What is BPAN

What is BPAN?

Beta-Propeller Protein-Associated Neurodegeneration (BPAN) is a rare, progressive genetic disorder that affects the nervous system. It belongs to a group of conditions called Neurodegeneration with Brain Iron Accumulation (NBIA), where excess iron builds up in certain areas of the brain, causing damage over time.

BPAN typically starts in early childhood with developmental delays and seizures, then progresses in adolescence or adulthood to worsening movement problems, cognitive decline, and other neurological issues. It is caused by mutations in the *WDR45* gene on the X chromosome. Most cases are not inherited from parents but occur as new (de novo) mutations.

Causes and Genetics

BPAN is caused by changes (mutations) in the WDR45 gene, which provides instructions for making a protein called WIPI4 (also known as WDR45). This protein has a distinctive seven-bladed beta-propeller structure and plays a key role in autophagy—a vital cellular "cleanup" process.

The WDR45 gene is on the X chromosome, so BPAN follows an X-linked dominant inheritance pattern. This means:

• A single mutated copy of the gene is enough to cause the disorder in both females (who have two X chromosomes) and males (who have one).

• Most cases are in females, as many affected males may not survive to birth.

• Almost all cases are new mutations, with no family history. Rarely, it can be passed from a mildly affected mother.

Symptoms

BPAN often unfolds in two main phases:

Childhood Phase (Developmental Delay Phase) 

Starts in infancy or early childhood. Common signs include:  

•   Developmental delays (e.g., delayed walking, talking, or other milestones).  

•   Intellectual disability (often moderate to severe).  

•   Limited or absent speech.  

•   Recurrent seizures (epilepsy)—these may include absence seizures (staring spells), tonic-clonic (convulsions), myoclonic (jerks), or syndromes like West or Lennox-Gastaut. Seizures often improve or resolve in adolescence.  

•   Clumsy or unsteady gait (ataxia).  

•   Repetitive hand movements, sleep disturbances, teeth grinding, or behaviors similar to autism spectrum disorder or Rett syndrome.

Adolescence/Adulthood Phase (Neurodegeneration Phase)

Usually begins in the teens to 30s (average around age 25).  Progressive worsening includes:  

•   Cognitive decline leading to dementia.  

•   Movement disorders: dystonia (involuntary muscle contractions/twisting), parkinsonism (slow movements, rigidity, tremors, shuffling gait, falls), and spasticity.  

•   Loss of previously acquired skills (e.g., walking).  

•   Other issues: swallowing difficulties, sleep problems, or vision/hearing concerns in some cases.

Diagnosis

Diagnosis is confirmed through genetic testing for WDR45 mutations, often via whole-exome or genome sequencing. Doctors may suspect BPAN based on:  

• Clinical history (childhood seizures/delays + adult-onset movement issues).  

• Brain MRI showing iron accumulation in the substantia nigra and globus pallidus (often with a distinctive "halo" appearance on T1-weighted images).

  • Early childhood MRIs may look normal or show mild changes; iron buildup often becomes clear later.

Treatment and Management

There is no cure for BPAN, but supportive care can improve quality of life and help manage symptoms:  

• Anti-seizure medications for epilepsy.  

• Dopaminergic drugs (e.g., levodopa) for parkinsonism, with careful monitoring.  

• Therapies: physical, occupational, speech, and feeding therapy.  

• Assistive devices, alternative communication tools, and behavioral support.  

• Regular follow-up with neurologists, ophthalmologists, and other specialists.

Prognosis

BPAN is progressive and worsens over time. With good symptom management, many individuals live into middle age or beyond. Challenges include increased risk of falls, swallowing issues, and complications like pneumonia. Ongoing research into autophagy-targeted therapies offers hope for future options.

Resources and Support

• NBIA Disorders Association: https://www.nbiadisorders.org/about-nbia/bpan  

• Beat BPAN: http://www.beatbpan.org

• MedlinePlus Genetics: https://medlineplus.gov/genetics/condition/beta-propeller-protein-associated-neurodegeneration  

• Consensus Clinical Management Guidelines: https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.14980