Beta-propeller protein-associated neurodegeneration
Other names	Static encephalopathy of childhood with neurodegeneration in adulthood, Neurodegeneration with brain iron accumulation 5
Specialty	Neurology
Symptoms	Developmental delay, seizures, mental handicap. In 2nd and 3rd decade patients develop parkinsonism or dystonia.
Treatment	Anticonvulsant, ketogenic diet, and vagus nerve stimulation might be used for seizures, and DBS for dystonia.

Beta-propeller protein-associated neurodegeneration (BPAN) (previously known as Static encephalopathyof childhood with neurodegeneration in adulthood-SENDA) is a rare hereditary X-linked dominant disorder, which is caused by a mutation in the gene WDR45. ^[1] BPAN belongs to class of disorders called neurodegeneration with brain iron accumulation (NBIA), which causes brain iron elevation and neurodegeneration. ^[2] Patients with BPAN, develop symptoms, such as early onset developmental delay, seizures, and further neurological decline (such as dystonia, parkinsonism, and dementia, which develops by early adulthood). ^{[3] [4]} BPAN is one of the most common NBIA disorder. ^[5]

Contents

• Symptoms
• Diagnosis
• Cause
• Pathophysiology
• Treatment
• Research
• History
• References

As of 2024, 123 individuals with BPAN have been identified. ^[6] There are more females than males with this disease, due to nonviability in males with germline mutations (because males have only one X chromosome, where the WDR45 gene is located). ^[3] Oldest patient is 50 years old, also patient experienced mild symptoms of this disease (at the time of the article’s publication). ^[7]

Symptoms

Patients with BPAN might experience symptoms such as dysautonomia, abnormal eye movements, atrophy of cerebrum and cerebellum, slow movements, dementia, frontal release signs, developmental delay with Intellectual disability, poor speech, parkinsonism, encephalopathy, rigidity, trouble sleeping, and tremor. ^[8] Patients might occasionally experience aggressive behavior and optic atrophy. ^[8] Seizures often start as febrile seizures. ^[9] Various seizure types have been reported in BPAN, such as absence seizures, myoclonic seizures, generalized tonic-clonic seizures, epileptic spasms, atonic seizures. ^[10] Some patients experienced precocious adrenarche as young as one to two years of age. ^[11] Patients also can experience problems with eye vision, such as myopia, astigmatism, strabismus, and amblyopia. ^[11]

On MRI scan of th brain, accumulation of iron in globus pallidus and substantia nigra can be seen, with a "halo" T1 hyperintense signal in the substantia nigra. ^[10] Patients with WDR45 mutations might also experience Rett-like syndrome, intellectual disability, West syndrome, early infantile developmental and epileptic encephalopathy, and developmental and epileptic encephalopathy. ^[12]

Diagnosis

Diagnosis can be suspected by clinical findings, such as: ^[4]

• Debut in early childhood
• The emergence of multiple types of seizures.
• Seizures that are worse in childhood, but declines with age
• Abnormal behaviour (such as teeth grinding while awake, repetitive hand movements)
• Developmental delay/Mental handicap (with poor speech)
• MRI findings such as hypomyelination (deficiency of myelin deposition) ^[13] and small corpus callosum, on T1 "halo"-like structure within substantia nigra, and on T2 iron accumulation in substantia nigra and globus pallidus can be seen.

Cause

BPAN is caused by a mutation in a gene WDR45. ^[1] Most people with BPAN have a new mutation (which means that mutation is new and none of the parents have it), although there have been cases of person inheriting the pathogenic variant of WDR45 from a asymptomatic parent due to mosaicism. ^[14] Male patients with BPAN usually have somatic mosaicism, which in turn, might range from mild BPAN to classic form of BPAN, although males with a germline mutations can have symptoms worse than typical female cases. ^[11] The spectrum of symptoms in females is not only ranged by somatic mosaicism, but also by X-chromosome inactivation (a process where one of the X chromosomes is randomly "turned off"), non-random inactivation might influence the phenotype. ^[11]

Pathophysiology

In the cell-line model of BPAN, researchers found that WDR45 deficiency impairs ferritinophagy (a process where ferritin is targeted and degraded, consequently iron is released in lysosomes). ^{[15] [16]} Due to impairment of ferritinophagy, non-TF (transferrin)-bound iron pathway predominates iron transporting, which causes accumulation of iron in cell and mitochondria. ^[15] Due to accumulation of iron in mitochondria, its function is impaired, by impairing mitochondrial respiration, also iron goes Fenton reaction and generates reactive oxygen species, which is harmful to cells and can initiate apoptosis (a form of programmed cell death) and neurodegeneration. ^[15] Furthermore, WDR45 deficiency induces endoplasmic reticulum stress-dependent autophagy of FTH1 (ferritin heavy chain) and GPX4, which causes iron accumulation and lipid peroxidation. ^[17] Also, accumulation of lipofuscin (an indicator of oxidized lipid aggregates) can be seen. ^[18] WDR45 deficiency promotes abnormal localisation of ATG2A to endoplasmic reticulum-mitochondria contact sites, which enhances transmission of phosphatidylserine (to mitochondria), and consequently phosphatidylethanolamine is synthesised, phosphatidylethanolamine is highly sensitive to peroxidation, due to that composition, cell is driven to lipid damage by iron and cause ferroptosis. ^[18] Fatty acid synthase is not degraded in WDR45 deficiency, which causes lipid droplet accumulation and might contribute to disease progression due to excess lipid droplet toxicity. ^[19]

WDR45 participates in disassembly of stress granule, by competing with G3BP1, which in turn releases caprin-1 protein (which is also implicated in neurodevelopmental disorder), and in BPAN this function is lost, which might provide a link between neurodevelopmental and neurodegenerative phenotype. ^[20]

Treatment

This disease does not have a cure, but management of symptoms is possible. ^{[14] [21]} Anti-seizure medications are generally used to control seizures; ketogenic diet, and vagus nerve stimulation can also be used. ^[14] deep brain stimulation can be used for dystonia in older patients with BPAN. ^[14] Early involvement of patients in speech, physical, and occupational therapy, might benefit them and might maximize their developmental potential. ^[11]

Iron chelation therapy had been tried, but did not show any results, and one patient experienced worsening of Parkinsonism, which caused withdrawal of the medication. ^[22]

Research

In 2024, researchers successfully skipped an abnormal pseudoexon (pseudoexon is a sequence that resembles an exon, and mutations can activate pseudoexon, which in turn causes aberrant protein form/frameshift or premature termination of translation) in patient with BPAN, using ASOs, which could prevent or attenuate onset of extrapyramidal (such as parkinsonism) symptoms in patient. ^{[23] [24]}

In 2025, researchers found that biotin(vitamin B7) might increase WDR45 transcription on inactive X chromosome (by X-chromosome reactivation) in BPAN female patient's fibroblasts, through histone biotinylation (a process where biotin is attached to histones). ^[25] In the same year (2025) researchers successfully reversed BPAN phenotype in mouse using AAV-mediated gene transfer by transfer normal copy of the gene in brain. ^[26]

History

BPAN was described first time by Gregory and colleagues in 2009, where patients experienced developmental delays at first, then patients developed parkinsonism in their 20s-30s, in addition some patients responded well to Levodopa. ^[27] In 2012 Haack and colleagues found the causing gene and propesed the name for that disorder "Beta-propeller protein-associated neurodegeneration" before that it was called "Static encephalopathy of childhood with neurodegeneration in adulthood". ^{[3] [1]}

References