neurodegeneration with brain iron accumulation 5

Neurodegeneration with brain iron accumulation 5, often called beta-propeller protein-associated neurodegeneration (BPAN), is a neurological disorder marked by excess iron deposition in deep brain regions that control movement and cognition. The condition results from pathogenic changes in the WDR45 gene, which encodes a protein needed for cellular recycling processes that keep nerve cells healthy. Symptoms usually appear in early childhood, and because the gene is located on the X chromosome, both males and females can be affected, though most reported individuals are female. BPAN is very rare, affecting fewer than one in a million people worldwide. Severity and symptoms vary widely between individuals.

Children with BPAN often come to medical attention because of global developmental delay, with speech and language skills being particularly affected. Many children speak few words or remain non-verbal, and walking may also be delayed. During childhood development tends to plateau, but in adolescence or early adulthood a second phase of neurological decline typically emerges. Progressive cognitive changes can include mental deterioration and dementia, and movement difficulties such as parkinsonism, bradykinesia, rigidity, dystonia, tremor, and spastic paraparesis become increasingly noticeable. Brain imaging frequently shows iron accumulation in the substantia nigra and other deep brain structures, and some individuals develop cerebellar or cerebral atrophy. Additional features can involve sleep disturbances, autonomic dysfunction (for example problems with temperature or blood-pressure regulation), abnormal eye movements, or aggressive behaviour. Not all individuals experience all features, and severity varies considerably.

BPAN is caused by pathogenic variants in the WDR45 gene. WDR45 is located on the X chromosome and makes a protein that helps cells recycle damaged components, a process that is especially important for long-lived brain cells. The condition is inherited in an X-linked pattern, meaning a single altered copy of the gene can lead to symptoms. Both males and females can be affected, but presentation may differ because females have two X chromosomes while males have one. Each child of an affected individual has a chance of inheriting the altered gene, and females who inherit it may or may not be as severely affected as males because of variable X-inactivation. Families are encouraged to consult a genetic counselor to discuss testing options and reproductive planning.

Currently, management focuses on supportive care and symptom management. Physical, occupational, and speech therapies aim to maximise cognitive and motor skills, while medications such as anticholinergic agents or dopamine agonists may help ease parkinsonism, dystonia, or tremor. Because BPAN can involve multiple neurological systems, long-term care usually relies on a multidisciplinary team that may include neurologists, physiatrists, rehabilitation therapists, and behavioural specialists. Regular surveillance is an essential part of long-term care, helping to identify emerging complications such as worsening movement disorders, swallowing difficulties, or sleep problems before they become serious. Genetic counseling provides families with information about inheritance and available resources. Patients should discuss management strategies with their healthcare team to determine which approaches are appropriate for their situation.

BPAN follows a two-stage course. Early childhood is characterised by stable, though impaired, cognitive and motor development. In adolescence or early adulthood many individuals experience a gradual decline in motor and cognitive abilities, with parkinsonism and dementia becoming more prominent, yet the pace and extent of progression vary greatly among individuals. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with neurologists familiar with BPAN, participate in natural-history registries, and seek genetic counseling for future planning.

Clinical trials are underway exploring new treatment approaches for BPAN. Individuals interested in participating can search ClinicalTrials.gov or talk with their healthcare team about eligibility and potential benefits.