmental delay, often with absent or minimal expressive language and significant cognitive impairment, early-onset spastic paraplegia, and epilepsy. The severity of the developmental delay may vary with some subjects exhibiting significantly milder phenotypes.3 The second phase is usually characterized by progressive cognitive decline, and development of severe parkinsonism and dystonia, usually with onset during adolescence or early adulthood.4 Our patient, carrying a known pathogenic WDR45 variant, deviated from this classical presentation. She presented exclusively with adult-onset levodopa-responsive early-onset parkinsonism. Aside from mild static ID and hearing loss, she did not exhibit the profound developmental impairment or other early neurological symptoms typically seen in BPAN. Late-onset BPAN with isolated parkinsonism has been very rarely described. A subset of a few documented cases shares a similar clinical profile with mild static intellectual disability and late onset of parkinsonism resembling EOPD. These individuals are verbal and functionally independent. One case involved a 50-year-old woman presenting with asymmetric parkinsonism, mild weakness and spasticity, with a good response to levodopa treatment.5 Another report described a 31-year-old woman with mild static intellectual disability, EOPD and spasticity but no response to levodopa.6 Interestingly, in the latter case (123)I-Ioflupane SPECT imaging showed bilateral striatal dopamine transporter uptake reduction with significant asymmetry.6 It has been suggested that X-chromosome inactivation may influence the disease severity in BPAN patients.7 Thus, we speculate that the milder presentation of our case may be explained by an imbalanced inactivation of the chromosome carrying the WDR45 variant. Importantly, affected females remain at risk of transmitting the complete BPAN phenotype,8 highlighting the need for comprehensive genetic counseling for BPAN female subjects, particularly those with a milder phenotype. In conclusion, this case demonstrates that BPAN can present as isolated early-onset parkinsonism, closely resembling EOPD. While WDR45 variants are very rare in cases of early-onset parkinsonism (no additional cases observed in the PD GENEration database, which contains ~10,000 PD cases), this underscores the importance of including WDR45 in genetic panels for EOPD screening, particularly for those cases where mild ID is present. This finding, along with similar reports of typical EOPD in carriers of pathogenic variants in other genes traditionally linked to atypical parkinsonism (eg, PLA2G6 and FBX07),9 challenges the conventional clinical distinction between typical and atypical monogenic parkinsonism, suggesting that comprehensive genetic analysis should be considered for all individuals with early-onset parkinsonism, even in the absence of atypical clinical features. Beyond its diagnostic implications, this observation also raises important questions about the underlying disease mechanisms. It has been shown that WDR45 dysfunction causes cellular defects affecting pathways implicated in PD pathogenesis.10 Our clinical observation reinforces the concept that understanding the cellular disease mechanisms of BPAN may also be relevant to PD. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. M.H.G.M.: 1A, 1B, 1C, 3A, 3B. P.V.: 1C, 3B. I.J.K.S.: 1C, 3B. L.K.: 1C, 3B. D.K.: 3B. N.E.M.: 1A, 1B, 1C, 3A, 3B. Biospecimens used in the analyses presented in this article were obtained from the Northwestern University Movement Disorders Center (MDC) Biorepository. As such, the investigators within MDC Biorepository contributed to the design and implementation of the MDC Biorepository and/or provided data and collected biospecimens but may not have participated in the analysis or writing of this report. MDC Biorepository investigators include Rizwan Akhtar MD, PhD; Tanya Simuni MD; Puneet Opal MD, PhD; Joanna Blackburn MD; Monika Szela MHA; and Lisa Kinsley MS, CGC. A gift from the Malkin family generously supported the work of the MDC Biorepository. Data used in the preparation of this article were obtained from the Parkinson's Foundation PD GENEration study. PD GENEration is a flagship initiative of the Parkinson's Foundation in partnership with Aligning Science Across Parkinson's (ASAP) and the Global Parkinson's Genetics Program (GP2). Additional financial and in-kind support comes from the Parkinson's community–industry partners, nonprofit organizations, and individuals whose lives have been touched by Parkinson's. For up-to-date information on the study, visit https://www.parkinson.org/advancing-research/our-research/pdgeneration. Ethical Compliance Statement: Name of the institutional review board or ethics committee that approved the study: No IRB or ethics committee was needed for this study. Declaration of patient consent: The patient has provided written consent for video recording. This consent includes permission for the video clip and/or photograph to be submitted for publication in a peer-reviewed medical journal. The patient acknowledged and agreed that the published material may be used by readers for educational purposes. Affirmation that all authors have read and complied with the Journal's Ethical Publication Guidelines: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: The authors declare that there are no funding sources or conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: MHGM is an employee from McGaw Medical Center of Northwestern University and receives support from Northwestern University Feinberg School of Medicine (Starzl Scholar Award). DK is the Founder and Scientific Advisory Board Chair of Lysosomal Therapeutics Inc. and Vanqua Bio. DK serves on the scientific advisory boards of The Silverstein Foundation, Intellia Therapeutics, AcureX and Prevail Therapeutics and is a Venture Partner at OrbiMed. NEM receives NIH funding (1K08NS131581) is supported by the Align Science Across Parkinson's (ASAP) Global Parkinson's Genetics Program (GP2). He is member of the steering committee of the PD GENEration study for which he receives an honorarium from the Parkinson's Foundation. The data that support the findings of this study are available from the corresponding author upon reasonable request.