Idiopathic NBIA

Idiopathic NBIA is of unknown origin, although it is suspected to be genetic. For many families, the person diagnosed with NBIA is the first and only affected individual, so it is difficult to know whether there is a specific pattern of inheritance. It is thought that most of these cases are probably recessive because some families have more than one affected child and idiopathic NBIA is more common in families in which the parents are related, such as distant cousins. That would make it more likely that they share a recessive gene.

The symptoms are more varied because there are probably several different causes of neurodegeneration for individuals in this group. As with other forms of NBIA, the idiopathic form features early- and late-onset types. Currently, about five percent of those diagnosed with NBIA are believed to be in this group.

Clinical Diagnosis

Suspicion of NBIA usually arises when an MRI of the brain shows excessive iron accumulation, along with a movement disorder. Depending on symptoms, genetic testing is done to rule out other forms of NBIA or other genetic disorders. If all are negative, but the findings are characteristic of NBIA, then the diagnosis of Idiopathic NBIA is given until further evidence of the genetic origin or another cause is determined.

Evaluations Following Initial Diagnosis

• Neurologic examination for movement disorders, including dystonia, rigidity, spasticity and choreoathetosis, which are involuntary movements that include contractions, twisting and writhing. Walking ability and speech also are assessed.
• An eye exam to check for such problems as retinopathy (damage to the small blood vessels in the retina) and optic atrophy (the loss of some or most of the fibers of the optic nerve).
• Developmental screening, with referral for more formal testing if delay is indicated.
• Assessment to see if physical therapy, occupational therapy and/or speech therapy are warranted.
• Assessment of behavior and neuropsychiatric changes.
• Medical genetics consultation.

Management

Doctors treat patients with medication when appropriate. Also, affected individuals may need a feeding tube or other assistance to achieve adequate nutrition. Other therapies might also be warranted.

Genetics

Testing to find the gene responsible for an individual’s form of NBIA may be pursued.

Prenatal Testing

In the absence of a known genetic mutation, testing during pregnancy to assess risk is not possible.

Research

Researchers continue their search for remaining genes that cause NBIA disorders, and much progress is being made with new technology. If a new gene is found by researchers, the person’s samples will be examined to see if they have mutations and their form of NBIA identified. Affected individuals diagnosed with Idiopathic NBIA might want to participate in the TIRCON International Patient Registry.

Beta-propeller
Protein-associated
Neurodegeneration (BPAN)

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 behaviors.

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 dyskinesias (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 orthopedic 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 behavior 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 individualized education plan (IEP).

Genetics

With genetic testing available, a BPAN diagnosis during childhood is now possible. Earlier detection also gives families an opportunity to find others with the same diagnosis for emotional support and advice on therapies. It further enhances the ability to participate in research and may enable earlier intervention for subtle symptoms of parkinsonism.

After a child is diagnosed, parental testing is recommended. Though most cases are simplex and de novo (only one individual is affected in the family because of spontaneous mutation in the germ cell), cases have been reported in which parents have another child with BPAN.

While many individuals with BPAN do not have children, mildly affected individuals that choose to conceive should seek genetic counseling. The chance to pass on a WDR45 mutation (pathogenic variant) is as great as 50%.

The main resource for the clinical information provided here is BPAN - GeneReviews. GeneReviews is primarily used by genetics professionals, so the terminology and information may be difficult for the general public.

All information is for informational purposes only. We do not endorse specific studies or clinical trials, experimental drugs, procedures, biotech or pharmaceutical companies.

Natural History Studies

BPANready

Oregon Health & Science University has a registry and conducts natural history studies that involve patients or guardians entering data remotely by phone, paper or online. It involves the retrospective use of medical records as well as listing BPAN milestones and patient (or parent) reported outcome measures.

The research team is using Latent Growth Models (LGM) in which latent growth curves model disease progression. Understanding the progression of the disease and how it manifests in different cases will increase clinical knowledge and help researchers identify important avenues for study and treatment.

BPAN families wishing to participate can find more information and register at NBIAcure.

RARE-X BPAN Data Platform

RARE-X is a nonprofit created to accelerate rare disease research, treatments, and cures by removing barriers for data collection and sharing. The Rare-X platform is designed to encourage data-sharing and thus quicken the speed of information and the pace of research into BPAN.

The platform is currently open to BPAN families that speak English, with plans to expand to other languages in the future. Those wishing to participate can access the site at https://bpan.rare-x.org.

The platform is free for families to use. It keeps health information confidential by providing only data that is not attached to individual names. BPAN families and individuals control whether to allow or deny access to their personal health information for any research project.

RARE-X BPAN asks BPAN families about their experiences with the condition through various structured and standardized surveys on various topics which can be updated by families as needed. A researcher who is studying mitochondria for example, can do a query for all relevant information on a specific symptom and might find similarities across various diseases that provide insights into new treatment pathways.

RARE-X provides support, technology, tools and resources necessary for successful data collection, and secure but open data sharing on a global scale.

The platform does not replace other forms of data collection that we have available in our NBIA community such as BPANready, Citizen and the TIRCON International NBIA Registry and Biobank. In fact, these existing projects can be connected to the RARE-X platform and expand the data available to interested researchers.

It is hoped that RARE-X BPAN will enhance our readiness for clinical trials and engage new researchers and biotech companies. It is cloud-based and researchers can query the database in many ways to find data that is brought together rather than in separate silos. The de-identified data never leaves the system. Researchers can link to it but cannot download it.

TIRCON International NBIA Registry

The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.

The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry.

Articles

Research

The WDR45 gene was discovered in 2012 by Dr. Tobias Haack of Helmholtz Zentrum München, a German research center. The discovery resulted from a collaborative study involving the lab of Dr. Susan Hayflick at the Oregon Health & Science University. It applied next generation sequencing to individuals suffering from NBIA with no known genetic cause. This study resulted in the finding of the WDR45 gene, causing BPAN, with the findings reported in December 2012 in the American Journal of Human Genetics entitled "Exome Sequencing Reveals De Novo WDR45 Mutations Causing a Phenotypically Distinct, X-Linked Dominant Form of NBIA."

The focus of the following research has been on finding suitable model organisms to perform pre-clinical testing. These organisms can provide important clues on the cause of disease as well as help develop and test potential treatments through drug screening that can be later translated to clinical trials. It is important that the model mimics the condition seen in patients. Below are various study models for BPAN.

• C. elegans - roundworm
• Drosophila - fruit flies
• Mice
• Pluripotent Stem Cells - skin cells from BPAN patients reprogrammed into neurons to model the disease. This enables scientists to learn more about the progression of the disease and to screen large numbers of small molecule drugs for potential treatment.

Other research areas focus on understanding the role of iron in BPAN and how a WDR45 mutation leads to neurodegeneration.

Many research efforts have indicated that BPAN causes impaired autophagic activity. Autophagy is essential for maintaining a stable environment in cells. It is the process by which cells clean out waste materials. In normal cells, waste materials are aggregated into a sac called the autophagosome and are transported to an organelle called the lysosome. The autophagosome and lysosome fuse and become an autolysosome. The waste is then broken down by enzymes that can digest the waste products and recycle them for further use in the cell.

When neural-specific depletion of genes for autophagosome formation occurs in the brain, it leads to massive neuron loss and axonal degeneration. Neurons and axons are fundamental units of the brain responsible for sending electrical signals to receive sensory information and motor commands to muscles.

Researchers want to understand the role that WDR45 plays in the incredibly intricate cascade of genes and proteins in the autophagy process. Once the precise mechanisms are determined, therapeutic drugs can be tested to target the specific pathways necessary to restore autophagy function in the cell.

Several potential pathways to treatments exist. One is testing known drugs that target neuroinflammation, oxidative stress and mitochondrial dysfunction. Another is gene therapy. This would involve providing a working copy of the WDR45 gene into cells or activating the inactive copy of WDR45 on the X chromosome. Scientists have yet to establish if these are viable options for BPAN.

The 7th International Symposium on NBIA & Related Disorders held Sept. 30 to Oct. 3, 2020, has recorded sessions #14-16 pertaining to BPAN research.

BPAN Research Articles:

Following is a list of BPAN research articles published recently and early papers after the gene discovery. Other free access BPAN articles can be found at Pub Med Central.

2006 - Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase