BPAN is a rare genetic disorder that affects the nervous system. It is characterized by developmental delay, seizures, and movement disorders. Currently, there is no cure for BPAN, which is why our foundation is committed to funding research and supporting individuals and families affected by this condition.

Beta-propeller Protein-Associated Neurodegeneration

(BPAN) is caused by mutations in the WDR45 gene on the X chromosome. It is inherited in an X-linked dominant manner, meaning that a single copy of the mutated gene is enough to cause disease in both males and females. Most affected individuals identified so far have been simplex, or isolated, cases; they are the only person in their family to have the disease. The majority are females, indicating the mutations are new, or de novo, and suggesting that mutations may be lethal in most males before birth. Rarely, the disorder may also occur in a sibling. In these cases, the mutation was inherited from a mildly affected parent. BPAN is the most common NBIA disorder at 35-45% of the NBIA population, with an estimated prevalence of 2 to 3 per million individuals.

Clinical Features

BPAN has a wide phenotypic spectrum, meaning that symptom presentation and severity can vary greatly among patients. The disease progresses in two stages. The first stage occurs in childhood and is characterized by developmental delay and intellectual disability. Most children are described as clumsy with an ataxic, or unsteady, staggering gait. In addition, children with BPAN usually show expressive language delay disproportionate to their other disabilities. Consequently, most individuals with BPAN can only speak a few words.

Several other common features are sleep disorders, seizures and ocular defects, such as retinal and optic nerve disease. Individuals may present with some autistic features, such as involuntary, repetitive and seemingly meaningless hand movements and other repetitive behaviours.

Many families report that their young children with BPAN have difficulty falling asleep and staying asleep, and thus tend to sleep in spurts. The abnormal sleep patterns may be caused by unrecognized nocturnal seizure activity, dysregulation of the sleep cycle, sleep-disordered breathing, reflux or spasticity.

Seizures are a common symptom of BPAN. Beginning in infancy and early childhood, they occur in about two-thirds of children with BPAN and typically cease in adolescence. They often start as febrile, or fever, seizures in a young child. Other types of seizures in BPAN individuals include generalized seizures, focal seizures with impaired consciousness, and epileptic spasms. Focal seizures begin in one area of the brain, while generalized seizures occur in both hemispheres of the brain at the same time. Generalized seizures can be categorized in the following ways:

• Absence: brief, sudden lapses of consciousness
• Tonic: sudden tension or stiffness that may affect the arms, legs or body, lasting about 20 seconds and occurring typically during sleep
• Tonic-clonic: loss of consciousness in which muscles stiffen and jerking movements last one to three minutes
• Myoclonic: brief, shock-like jerks of a muscle or group of muscles, in which the person is usually awake and able to think clearly

Seizure patterns can be similar to those of epileptic syndromes such as West syndrome and Lennox-Gastaut syndrome. Seizures are typically worse in early childhood and lessen with age.

Typically, BPAN individuals lose brain cells and tissue in the cerebral area of the brain, a condition called generalized cerebral atrophy. During adolescence or adulthood, affected individuals experience a relatively sudden onset of progressive dystonia-parkinsonism and cognitive decline.

Parkinsonism is caused by the degeneration of nerve cells in the brain and is characterized by tremors and shaking, slow movements, stiffness in the arms, legs or trunk, instability while standing, and frozen gait, which is a pause in one’s attempt to move forward when walking.

Dystonia, a movement disorder in which a person’s muscles contract uncontrollably, also is common. The affected body part will twist involuntarily, resulting in repetitive movements. This can affect a single muscle, a muscle group or the entire body.

BPAN is progressive, meaning the symptoms worsen over time.

Clinical Diagnosis

Delayed development and other symptoms often lead to genetic testing to uncover a diagnosis. Since BPAN is very rare and often not suspected, it typically is diagnosed with Whole Exome Sequencing (WES), which looks at all the protein-coding regions of the genome. Whole Genome Sequencing (WGS) is becoming more common, as this test looks at the entire genome and is the most extensive one currently available.

As a child progresses into adolescence, evidence of the disease can be seen in a brain MRI that shows iron accumulation in the basal ganglia, specifically in the substantia nigra and globus pallidus. Early imaging findings include mild white matter volume loss, delayed myelination and a thin corpus callosum. However, a young child with BPAN may have a normal brain MRI.

One possibly unique feature of BPAN can be detected on an MRI of the brain: the presence of a bright halo seen in a certain view (T-1 weighted) in the substantia nigra and cerebral peduncles. Hyperintense signal (an abnormality that shows as bright white on an MRI) in this region seems to appear at the same time or soon after the symptoms of progressive dystonia-parkinsonism emerge. On an MRI T-2 weighted view, a hypointense signal (an abnormality that appears dark on the MRI) appears in the substantia nigra that is usually detectable early in the second decade of life and possibly sooner.

Symptom Management

Various types of treatments help manage symptoms. Because symptom severity and complexity varies widely, management should be tailored to the individual. Individuals will benefit from routine follow-up by a neurologist for medication management and interval assessment of neurological regression, ambulation, seizure activity, speech, sight and swallowing.

Anti-seizure medication is recommended for children with recurrent, unprovoked seizures. Many children will outgrow their seizures and may be taken off the medication in adolescence as directed by their doctor.

Dopaminergic drugs, which mimic the effects of dopamine, a chemical involved in movement, are sometimes given for parkinsonism. Those drugs need to be further monitored for adverse neuropsychiatric effects and disabling motor fluctuations and dyskinesia's (abnormal, uncontrollable, involuntary movements).

Other therapies that can help BPAN individuals include physical therapy to address gross motor dysfunction, maximize mobility and reduce the risk of later-onset orthopaedic complications. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function, such as feeding, grooming and dressing. Feeding therapy, by an occupational or speech therapist, is recommended for difficulty feeding due to poor oral motor control.

Since most individuals are nonverbal or can only say a few words, speech therapy is recommended to help with augmentative and alternative communication. If the child also has autism symptoms, a comprehensive treatment model is recommended that may include applied behaviour analysis and developmental approaches to support communication. All children with BPAN should have a formal audiological evaluation.

Developmental delays and intellectual disabilities are often managed in school through an Educational Health Care Plan (EHCP).