INTRODUCTION

Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked disorder caused by pathogenic variants in the WDR45 gene and belongs to the spectrum of neurodegeneration with brain iron accumulation (NBIA) disorders [1,2].

BPAN typically follows a biphasic clinical course [2,3]. During infancy and early childhood, affected individuals present with global developmental delay and typically experience seizures. In late adolescence or early adulthood, cognitive decline, dystonia, and parkinsonism may develop. In Korea, all previously reported BPAN patients were adults who exhibited a typical diphasic clinical course and showed iron-related magnetic resonance imaging (MRI) changes, including the T1 hyperintense halo sign in the substantia nigra (SN), as well as presynaptic dopaminergic loss detected on dopamine transporter imaging (Supplementary Table 1). These features delineate BPAN as distinct from other NBIA disorders [4-7].

Despite this general pattern, early manifestations are highly variable and often nonspecific, making early diagnosis particularly challenging [2,3,8]. Moreover, early childhood brain MRI often does not reveal iron accumulation in the SN and globus pallidus (GP), which is characteristic of the later disease stage [9-11].

Here, we report six pediatric cases of BPAN from Korea identified via genetic testing performed during evaluations for neurodevelopmental disorders. This study aims to delineate early clinical signs that may facilitate timely recognition of BPAN in young children.

MATERIALS & METHODS

We recruited six female Korean patients diagnosed with BPAN on the basis of the presence of heterozygous pathogenic variants in the WDR45 gene. Clinical and genetic data, including initial symptoms, developmental history, and neurological findings, were obtained through medical chart review and semistructured assessments.

Brain MRI was performed at diagnosis or at follow-up in all patients. In addition to evaluating iron accumulation in the SN and GP, attention was given to early nonspecific findings such as corpus callosum thinning, cerebral atrophy, and white matter abnormalities [9,12]. Routine laboratory testing included assessment of neuron-specific enolase (NSE) levels, given prior reports of its potential role as a biomarker of BPAN [13].

Genetic testing was performed as part of the diagnostic workup. In most patients, WDR45 variants were incidentally identified during evaluations for developmental delay or epilepsy using epilepsy panels (P3), whole-exome sequencing (P2 and P5), or whole-genome sequencing (P4 and P6). In only one patient (P1), BPAN was confirmed by targeted WDR45 sequencing prompted by MRI findings. All WDR45 variants (NM_007075.4) were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. For adult BPAN patients, genetic variant data were obtained from previously reported cases in Korea.

This study was approved by the Institutional Review Board of Pusan National University Yangsan Hospital (IRB No. 11-2024-013), and written informed consent was obtained from the parents or legal guardians of all participants in accordance with the recommendations of the Declaration of Helsinki.

RESULTS

All six patients were female, which is consistent with the known female predominance in BPAN. The clinical characteristics are summarized in Table 1. One patient (P2) has been previously reported [14]. The patients’ ages at the last clinical evaluation ranged from 19 months to 16 years. None of the six patients had known family history. All patients presented with early developmental delay, intellectual disability, and profound language impairment. Three patients over the age of 10 (P1, P2, and P3) were nonverbal and produced only nonmeaningful sounds. The language of P4, aged 9 years, was limited to short two-word phrases. Among the patients younger than 3 years, P5 (32 months) was nonverbal, whereas P6 (19 months) produced a few words.

Motor development was variably impaired, with Gross Motor Function Measure (GMFM) scores in the cohort ranging from 19.7% to 95.3%. Most patients had gait abnormalities. P1 and P3 could walk short distances with a spastic, wide-based gait. P6 was ambulatory with poor balance and frequent falls. P2 and P5 were nonambulatory and required wheelchairs. Only P4 was able to walk without notable gait abnormalities. Dystonic limb posturing during voluntary movement was noted in three patients (P1, P2, and P3). P2 had a history of dysphagia and needed dietary modification. None of the patients met the formal diagnostic criteria for parkinsonism at the time of evaluation.

Four patients had seizures, with onset ranging from infancy to early childhood. P2 developed afebrile seizures at age 4, including generalized tonic–clonic and atonic events, with poor seizure control despite the use of multiple antiseizure medications (ASMs). P3 had a single febrile and afebrile seizure at one year, with no recurrence during follow-up. P4 and P5 experienced only febrile seizures. P5 had recurrent febrile seizures without afebrile progression, whereas P4 developed two brief generalized seizures at ages 2 and 6 but has remained seizure-free since starting ASM therapy.

Two patients showed signs of precocious puberty, defined as the onset of secondary sexual characteristics before age 8. Both underwent gonadotropin-releasing hormone stimulation testing at age 8, which demonstrated peak luteinizing hormone (LH) levels ≥5 IU/L (P1: 9.75; P2: 12.0), pubertal LH/follicle-stimulating hormone ratios, and bone age advancement, consistent with a diagnosis of central precocious puberty [15]. None of the patients had clinically relevant ophthalmologic, autonomic, or sleep-related findings.

Serum NSE concentrations were measured in five of the six patients, all of whom had elevated levels, with most showing values more than twice the age-specific upper reference limit (30.7–73.2 ng/mL; 47.8±11.4; ref. <16.3).

The timing of the MRI scans varied across patients (Table 1). Susceptibility-weighted imaging (SWI) was available for five patients. In P1 and P2, both of which were >5 years old, evidence of iron accumulation was more prominent on SWI than on conventional T2-weighted images. SWI hypointensity was more pronounced in the SN than in the GP, particularly in P2. No SWI abnormalities suggestive of iron accumulation were found in three patients (P4, P5, and P6) who underwent SWI at ≤4 years of age. The “halo” sign was not visible on conventional T1-weighted imaging. Corpus callosum thinning was consistently observed in all six patients, along with mild cerebral atrophy. No imaging evidence of myelination defects was identified in patients older than 4 years, while assessment in younger patients was limited by the absence of serial MRI.

As illustrated in the Korean cases summarized in Figure 1, the spectrum of WDR45 variants comprised two nonsense (P5: c.887G>A, p.Trp296*; P6: c.873C>G, p.Tyr291*), two splice-site (P2: c.977-1G>A; P3: c.830+1G>A), and two deletions: an inframe deletion (P1: c.408_413del, p.Glu138_Phe139del) and a novel frameshift deletion (P4: c.791_792del, p.Phe254Cysfs* 41). The novel variant was classified as pathogenic on the basis of ACMG guidelines (PVS1, PS2, PM2, and PP4). Parental testing, performed for P2, P4, and P5, confirmed that the variants were de novo. Adult BPAN patients likewise exhibit heterogeneous WDR45 variants [4-7].

DISCUSSION

This study presents a comprehensive characterization of Korean patients with BPAN, highlighting phenotypic clues that may support early diagnosis in pediatric patients. Compared with international pediatric BPAN cohorts, our patients demonstrated similar key features, including global developmental delay and seizures, as well as comparable frequencies of other characteristic clinical signs [8,16]. In addition, a wide range of WDR45 variant types was observed in our patients, reflecting the well-recognized genetic heterogeneity of BPAN.

Language impairment was the most prominent and consistent clinical feature in this case series. Two-thirds (n=4) were nonverbal, and none achieved age-appropriate expressive language milestones. This pronounced and early onset of expressive language impairment is a well-established feature of BPAN and may represent a useful clinical marker for identifying BPAN among children with unexplained developmental delay [1,2,8,12].

Seizures were observed in four out of six patients, which aligns with the findings of prior studies reporting epilepsy in approximately 80% of BPAN patients [8,16]. The seizure types were heterogeneous, which is consistent with previous reports of variable semiology and mixed ASM responses. Although refractory epilepsy has been reported in up to 50% of BPAN patients [8,16], only one of our four patients was pharmacoresistant, suggesting individual differences in treatment response. In addition, an infantile-onset epileptic encephalopathy phenotype, described in prior BPAN reports, was not observed in our patients [17]. Further studies in larger patient groups are warranted to more precisely define the epileptic phenotype in BPAN.

Gait disturbance is among the most frequently observed motor impairments and has a broad range of severity [8]. Fine motor impairments, including limited purposeful hand use, were also observed and contributed to functional disability. Dystonia and spasticity, when present, were mild and nonprogressive. These preexisting features may obscure the recognition of later-onset parkinsonism. Given that BPAN is known to progress to dystonia-parkinsonism during late adolescence or early adulthood [1-3], longitudinal assessment of motor function is warranted for early detection and timely intervention.

A noteworthy finding was the presence of central precocious puberty. Early pubertal onset may reflect dysfunction of the hypothalamic–pituitary–gonadal axis during the neurodevelopmental phase [15]. Although central precocious puberty has been noted as a potential feature of BPAN, its prevalence, clinical course, and response to treatment have not been systematically reported [12].

Serum NSE levels were consistently elevated, as reported in previous studies [13,18]. This may serve as an ancillary marker in the early diagnostic workup of BPAN. Although serum NSE is a marker of neuronal injury, the underlying pathophysiological mechanism remains unclear. A prior observational study revealed persistently elevated serum NSE levels without neurological decline, and the possibility of a systemic process, such as impaired autophagy, has also been suggested [13]. These findings indicate a need for complementary central nervous system–specific markers, including neurofilament light chain and glial fibrillary acidic protein [19].

MRI changes in BPAN follow an age-dependent course, initially presenting with subtle structural changes, such as corpus callosum thinning, and subsequently progressing to marked iron accumulation [3,9,10,12]. As observed in our cases, iron accumulation in early childhood may not be clearly detectable even with iron-sensitive MRI, and reliance on MRI evidence of iron accumulation or the “halo” sign alone for diagnosis is not advised [9,12].

Early BPAN features are nonspecific, overlap with those of other neurodevelopmental disorders and often delay diagnosis [3,8,12]. The increasing availability of next-generation sequencing has facilitated earlier detection. BPAN should be considered in pediatric patients with developmental disorders characterized by profound language impairment, epilepsy, corpus callosum thinning, and unexplained elevations in serum NSE levels.

Supplementary Materials

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This work was supported by a 2-year Research Grant of Pusan National University.

Acknowledgments

We are deeply grateful to the patient’s family for their understanding, cooperation, and consent.

Author Contributions

Conceptualization: Jae-Hyeok Lee. Data curation: Yun Soo Kim. Formal analysis: Yun Soo Kim. Funding acquisition: Jae-Hyeok Lee. Investigation: Soo-Yeon Kim, Yun-Jin Lee, Seung Hwan Oh, Seong-Min Choi. Supervision: Jae-Hyeok Lee. Writing—original draft: Yun Soo Kim, Jae-Hyeok Lee. Writing—review & editing: all authors.

Figure 1.

Exonic distribution of WDR45 variants identified in Korean BPAN patients. Each variant is mapped to the corresponding exon on the basis of the NM_007075.4 reference transcript. The numbers in brackets correspond to the reference list. Red variants indicate pediatric cases, whereas blue variants represent adult BPAN cases. UTR, untranslated region; BPAN, beta-propeller protein-associated neurodegeneration.

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