NBIA FAQ >>>
is Neurodegeneration with Brain Iron Accumulation (NBIA)?
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
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.
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
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.
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).
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.
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
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.
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.
occur in some forms of NBIA and may need to be treated with
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
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.
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.
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).
Kinase-associated Neurodegeneration (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.
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
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.
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.
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.
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
Neuroaxonal Dystrophy (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.
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.
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.
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.
Neuroaxonal Dystrophy (NAD)
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.
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.
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.
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.
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.
MRI shows abnormal iron accumulation in the basal ganglia during early
disease. As the disease
progresses, cysts can develop where iron previously accumulated.
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.
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.
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
dystonia becomes a chronic problem similar to other forms of 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.
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
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
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
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.
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.
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.
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.
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.
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.
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
benefits and limitations of any of the above treatments should be
discussed in detail with a physician.
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.
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.
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.
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.
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.