Beta-propeller Protein-associated Neurodegeneration

Beta-propeller protein-associated neurodegeneration (BPAN), previously known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), is a rare subtype of neurodegeneration with brain iron (NBIA), characterized by movement dysfunction, known as dystonia, and neurocognitive deficits.  

BPAN is a movement disorder thought to be caused by de novo (i.e., not inherited) mutations in the WDR45 gene. Individuals with BPAN experience early-onset seizures during infancy, developmental delay, progressive language and motor dysfunction, and intellectual disability. As children with BPAN enter into early adulthood their seizures either resolve or become less severe, while other signs become more apparent, including movement disorders (i.e., progressive Parkinsonism) and cognitive decline.

BPAN is an X-linked disorder caused by de novo mutations in the WDR45 gene located on the X chromosome. Typically, X-linked disorders affect genetic males because they only have one X chromosome (i.e., XY) compared to genetic females (i.e., XX) who have two X chromosomes. Because genetic males only have one X chromosome, any mutation or alteration on this chromosome will result in an expression of the disorder, whereas genetic females have an additional X chromosome that can compensate for the mutation. Although BPAN is an X-linked disorder, it doesn’t follow these traditional patterns. Instead, the phenotype, or the individual’s observable traits, regardless of their sex, is indistinguishable.  

The role of the WDR45 gene is not fully understood, however, it’s hypothesized that it has a role in the production of multiple proteins (i.e., beta-propeller protein) that play a role in neuronal autophagy, a process in which cells undergo degradation and recycle cellular components. Another distinguishing feature of BPAN and NBIA is the presence of abnormal iron accumulation in the basal ganglia, a structure in the brain that is responsible for coordinating and initiating voluntary movement. The mechanisms of iron uptake into the basal ganglia, however, are currently unknown.   

Clinical features of BPAN include early-onset seizures during infancy associated with severe developmental delay and progressive language dysfunction. The seizure types vary and include generalized, absence, and/or tonic-clonic types. As they enter early adulthood, seizures resolve or become less severe, while movement disorders emerge. Individuals experience Parkinson-like symptoms such as dystonia, tremors, and slowed movement due to the neurodegeneration of the globus pallidus. The globus pallidus is a structure located in the basal ganglia of the brain and is responsible for motor control and the initiation and regulation of voluntary movement.  

Individuals may also have intellectual disabilities and experience neurologic decline as they enter adulthood. 

Diagnosis of BPAN begins with a thorough medical history and physical exam. It’s important to establish a timeline of existing signs and symptoms including seizures, developmental delays, and movement-related symptoms. A thorough neurologic examination can help assess motor function and localize neurologic deficits, if present. Genetic testing is a critical component of diagnosis (i.e., positive WDR45 mutation) and can be established through single gene testing, which identifies one specific gene (i.e., an NBIA subtype) or through a screening gene panel, which can identify multiple genes simultaneously  

In children observed to have seizures, an electroencephalogram (EEG), a recording of the brain’s electrical activity, can be used to evaluate for epileptogenic activity. Neuroimaging with magnetic resonance imaging (MRI) can identify the presence of elevated brain iron and distinguishes BPAN from Parkinson disease. T2-weighted MRI (i.e., a specific MRI sequence) may show hyperintensity with a central band of hypointensity within the substantia nigra, a structure within the basal ganglia responsible for controlling movements and muscle tone. 

There is no current standard treatment for BPAN. Treatment of BPAN consists of supportive measures aimed at addressing each individual’s symptoms. However, the neurocognitive symptoms of BPAN are typically irreversible.  

Management of seizure disorders includes anti-epileptic medications such as valproic acid, which is a sodium channel blocker. For movement disorders, dopaminergic precursors, such as L-dopa, or agonists, like pramipexole. may be used. Muscle relaxants (e.g., baclofen), benzodiazepines (e.g., clonazepam), and intramuscular botulinum toxin may relieve muscle stiffness, spasms, and/or dystonia. For children, an early intervention program with access to occupational therapy, physical therapy, and speech-language pathologists is recommended to help the individual manage their condition. 
 
While the pathophysiology of BPAN involves excess iron deposition within the basal ganglia, iron chelation therapies (i.e., deferoxamine, deferiprone) and antioxidant supplementation have not been effective. Because BPAN is a complex disease, individuals may benefit from a multidisciplinary team approach consisting of physicians, nurses, behavioral and physical therapists, speech and occupational therapists, and dieticians, in order to improve their functional status and quality of life. Finally, genetic counseling and education should be provided to family members of children with BPAN.