Beta-propeller protein-associated neurodegeneration: A clinical update with a case report

Graphical abstract Unlabelled Image


Brief discussion
Global developmental delay, early childhood neurocognitive decline that remains static for years, juvenile or young-adult onset of worsening neurocognitive changes, and the development of progressive, levodopa-resistant Parkinsonian features suggest the diagnosis of beta-propeller proteinassociated neurodegeneration (BPAN), which is the only X-linked subtype of neurodegeneration with brain iron accumulation (NBIA) [1][2][3][4]. In the past, this entity was named static encephalopathy (of childhood) with neurodegeneration in adulthood (SENDA), but after the underlying genetic defect was identified, this NBIA subtype was renamed or reclassified as BPAN, similar to the other subtypes of NBIA [5]. In BPAN, and as discussed earlier, patients present with global developmental delay, mainly including language and motor skills. In contrast to other subtypes of NBIA, the clinical presentation of delayed development remains relatively static until adolescence/young adulthood [3]. Abnormal movement or neurocognitive decline is absent in childhood, but as the patient approaches adolescence and early adulthood, progressive neurodegeneration symptoms including dystonia, Parkinsonian features, and neurocognitive decline start to appear [2,3]. Although the benefit is only short-lasting, Parkinsonian symptoms may improve with the initiation of levodopa therapy as our patient did [6]. Some previous studies reported a correlation between the detected WDR45 mutations and responsiveness to L-Dopa [2,7], but with no available or unknown data regarding the variant NM_007075.3: c.186delT, p.L63Wfs*19, making our study the first to report such a finding (i.e., positive response to L-Dopa).
As in other subtypes of NBIA, iron deposition is the key imaging abnormality [8]. The earliest and most concentrated iron accumulation occurs in the substantia nigra. Although iron deposition generally occurs in the globus pallidus, it usually follows iron deposition in the substantia nigra. Therefore, evidence of increased iron deposition involving bilateral substantiae nigrae as demonstrated by the high T1 signal and the low T2 signal is virtually a pathognomonic finding in patients with BPAN [8]. Late-onset pantothenate kinase-associated neurodegeneration (PKAN) may be considered in the differential diagnosis of BPAN; however, the typical eye-of-the-tiger sign in the globus pallidus, which is reported as a specific sign of PKAN [9], is absent in our case. Moreover, the T1 hyperintensity of the subthalamic nucleus (STN), as seen in our case, is not characteristic of PKAN [8,9]. Phospholipase-associated neurodegeneration (PLAN), which may also be considered in the differentials, is a disease of early childhood and is characterized by more severe symptoms, most notably cerebellar atrophy which is not present in our case [10]. Furthermore, most patients with PLAN succumb to the disease by 10 years of age [10]. While our patient's symptoms complex is also suggestive of Parkinson's disease, especially with the marked response to L-Dopa, the evidence of excessive iron accumulation in the deep nuclei is not a feature of early-onset Parkinson's disease [11].
BPAN is thought to be caused by an error in autophagy, the process of cellular recycling [12]. Thus far, several research groups have been working to unveil how a disruption in this process leads to iron build-up in the brain, and consequently the characteristic clinical phenotype. To date, no targeted therapies are approved or readily available for this condition, with most current treatments directed toward the manifested symptoms; however, we and the families of our BPAN patients remain hopeful that new targeted therapies may become available shortly as we learn more about this rare disease.

Ethics approval and consent to participate
The approval was obtained from the Ethics Committee of Al-Azhar University Hospitals [REF. HSUZ-21-00032711]. The patient's guardians gave a written informed consent to publish the case and any related data.

Funding
None declared.

Contribution
M.M. was responsible for the conception of the work, data collection, drafting the article, critical revisions, illustrating the abstract, and obtaining approval of the final version of the manuscript. Y.M. contributed by drafting the article, and critical revisions. H.A. contributed by critical revisions of the article. All authors read the final manuscript and were involved in direct patient care.

Declaration of Competing Interest
None declared.