The Road to Diagnosis: MRI and Genetic Testing

Getting to a diagnosis of Beta-propeller Protein-Associated Neurodegeneration (BPAN) is often a long and winding road. Because the condition is so rare and its features change over time, many families spend years searching for answers—a period often called the “diagnostic odyssey” ^[1]. In one study of 160 cases, the median delay between the first symptoms and a final diagnosis was more than six years ^[1].

Why BPAN is Often Misdiagnosed

In early childhood, the symptoms of BPAN are nonspecific, meaning they look like many other developmental conditions. Because of this, individuals are frequently given other diagnoses first:

• Cerebral Palsy (CP): Because BPAN often involves motor delays, low muscle tone (hypotonia), or stiffness (spasticity), it may initially be labeled as a non-progressive form of cerebral palsy ^[2][3].
• Rett Syndrome: Many show “Rett-like” features, such as repetitive hand-wringing, loss of purposeful hand use, and seizures ^[4][5]. If someone tests negative for the gene typically associated with Rett syndrome (MECP2), it should prompt a broader genetic evaluation rather than assuming BPAN is the only other option ^[6].
• Developmental and Epileptic Encephalopathy: Because seizures often start early and can be severe, the focus may initially be on the epilepsy alone rather than the underlying genetic cause ^[7][8].

The Evolution of MRI Findings

One reason diagnosis is delayed is that MRI (Magnetic Resonance Imaging) scans often look normal early in life ^[9]. Unlike some conditions that show clear signs from birth, the characteristic features of BPAN “evolve.” Note that repeat MRI timing is individualized; it should not delay genetic testing or be scheduled purely based on age without a clinical rationale.

Early Scans

In early childhood, brain iron is often completely absent on an MRI ^[9]. Instead, doctors may see subtle “clues” that are not specific to BPAN:

• Delayed Myelination: The protective coating on nerve fibers (myelin) may develop more slowly than usual ^[10].
• Thin Corpus Callosum: The “bridge” connecting the two halves of the brain may appear unusually thin ^[11].
• Brain Atrophy: Mild shrinking or loss of volume in the brain or cerebellum ^[10].
• Swelling: Occasionally, early scans show temporary swelling in specific brain regions like the substantia nigra or globus pallidus ^[9].

Later Scans

As the individual approaches adolescence or adulthood, changes can emerge that create a very specific pattern, helping to support the diagnosis ^[3][12].

• The T1 Substantia Nigra Halo: This is considered highly suggestive of BPAN. On a specific type of MRI scan (T1-weighted), doctors may see a bright, “halo-like” signal surrounding a dark, thin central band in the substantia nigra ^[13]. While distinctive, a pathogenic WDR45 variant—not the halo alone—is what definitively confirms the diagnosis ^[2].
• Globus Pallidus Iron: On certain sequences (like T2*), iron buildup can appear as dark areas on the scan ^[3].
• Comparison to PKAN: You may hear about another NBIA disorder called PKAN, which classically features an “eye-of-the-tiger” sign in the globus pallidus ^[14]. While that sign heavily favors PKAN, it is not universally present in all NBIA disorders. BPAN is more classically associated with the T1 halo ^[13][9].

The Definitive Test: Genetic Sequencing

While MRIs provide critical clues, the only way to definitively diagnose BPAN is through genetic testing ^[15]. A diagnosis is confirmed when a laboratory identifies a pathogenic or likely pathogenic variant in the WDR45 gene ^[16]. (A “Variant of Uncertain Significance” does not establish BPAN).

Testing, such as Whole Exome Sequencing (WES), can identify BPAN even before iron appears on an MRI ^[1][15]. However, WES can sometimes miss exon-level deletions, duplications, or low-level mosaicism. If clinical suspicion remains high after a negative WES result, geneticists may direct specialized deletion testing or broader genomic testing ^[9]. Identifying the WDR45 variant early allows families to stop the odyssey and focus on specialized care ^[15].