What
is Neurodegeneration with Brain Iron Accumulation (NBIA)?
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.
General Symptoms
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.
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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