What is Neurodegeneration with Brain Iron Accumulation (NBIA)?
Updated December 2007

NBIA is a rare, inherited, neurological movement disorder characterized by the progressive degeneration of the nervous system (neurodegenerative disorder). To date, four different genes have been found that cause NBIA; there are most likely other causative genes that have not yet been identified. 

The common feature among all individuals with NBIA is abnormal iron accumulation in the brain with a progressive movement disorder. Individuals can plateau for long periods of time and then experience intervals of rapid deterioration. Symptoms may vary greatly from case to case, partly because the genetic cause may differ between families. Also, different changes (mutations) within a gene could lead to a more or less severe presentation. The factors that influence disease severity and the rate of progression are still unknown.  The diagram below shows the different forms of NBIA and, when known, the genes that cause them.  Although NBIA is generally divided into early onset and late onset forms, there are always exceptions to this rule and some cases will fall between these two categories. 

The category of NBIA includes patients previously diagnosed with Hallervorden-Spatz syndrome.  “Neurodegeneration with brain iron accumulation” reflects the ongoing discoveries about the underlying causes of NBIA.  The term NBIA is general enough to cover all conditions previously categorized as Hallervorden-Spatz syndrome plus other conditions found to fit in this group.  In addition, concerns about the unethical activities of Dr. Hallervorden (and perhaps also Dr. Spatz) involving euthanasia of mentally ill and physically disabled patients during World War II provided motivation to change the name. 

Individuals with NBIA have high iron levels in part of the brain called the basal ganglia.  The basal ganglia is a collection of structures deep within the base of the brain that assist in regulating movements. The exact relationship between iron accumulation and the symptoms of NBIA is not fully understood.  Although we all normally have iron in this area, people with NBIA have extra iron here that can be seen on MRI (magnetic resonance imaging).  Certain MRI views (T2-weighted images) show the iron as dark regions in the brain.  High brain iron is most often seen in the part of the basal ganglia called the globus pallidus.  It is also often seen in another part called the substantia nigra. 

Individuals with NBIA also all share a finding in the nerve cells that can only be detected by performing electron microscopy on nerve tissue obtained from a biopsy.  Nerve cells have long extensions, called axons, that transmit messages from one nerve cell to the next.  In NBIA, some axons are found to be swollen with collections of cellular debris or “junk” that should not be there.  These swellings are called spheroids, spheroid bodies, or axonal spheroids.  In most forms of NBIA, spheroids are only located in nerves of the brain and spinal cord.  Therefore, they are usually not detected until an autopsy is performed on someone who has passed away.  In infantile neuroaxonal dystrophy (INAD), however, spheroids are also found in nerves throughout the body and a biopsy can be done on skin, muscle, or other tissue to look for them.

There are several descriptive terms for the neuromuscular symptoms associated with all forms of NBIA.  Dystonia describes involuntary muscle cramping that may force certain body parts into unusual, and sometimes painful, movements and positions. Choreoathetosis is a condition characterized by involuntary, rapid, jerky movements (chorea) occurring in association with relatively slow, sinuous, writhing motions (athetosis). In addition, there may be stiffness in the arms and legs because of continuous resistance to muscle relaxing (spasticity) and abnormal tightening of the muscles (muscular rigidity). Spasticiy and muscle rigidity usually begin in the legs and later develop in the arms. As affected individuals age, they may eventually lose control of voluntary movements. Muscle spasms combined with decreased bone mass can result in bone fractures (not caused by trauma or accident). 

Dystonia affects the muscles in the mouth and throat, which may cause poor articulation and slurring (dysarthria) and difficulty swallowing (dysphagia). The progression of dystonia in these muscles can result in loss of speech as well as uncontrollable tongue-biting. 

Specific forms of dystonia that may occur in association with NBIA include blepharospasm and torticollis. Blepharospasm is a condition in which the muscles of the eyelids do not function properly, resulting in excessive blinking and involuntary closing of the eyelids. Torticollis is a condition in which there are involuntary contractions of neck muscles resulting in abnormal movements and positions of the head and neck. 

Most forms of NBIA involve eye disease.  The most common problems are retinal degeneration and optic atrophy.  The retina is a thin membrane that lines the back of the eyeball; it helps the eye perceive an image and send it into the brain.  In NBIA, early signs of retinal degeneration may be poor night vision or tunnel vision.  It can eventually cause significant loss of vision.  Optic atrophy affects the optic nerve, which sends messages between the retina and the brain.  The optic nerve is like a cable with thousands of tiny electrical wires that each carry some visual information to the brain.  When the nerve is damaged or breaks down, vision can become blurry, side vision or color vision may be abnormal, the pupil may not work properly, or there may be decreased lightness in one eye compared to the other.  Eventually, optic atrophy can cause blindness. 

Some forms of NBIA involve delays in development, mainly pertaining to motor skills (movement), although a small subgroup may have intellectual delays. Although intellectual impairment has often been described as a part of the condition in the past, it is unclear whether this is a true feature for the majority of NBIA individuals. Intellectual testing may be hampered by the movement disorder; therefore, newer methods of studying intelligence are necessary to determine if there are cognitive features involved.  For some of the later-onset forms of NBIA, cognitive decline may occur. 

Seizures occur in some forms of NBIA and may need to be treated with anticonvulsants. 

GENETICS 

A person carries a complete set of genetic material in most cells of their body. The total amount of information is contained on 46 chromosomes. These exist in 23 pairs, where one chromosome in each pair comes from the mother and the other from the father. Chromosomes are like miniature filing cabinets for the thousands of genes that control normal health and development. 

Because all of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change (mutation) in it, the person should still have normal health. That person is called a carrier. Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed gene on to their child. Statistically, there is a 1 in 4 chance that two carriers would have an affected child, a 2 in 4 chance to have a child who is also a carrier, and a 1 in 4 chance to have a child who did not receive the gene mutation. 

Classic and atypical PKAN, classic INAD, atypical NAD and aceruplasminemia are recessive conditions.  Most other forms of idiopathic NBIA are also thought to be recesssive.  Neuroferritinopathy is a dominant condition.  In this case, a person affected with neuroferritinopathy has one working copy and one copy of the gene that has a change, or mutation.  This single mutation is enough to cause the disease.  There is a 1 in 2 chance (50%) that an affected individual will pass the gene change on to any of his/her children.  For neuroferritinopathy, most affected individuals have one parent who is also affected. 

FORMS OF NBIA 

The largest subgroup of NBIA observed so far is PKAN (pantothenate kinase-associated neurodegeneration). PKAN is caused by changes in the PANK2 gene, which causes a deficiency of the enzyme pantothenate kinase. We think PKAN accounts for about half of all NBIA.  Other more rare forms of NBIA include INAD (infantile neuroaxonal dystrophy), atypical NAD (neuroaxonal dystrophy), neuroferritinopathy, and aceruloplasminemia.  These have been included under the NBIA umbrella because they all involve neurodegeneration and abnormal accumulation of iron in the brain.  Aceruloplasminemia and neuroferritinopathy are mainly studied by investigators overseas.  The Hayflick laboratory at OHSU primarily focuses on PKAN, INAD, atypical NAD, and other idiopathic NBIA (meaning we do not yet know the cause in these remaining cases). 

Pantothenic Kinase-associated Neurodegeneration (PKAN)

PKAN is generally separated into classic and atypical forms, although some people will have findings that place them between these two categories. Individuals with classic disease have a more rapid progression of symptoms. In most cases, atypical disease progresses slowly over several years. The symptoms and physical findings vary from case to case. 

Classic PKAN develops in the first ten years of life (average age for developing symptoms is 3 1/2 years). These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Eventually, falling becomes a frequent feature. Because of the limited ability to protect themselves during falls, children may have repeated injury to the face and chin. Many individuals with the classic form of PKAN require a wheelchair by their mid-teens (in some cases earlier). Most lose the ability to move/walk independently between 10-15 years after the beginning of symptoms.  By this time many individuals will also have limited speech and may have enough trouble with chewing and swallowing that a feeding tube becomes necessary. 

Approximately 2/3 of individuals with PKAN develop retinal degeneration.  Loss of peripheral vision may contribute to falling and gait disturbances in the early stages of PKAN. Optic atrophy is only found in 3% of patients. 

The atypical form of PKAN usually occurs after the age of ten years and progresses more slowly. The average age for developing symptoms is 13 years. Loss of independent walking often occurs 15-40 years after the initial development of symptoms. The initial presenting symptoms usually involve speech. Common speech problems are repetition of words or phrases (palilalia), rapid speech (tachylalia), and poor articulation/slurring (dysarthria). Psychiatric symptoms are more commonly observed and include impulsive behavior, violent outbursts, depression, or a tendency to rapid mood swings. While the movement disorder is a very common feature, it usually develops later. In general, atypical disease is less severe and more slowly progressive than early-onset PKAN.  Retinal degeneration also occurs in these individuals. 

All individuals with PKAN have high levels of brain iron, mainly in the globus pallidus (described above).  PKAN has a unique finding seen on MRI.  As described above, iron accumulation generally makes the brain look dark on certain (T2-weighted) MRI views.  In PKAN, this dark area has a very bright spot in the center.  This finding, called the “eye of the tiger sign,” is specific to PKAN and very rare for other forms of NBIA. 

PKAN is caused by changes (mutations) in the PANK2 gene. This gene provides the instruction for making an enzyme called pantothenate kinase. Current research is investigating how this missing enzyme results in damage to nerve cells in the brain as well as the characteristic iron build-up. 

Infantile Neuroaxonal Dystrophy (INAD)

INAD has only recently been proposed to belong to the NBIA group of disorders, although it has been known for some time that individuals with INAD share some of the defining features of NBIA. 

Classic INAD has early onset and rapid progression.  Children with classic INAD usually develop signs and symptoms of the disease between birth and two years of age.  The first signs are often delays in developing skills, like walking and talking.  Later, children may begin to lose skills that they previously had (regression). Children may be floppy or have low muscle tone early on (hypotonia), but this later turns into stiffness (spasticity) as they get older, especially in the arms and legs.  Eye disease caused by degeneration of the optic nerve (optic atrophy) is common and can cause poor vision and eventual blindness. 

About half of all patients with classic INAD have high brain iron. It is unclear why the other half of individuals does not have iron accumulation or whether they might develop it later. 

Classic INAD is caused by changes (mutations) in the PLA2G6 gene.  This gene is thought to be important for helping cells maintain a healthy membrane (outer layer).  It is involved in fat (lipid) metabolism.  At this point it is unclear how changes in this gene cause the symptoms of INAD or high brain iron in some affected individuals. 

Atypical Neuroaxonal Dystrophy (NAD)

Atypical NAD usually starts at a later age than INAD, although still during the first decade.  It has a slower progression and a different variety of movement problems than INAD. In the beginning, children may have speech delay or features similar to autism.  Eventually difficulty with movement develops.  Unlike classic INAD, these “atypical” individuals usually have dystonia.  They are also more likely to have behavior changes, such as being impulsive, not able to pay attention for long periods of time, or becoming depressed, which may require treatment by a doctor. 

In the small number of atypical NAD patients that have been evaluated, high brain iron was seen in all cases. NAD is also caused by changes (mutations) in the PLA2G6 gene. 

Aceruloplasminemia

Aceruloplasminemia has mainly been studied in Japan, where it occurs in about 1 in 2 million adults.  It is unclear how often it occurs in other populations.  The main symptoms are retinal degeneration, diabetes, and neurologic disease related to iron build-up in the basal ganglia.  Movement problems include face and neck dystonia, blepharospasm, tremors, and jerky movements. Brain MRI shows abnormal iron accumulation in the basal ganglia. 

Aceruloplasminemia is a disorder of iron metabolism caused by the complete absence of ceruloplasmin ferroxidase activity resulting from mutations in the CP gene that encodes ceruloplasmin. 

Neuroferritinopathy

Neuroferritinopathy typically starts during adulthood with dystonia, jerky movements (chorea), and mild changes in thinking (cognitive effects).  Within 20 years it usually begins to affect movement in all the limbs and causes difficulty speaking.  Although the prevalence is unknown, only about 50 cases have been found and most of these share the same gene change, suggesting they have descended from a common ancestor. 

Brain MRI shows abnormal iron accumulation in the basal ganglia during early disease.  As the disease progresses, cysts can develop where iron previously accumulated. 

Neuroferritinopathy is caused by mutations in a gene FTL, which stands for ferritin light.  This refers to one of two protein subunits that make up ferritin, a protein in the body that helps store and detoxify iron.  Unlike other NBIA, neuroferritinopathy is inherited as a dominant trait, so it is usually seen in several generations in a family. 

Idiopathic NBIA

Of all cases of NBIA, about one-half to two-thirds are accounted for by one of the conditions described above, with PKAN being the most common. The remaining individuals are said to have “idiopathic NBIA,” meaning that the underlying cause is not yet known.  For many of these families, the person diagnosed with NBIA is the first and only affected invididual, 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 (a) there are some families with more than one affected child and (b) idiopathic NBIA is more common in families where the parents are related, such as distant cousins (this makes it more likely that they share a common recessive gene).  The symptoms in this group are more varied because there are probably several different causes of neurodegeneration in this group. As with other forms of NBIA, there are both early-onset and late-onset types. 

There is also a small group of affected individuals with moderate to severe mental retardation.  People in this subgroup have developmental delay starting in childhood, but trouble with movement does not start until early adulthood (twenties to thirties).  Eventually dystonia becomes a chronic problem similar to other forms of NBIA. 

AFFECTED POPULATION 

NBIA affects males and females in equal numbers. The frequency of NBIA in the general population is estimated between 1-3/1,000,000 individuals. Because rare disorders like NBIA often go unrecognized, these disorders may be underdiagnosed or misdiagnosed, making it difficult to determine the accuracy of these estimates. 

THERAPIES 

Treatment is directed towards the specific symptoms that appear in each individual. Research is focusing on a better understanding of the underlying causes of NBIA, which may eventually reveal a more comprehensive treatment. 

Treatment may require the coordinated efforts of a team of specialists. Physicians that the family may work with include the pediatrician or internist, neurologist, ophthalmologist, orthopedist, and clinical geneticist. A team approach to supportive therapy may include physical therapy, exercise physiology, occupational therapy, and speech therapy. In addition, many families may benefit from genetic counseling. 

One of the most consistent forms of relief from dystonia is baclofen. This medication is first taken orally. A baclofen pump has been used to administer regular doses automatically into the spinal cord.  The pump may be an option for some NBIA individuals and an evaluation can be done to determine the likelihood they would respond positively to a pump. 

Artane is a second medication that may be taken alone or in combination with baclofen.  The combination of baclofen and artane has been found useful for many people with PKAN.  Levodopa/carbidopa (Sinemet) has been helpful for some patients with idiopathic NBIA, although it has not appeared helpful for PKAN patients. Individuals experiencing seizures usually benefit from standard anti-convulsive drugs. 

In addition, standard approaches to pain management are generally recommended where there is no identifiable treatment for the underlying cause of pain.  Many individuals with NBIA have ongoing constipation due to decreased activity, diet and/or medication side-effects.  Over-the-counter fiber supplements and stool softeners can often improve the situation. 

Drugs that reduce the levels of iron in the body (iron chelation) have been attempted to treat individuals with NBIA. So far these agents have proven ineffective and they can cause anemia.  However, new studies of another disorder involving iron accumulation have suggested newer forms of chelation therapy may provide some benefit, so this needs to be further explored for NBIA. 

Injection of botulinum toxin (BOTOX) into muscles affected by dystonia can also provide relief for several months at a time.  This causes temporary weakness of muscles that have involuntary contractions causing pain, twisting, abnormal posture, or changes in person’s voice or speech.  Because each affected muscle must be injected, this is most practical when an individual has dystonia significantly affecting a specific body area, such as the hand or jaw. 

Pallidotomy and thalmotomy have been investigational attempts at controlling dystonia. These are both surgical techniques which destroy (ablate) very specific regions of the brain, the pallidus and thalamus, respectively. Some families have reported some immediate and temporary relief. However, most patients returned to their pre-operative level of dystonia within a year of the surgery. In recent years deep brain stimulation, described next, has become an option for NBIA individuals, which will likely replace pallidotomy/thalmotomy procedures. 

Deep Brain Stimulation (DBS) is another treatment used to control dystonia.  It is performed by implanting electrodes into the brain with a programmable device (neurostimulator) under the skin of the chest or abdomen. The neurostimulator sends pulses to targeted areas of the brain and takes “off line” the part of the brain that is sending too many signals and causing the muscles to move in painful ways. DBS has been tried on several NBIA individuals with some good results, although it is unclear whether there is a long-term benefit.  A current study is underway to better determine how DBS should be done in people with NBIA and what the benefits of DBS might be. 

The discovery of the association between pantothenate kinase and NBIA suggests that for some individuals, taking pantothenate (vitamin B5) could provide some benefit. Supplemental pantothenate (pantothenic acid, calcium pantothenate) can be taken orally. Pantothenate is another name for vitamin B5, a water soluble vitamin. Theoretically, this is most likely to assist individuals with very low levels of pantothenate kinase activity (those with atypical PKAN). It is hypothesized that classic PKAN results from complete absence of the enzyme pantothenate kinase, whereas atypical PKAN results from a severe deficiency, although the individuals still may have some level of enzyme activity.  Treatment with pantothenate is currently being explored in animal models. 

The benefits and limitations of any of the above treatments should be discussed in detail with a physician. 

WHAT TO EXPECT 

NBIA is a progressive disorder.  Instead of progressing at a steady rate, most patients experience periods of rapid deterioration lasting one to two months, with relatively stable periods in between. The rate of progression correlates with the age at onset, meaning that children with early symptoms tend to worsen more rapidly. For those with early onset, dystonia and spasticity eventually compromise the ability to walk, usually leading to use of a wheelchair by the midteens.  As the disease progresses, adjustments commonly need to be made to medications and other treatments, and it may take several tries before the best combination is found. 

Premature death does occur in NBIA. However, the lifespan is variable. With improved medical care, a greater number of affected individuals are living into adulthood. Premature death usually occurs secondary to dystonia and impaired swallowing, which can lead to poor nutrition or aspiration pneumonia. For those with atypical, late-onset NBIA, many are diagnosed as adults and live well into adulthood. 

CURRENT RESEARCH 

The National Institutes of Health (NIH) support research on neurodegenerative movement disorders, including NBIA. The goals of this research are to increase understanding of these disorders and to find ways to better treat, or even cure, them. 

The NBIA Disorders Association also supports research into NBIA. Eleven research grants totaling $330,000 have been awarded from 2002-2007. These were each $30,000 seed grants with the purpose of supporting further grants with NIH or the private sector. New researchers are now studying NBIA, along with those at Oregon Health & Science University and University of California, San Francisco who have been doing NBIA-specific research since the early 90’s. 

The organization also supports research through our BioBank program. Blood, tissue and clinical histories are being collected on NBIA individuals to help promote research into the disease.
 

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