P318: Ironing out the BPAN phenotypic spectrum: A report of three new BPAN cases and review of the literature
Bibliographic record
Abstract
Neurodegeneration with brain iron accumulation (NBIA) refers to a spectrum of disorders, which as the name suggests, involve abnormal iron accumulation within the brain that leads to progressive nervous system degeneration. NBIA type 5, which is more commonly referred to as Beta-propeller protein-associated neurodegeneration (BPAN), is one example of a disorder within this group. BPAN is an X-linked condition and is typically caused by loss of function mutations in the WDR45 gene. Classically, BPAN has been characterized by global developmental delay and seizures in childhood, followed by neurodegeneration in adulthood. Neurological symptoms can progress to include parkinsonism, dystonia, and dementia. Since it was first reported in 2012, the phenotypic spectrum observed with BPAN has greatly expanded. The most recent review of disease associated with WDR45 was in 2020, at which time there were 123 individuals identified with WDR45-related disease. New case reports of patients with BPAN continue to be published, and additional patients continue to be diagnosed. We have identified three new cases of BPAN as well as provided updated clinical information on a previously reported case. All four patients are followed at a single center in Saskatchewan, Canada. Identification of WDR45 variants was accomplished through multi-gene testing panels or whole exome sequencing. Of the three unpublished cases, two of the patients were found to have de novo pathogenic frameshift variants (NM_007075.3: c.964del, p.Lys319Argfs*11 and NM_007075.3: c.561_564dup, p.Ile189Hisfs*8). The third patient was found to have a missense variant of uncertain significance (NM_007075.3: c.359T>C, p.Ile62Val) but with clinical signs and symptoms supporting a BPAN diagnosis. The patients range from 10 to 17 years of age. All the patients in the cohort are followed for seizures, however, only the oldest patient has started to exhibit some features of parkinsonism. One of the patients presents with iron deposition in the lungs, which has yet to be reported with WDR45-related disease in the literature. Improved awareness of the phenotypic variability of BPAN, the uptake of more comprehensive diagnostic modalities like whole exome sequencing, as well as advances in neuroimaging have greatly improved clinicians’ abilities to diagnose the disease. We aimed to provide a case series including three newly identified patients as well as provide an update on BPAN literature. This work further elucidates the phenotypic variability seen with WDR45 variants. In turn, it contributes to the body of literature regarding WDR45 related disease, which ultimately serves to facilitate earlier disease diagnosis for affected patients.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".