Beta-propeller Protein-Associated Neurodegeneration, the most common NBIA disorder, is caused by mutations in the WDR45 gene, located on the X chromosome. It is characterized by developmental delays and epileptic seizures in children, with movement problems in adulthood, including dystonia, disorders very similar to Parkinson’s.

To date, all affected individuals reported have been simple cases (i.e., only one occurrence in a family). The majority are females, indicating that the mutations are new, or de novo, and suggest that the mutations are fatal in most males. Affected people have an overall developmental delay during childhood with slow motor and cognitive gains. However, in adolescence or adulthood, they experience a relatively sudden onset of progressive dystonia such as parkinson’s and dementia.

SYMPTOMS

Symptoms of BPAN usually appear in early childhood. The most common symptoms are as follows:

Developmental delay is usually the first change that is noticed

– Expressive language is significantly affected and children generally develop few or no words.

It could also be a delay in overall development.

– Cognitive (mental) decline may progress to dementia in adulthood

Parkinsonism (symptoms similar to those of Parkinson’s disease):

– Usually does not start until early adulthood

– Tremors (tremors)

– Bradykinesia (slow movements)

– Stiffness (rigidity)

– Postural instability (loss of balance that causes instability)

 

Other muscle problems

– Dystonia (involuntary muscle contraction and spasms)

– Freezing of the step (freezing during the step)

– Spasticity (stiff and rigid muscles)

Epileptic seizures

Some children may have several types of epileptic seizures

Abnormal sleep (sleep problems)

Characteristic behaviors and stereotypes (repetitive and rhythmic movements)

-People with BPAN may have some symptoms that are generally associated with Rett syndrome:

Cognitive (mental) decline with specific loss of expressive language

Hand spin-drying

Epileptic seizures

Abnormal sleep

– However, unlike people with Rett syndrome, those with BPAN do not appear to have a small head size.

CAUSE/GENETICS

The human body is made up of millions of cells. Inside each cell, there is a structure called DNA, which is like an instruction manual. DNA contains detailed steps on how all parts of the body are assembled and how they work. However, DNA contains too much information to fit in a single “book”, so it is packaged in several volumes called chromosomes. Humans typically have 46 total chromosomes that are organized into 23 pairs. There are two copies of each chromosome because we receive one set of 23 chromosomes from our biological mother and the other set of 23 from our biological father. Chromosomes 1-22 are called autosomes and the last pair is called sex chromosomes because they determine a person’s sex. Females have two X chromosomes and males have one X and one Y.

If DNA is the body’s instruction book and is stored in several volumes (called chromosomes), then genes would be the individual chapters of these books. Genes are small pieces of DNA that regulate certain parts or functions of the body. Sometimes, several genes (or chapters) are needed to control a function. Other times, a single gene (or chapter) can influence several functions. Since there are two copies of each chromosome, there are also two copies of each gene. In some gene pairs, both copies must be expressed (or activated) in order for them to do their job properly. For other gene pairs, only one copy must be expressed.

When a single cell in the human body divides and replicates, its DNA is also replicated. This replication process is usually very precise but sometimes the body can make a mistake and create a “typo” (or mutation). Just like a mistake in a book, a mutation in DNA can be imperceptible, harmless or serious. A mutation with serious consequences can lead to the incorrect development of a part of the body or the dysfunction of a particular function.

In the case of NBIA disorders, the modification of certain genes leads a person to develop a particular type of NBIA. Changes in these NBIA genes lead to the symptom groups we observe, although we do not yet understand how the modified genes cause many of these symptom groups in patients. WDR45 is the only gene known to cause BPAN. The main task of WDR45 is to tell the body’s cells how to make a protein called WIPI-4, which is involved in the autophagy process or recycling plant of our cells (cells break down their own components to recycle parts). It is not yet clear to us how a decrease in this protein eventually leads to an accumulation of iron in the brain.

Inheritance

Although BPAN is a genetic disease and the WDR45 gene appears to function according to a dominant X-linked model, it is generally not inherited from a parent. To understand the heredity and variability observed in people with BPAN, it is first necessary to understand inactivation X and mosaicism.

X-inactivation

The WDR45 gene is located on the X chromosome. Females have two X chromosomes, and therefore two copies of the WDR45 gene. Males, on the other hand, have an X chromosome and a Y chromosome, and only one copy of the WDR45 gene. Since females have an “extra” X chromosome compared to males, their cells use only one copy and the other is “extinct”. This is called X inactivation. Males have only one X, so they do not need X inactivation, and they use their unique X chromosome in each cell.

This means that a female with BPAN would have cells in which the WDR45 gene with the mutation is “extinct” and other cells in which the working copy of the gene is “extinct”. This process is random and varies from cell to cell. Some women with BPAN may have milder symptoms because they have more cells where the WDR45 mutation has been “disabled” (inactivated). Males, on the other hand, have only one X chromosome. If their only copy of the WDR45 gene has a mutation, it will still be activated and they will have BPAN symptoms. This is why most males with BPAN probably cause miscarriage in early pregnancy or have more severe symptoms than women at birth.

Mosaicism

In rare cases, men and women with BPAN have a relatively high level of function, either benign or mild disease. These individuals can have two types of cells in their body: some with a WDR45 mutation and others without. This occurs when a normal sperm and egg meet at conception, but when the cells begin to divide, a mutation occurs in the WDR45 gene. Having two populations of cells like this one is called “mosaicism”. The ratio of cells with or without mutation depends on the stage of development and the cell division at which the mutation occurred.

Parents of children with BPAN may also have mosaics without having BPAN symptoms themselves. Some parents may have mosaics throughout their body, which can be demonstrated by blood or skin tests. Others have a very specific type called gonadal mosaic, where we believe that only part of the sperm or eggs have a genetic change, but we cannot find it elsewhere in the body. Mosaic or gonadal mosaic is distrusted when a healthy couple has more than one child with BPAN, which has been reported several times in the literature. Now that we have reviewed sex chromosomes, X inactivation and the concept of mosaicism, it is easier to understand how a child can be born with BPAN:

– Most often, this is a new change ONLY in children with BPAN. The WDR45 gene may have been altered in the sperm or egg, or it may have occurred during or shortly after conception. As a general rule, they are the only family members with a BPAN. It is important to test both parents to be as sure as possible that the genetic mutation is new.

Rarely, a couple has more than one child with BPAN. When this happens, it is assumed that the change in the WDR45 was inherited either from the mother or the father. Either parent may have gonadal mosaics or mosaics in other tissues. It is even possible that the mother may have a WDR45 mutation in ALL her cells, but inactivation X deactivated this copy of the gene, and this did not affect her health. Sometimes, we can prove by testing parental blood samples that one of the parents has mosaicism or a copy of the mutated gene WDR45, which helps us to understand the chance of having another child with BPAN.

Future pregnancies

Finally, because the genetics of BPAN is complicated, there are recommendations to consider after having a child with BPAN:

– Both parents of a child with BPAN must always be tested. In the vast majority of cases, this test will be negative. Although the tests do not detect all cases of mosaicism, a negative result is reassuring. If a mutation is detected in one of the parents, it will provide them with important information about themselves and possibly other family members, including their other children.

– If a couple has a child with BPAN and other healthy girls, their healthy daughters should be counselled as adults and perhaps even tested for WDR45 genetic change before having their own children. This is a conservative approach that takes into account the possibility that a healthy sister may inherit a WDR45 mutation that she does not have due to X inactivation, but that could be transmitted to her children.

– Genetic counselling can help to assess risks in various families and explain complex concepts such as X inactivation and mosaicism. Prenatal testing is also available during future pregnancies for those who want more comfort.

DIAGNOSIS AND TESTS

Brain MRI is a standard diagnostic tool for all NBIA disorders.

MRI stands for magnetic resonance imaging. An MRI produces an image of the body that is created using a magnetic field and a computer. The technology used in MRI is different from that of an X-ray. MRI is painless and is even considered safe during pregnancy. Sometimes, MRI is done all over the body, but most often a doctor requests an MRI of a particular part of the body.

Generally, the first indication of a BPAN diagnosis is evidence of iron accumulation in the brain during brain MRI. T1 and T2 MRIs are required for BPAN diagnosis.

The MRI results for BPAN are as follows:

– Hypointensity (darkness) in the substantia nigra and globus pallidus on T2 MRIThe dark spots in the substantia nigra and globus pallidus indicate iron accumulation.

Iron accumulates earlier and to a higher degree in the substantia nigra

– Hyperintensity (brightness) of the substantia nigra and cerebral peduncles on T1 MRI

The substantia nigra and the cerebral peduncles have a thin, dark central band surrounded by a “halo” of brilliance.

– Other changes

Generalized cerebral atrophy (decrease in brain size)

Slight cerebellar atrophy (decrease in cerebellar size)

Thinned brain stem (structure that connects the posterior brain to the anterior brain)

– An MRI performed at the beginning of BPAN progression may appear normal or show only non-specific brain atrophy. Iron may not appear until early adulthood.

The diagnosis of BPAN is confirmed by genetic tests of the WDR45 gene to find a genetic change. Genetic testing begins with sequential analysis and, if no genetic change is detected, continues with deletion/duplication analysis.

It is rare that a person with BPAN signs and symptoms is not identified as having a WDR45 gene change. This can happen because the genetic test is not perfect and has certain limitations. This does not mean that the person does not have a BPAN; it simply means that we do not yet have the technology to find the hidden genetic change. In these cases, it becomes very important that experienced physicians with BPAN examine the person’s MRI and symptoms very carefully to be as sure as possible of the diagnosis.

MANAGEMENT

There is no standard treatment for BPAN. Patients are managed by a team of health professionals who recommend treatments based on current symptoms.

After diagnosis, it is recommended that people with BPAN obtain the following assessments to determine the extent of their disease:

Neurological examination for dystonia, rigidity, spasticity and parkinsonism

Evaluation of walking and speech

Development evaluation

Assessment for physiotherapy, occupational therapy and/or speech therapy

Medical Genetics Consultation

Dystonia (involuntary muscle contraction and spasms) can be debilitating and painful for people with the disease and their caregivers. Therapies for the management of dystonia vary in terms of method and success rates.

Therapies for the management of dystonia may include:

Intramuscular botulinum toxin

Botox is injected into the spastic and dystonic muscles to help them relax for a while.

Oral artane (trihexyphenidyl)

Baclofen (oral or intrathecal)

One of the main drugs used in the treatment of dystonia, usually first taken orally and divided into several doses each day.

In the intrathecal method, an implanted baclofen pump administers the drug directly into the cerebrospinal fluid.

Deep brain stimulation

Used more often and has some evidence of benefit for some patients

This is the surgical implantation of a lead, an extension cord and a battery pack (IPG):

The probe contains 4 electrodes and is implanted in the region of the globus pallidus of the brain.

The extension cable connects the wire to the battery pack (IPG)

The GPI is a battery-powered neurostimulator that is placed in the abdomen (or in some cases under the clavicle).

Physiotherapy and occupational therapy

May or may not be indicated for those with only mild symptoms.

Drugs to manage Parkinson’s disease:

The symptoms of Parkinson’s disease can be treated with the same medications used in Parkinson’s disease. Treatment with dopamine agonists (such as levodopa) should be initiated and closely monitored. At first, the dose is gradually increased until the patient and doctor feel that the symptoms are under control. During the use of dopamine drugs, regular monitoring for adverse neuropsychiatric reactions, psychiatric symptoms and worsening parkinsonism should be performed. Parkinson’s medications are often very beneficial in the short term. However, this usually lasts only a few years and is often limited by the development of dyskinesias (a common side effect that creates unwanted movements).

Even after a diagnosis has been made and appropriate treatments have been chosen, it is recommended that long-term monitoring be continued to reduce the impact of BPAN symptoms and improve quality of life.

Long-term monitoring for BPAN may include:

Drugs for spasticity, dystonia and/or parkinsonism

Surveillance of persons receiving dopaminergic drugs for Parkinson’s disease for:

Adverse neuropsychiatric effects

Psychiatric symptoms

Worsening of Parkinson’s disease

Nutrition

Monitoring of children’s height and weight

Swallowing assessment and regular diet assessments

Ensure adequate nutrition

– Prevent aspiration

– Placement of the gastrostomy tube (if necessary)

Routine eye examinations

Regular assessments of walking and speaking skills

PROGRESS

In most individuals, developmental delay and intellectual disability appear for the first time in childhood. Once they reach adolescence or early adulthood, patients often begin to regress and cannot regain the skills they have lost.

Average life expectancy varies for people with BPAN, but due to improved medical care, more people affected are now living well beyond the average age.

RESEARCH

You can currently register (or register your child) for a natural history study of BPAN disease called BPANready, at www.nbiacure.org You can learn more about this study and register.

The purpose of this study is to help better understand the progression of BPAN and identify disease markers that can be used in future clinical trials. This study can be conducted entirely at home and involves data entry every six months and a blood test once a year.