BPAN

Beta-propeller Protein-associated Neurodegeneration (BPAN)

GENE: WDR45;
INHERITANCE: X-linked dominant (often de novo mutations);
ONSET: Childhood to adolescence;
SYMPTOMS: Developmental delay, dystonia, parkinsonism, and cognitive decline;
NOTES: BPAN is characterized by early developmental delay followed by progressive neurological deterioration.

Overview

BPAN is one of the NBIA disorders, and currently it’s the most commonly diagnosed NBIA subtype, representing about 35–45 % of NBIA cases. It is caused by mutations in the WDR45 gene (on the X chromosome) and is inherited in an X-linked dominant manner (a single mutated copy can cause disease). Most BPAN cases arise de novo (i.e. new mutations) – meaning neither parent carries the mutation. Because of its genetic nature, BPAN often appears in a single person within a family (simplex) rather than inherited across many family members.Females are more commonly affected, likely because many male fetuses with WDR45 mutations may not survive in utero.

Genetics & Mechanism

Gene and protein: The WDR45 gene encodes the WIPI4 protein, which is involved in autophagy – the cell’s process for recycling damaged components.
Pathophysiology: Mutations often lead to loss of function of WIPI4, impairing autophagy. This may cause accumulation of cellular waste, including iron or disrupted iron metabolism in neurons, contributing to neurodegeneration.
Inheritance: As an X-linked dominant disorder, one mutated copy on the X chromosome can cause disease in both females and males. In many BPAN cases, the mutation is de novo (not inherited). Rarely, mosaicism or inheritance from a mildly affected parent is possible.

Clinical Features & Progression

BPAN uniquely follows a two-phase clinical course:
1. Early (childhood) phase

Developmental delay, particularly in motor skills and cognition
Ataxic or unsteady gait (“clumsy walking”)
Expressive language delay: many children have limited speech or only a few words
Seizures, often starting in infancy or early childhood – they may include febrile seizures, generalized, focal, or epileptic spasms
Sleep disturbances, behavioral features, autistic-like traits, eye problems (retinal or optic nerve involvement)

2. Progressive / adult onset phase

Dystonia and abnormal involuntary muscle contractions
Parkinsonism: tremor, rigidity, slowness, disturbance of balance, “frozen gait” periods
Cognitive decline / dementia
The disease is progressive – symptoms worsen over time.

Additional features:

MRI may show iron accumulation in basal ganglia (substantia nigra, globus pallidus), and distinct imaging features such as a T1 “halo” in older patients.
In early stages, MRI may be relatively normal in some children.
Lifespan varies. With good symptom management, many live into adulthood, though complications from movement/dementia or swallowing can contribute to mortality.

Diagnosis & Imaging

Genetic testing is critical for diagnosis – most BPAN cases are confirmed through whole exome sequencing (WES) or whole genome sequencing (WGS).
MRI brain imaging often reveals iron deposits in the basal ganglia (especially substantia nigra and globus pallidus).
A characteristic MRI feature in BPAN is a bright “halo” on T1 images in the substantia nigra / cerebral peduncles – this may appear when movement symptoms begin.
Early MRI may show subtle changes like reduced white matter, thinning of corpus callosum, delayed myelination.

Management & Support

There is no cure currently, but interventions focus on symptom relief and quality of life:

Seizure control with anti-seizure medications; in some cases, devices like vagus nerve stimulation (VNS) might be considered.
Physical, occupational, speech therapy to manage motor dysfunction, maintain mobility, and assist communication.
Dystonia / Parkinsonism management – medications or sometimes deep brain stimulation (DBS) in selected cases.
Supportive care: feeding support, communication aids, mobility devices, and multidisciplinary team involvement.
Monitoring and adjusting care over time as symptoms evolve.

Research & Emerging Therapies

Painterly row of six portraits of young children in bright natural light, each wearing blue or white clothing and smiling softly against warm, softly textured backgrounds.
BPAN is a focus of ongoing research given its prevalence among NBIAs:

Because WDR45 mutations affect autophagy, research is exploring therapies to restore or enhance autophagy pathways.
Some NBIA approaches (for multiple subtypes) use iron chelators to reduce iron burden in the brain.
Other therapies target downstream molecular pathways, or aim to deliver functional gene copies (gene therapy) – though this is still largely preclinical.
Grants have been awarded to projects studying WDR45 function, mitochondrial defects, and single-cell gene expression in BPAN.

Resources

1. BPAN Warriors – patient advocacy, community, resources.
2. NBIACure / NBIA Disorders – background and research updates.
3. Orphan Disease Center – grants and research projects on BPAN.