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Classic PKAN

PKAN (Pantothenate Kinase-Associated Neurodegeneration) is the most common NBIA disorder. Based on the age of onset and rate of progression, individuals with PKAN may be classified as having classic or atypical forms. However, as we learn more about PKAN, we have found that some people fall between these 2 categories. In other words, there is a broad spectrum of symptoms.

SYMPTOMS

The symptoms of classic PKAN usually start to appear before age 6, on average around age 3.

Common symptoms include:

Dystonia (involuntary muscle contraction and spasms)
  • Starts early in disease progression
  • Cranial and limb dystonia are the most common types
    • Cranial dystonia affects the muscles of the head and neck, such as eyes, tongue, mouth and throat
    • Limb dystonia affects the arms and legs
Dysarthria (speech problems)
  • Difficulty using or controlling the muscles of the mouth, tongue, larynx or vocal cords, which are used to make speech
  • This can make a person’s speech difficult to understand in several different ways, including stuttering, slurring, or soft or raspy speech
Corticospinal tract (communication pathway between brain and limbs) involvement
  • Spasticity (stiff, tight muscles)
  • Hyperreflexia (overactive reflexes)
Retinal degeneration (deterioration of the retina in the back of the eye)
  • Seen in 2/3 of individuals with classic PKAN
  • May progress from night blindness to loss of peripheral vision
  • Occasionally results in blindness
Other eye symptoms
  • Slower vertical saccades (slow eye movements in a vertical pattern)
  • Abnormal saccadic pursuits (jerky eye movements while following a moving object)
Impaired gait (difficulty with walking)
  • Commonly the first change that is noticed
  • Caused by a combination of various symptoms:
    • Lower limb rigidity
    • Dystonia
    • Spasticity
    • Poor balance
    • Restricted visual fields
Developmental delay
  • Seen in some children with classic PKAN
  • Typically motor delay (related to movement)
  • May be overall delay
  • Many children with PKAN are diagnosed with hyperactivity and/or attention deficit (ADHD)
Intellectual function
  • Skills can range from high average to significantly below average in some cases

CAUSE/GENETICS

The human body is made up of millions of cells. Inside every cell there is a structure called DNA, which is like an instruction book. DNA contains detailed steps about how all the parts of the body are put together and how they work. However, DNA contains too much information to fit into a single “book,” so it is packaged into multiple volumes called chromosomes. Humans typically have 46 total chromosomes that are organized in 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 the sex chromosomes because they determine a person’s gender. Females have two X chromosomes and males have one X and one Y.

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

When a single cell in the human body divides and replicates, its DNA is also replicated. This replication process is usually very accurate but sometimes the body can make a mistake and create a “typo” (or mutation). Just like a typo in a book, a mutation in the DNA can be unnoticeable, harmless, or serious. A mutation with serious consequences can result in a part of the body not developing correctly or a particular function not working properly.

In the case of NBIA disorders, mutations in certain genes cause a person to develop a particular type of NBIA. PANK2 is the only gene known to cause PKAN. PANK2’s main job is to tell the body’s cells how to turn vitamin B5 (pantothenate) into an essential chemical (coenzyme A). Coenzyme A plays a key role in the body’s energy metabolism. It is not yet clear to us how the decrease in coenzyme A eventually leads to iron accumulation in the brain.

As mentioned earlier, humans have a total of 23 pairs of chromosomes. Half of these chromosomes are passed down (or inherited) from the biological mother and half from the biological father. The way in which a gene carrying a mutation is passed down from parents to child varies from gene to gene. The PANK2 gene that is mutated in those with PKAN is inherited in an autosomal recessive manner.

“Autosomal” refers to the fact that the PANK2 gene is located on chromosome 20, which is one of the autosomes (chromosome pairs 1-22). Since the sex chromosomes are not involved, males and females are equally likely to inherit a mutation located in the autosomes. “Recessive” refers to the fact that a mutation must be present in both copies of the PANK2 gene for a person to have PKAN. If an individual has only one PANK2 mutation, then they are called a “carrier” for PKAN. Carriers do not have health problems related to the mutation and often do not know they carry a recessive gene mutation. However, if two PKAN carriers have a child together, then there is a 25% chance that they will both pass on their recessive PANK2 gene mutations and have a child with PKAN.

As seen in the image to the left, in a pregnancy between two PKAN carriers:

  • There is a 25% chance of the child having PKAN
  • There is a 50% chance that the child will be a carrier like his/her parents
  • There is a 25% chance that the child will not have PKAN or be a carrier

DIAGNOSIS & TESTING

A brain MRI is a standard diagnostic tool for all NBIA disorders. MRI stands for magnetic resonance imaging. An MRI produces a picture of the body that is created using a magnetic field and a computer. The technology used in an MRI is different from that of an x-ray. An MRI is painless and is even considered safe to do during pregnancy. Sometimes an MRI is done of the whole body, but more often, a doctor will order an MRI of one particular part of the body.

Evidence of iron accumulation on a brain MRI is often an important clue leading to the diagnosis of PKAN. A T2 sequence is the preferred type of MRI for NBIA diagnosis because it is highly sensitive to the detection of brain iron.

In both the classic and atypical forms of PKAN, an “eye of the tiger” sign is almost always seen on a brain MRI.

  • Most individuals with PANK2 mutations have the “eye of the tiger” MRI sign
  • Almost all individuals with the “eye of the tiger” sign have at least one PANK2 mutation
  • Brain MRI has also accurately predicted PKAN in pre-symptomatic siblings of affected individuals

PKAN “Eye of the Tiger” MRI Sign

The image on the right shows a T2 MRI with an “eye of the tiger” sign. On a T2 MRI, the bright areas indicate pockets of swelling and fluid and the dark areas show iron accumulation. In the majority of PKAN cases, iron accumulation is restricted to the globus pallidus and substantia nigra regions of the brain, which help control movement.

An “eye of the tiger” sign is defined as an area of central hyperintensity (bright) surrounded by hypointensity (dark) in the globus pallidus region of the brain. The bright areas are usually large in the first stages of PKAN and represent early damage and fluid accumulation in the tissue. The dark regions seen in the “eye of the tiger” are deposits of iron. As the disease progresses, the bright spots tend to shrink and the darker areas of iron accumulation become larger and more noticeable. The combination of a dark region with a bright center creates the “eye of the tiger” sign.

Diagnosis of PKAN is confirmed through genetic testing of the PANK2 gene to find two gene changes. At least one PANK2 gene change is found through DNA sequence analysis in greater than 99% of individuals with NBIA who had an “eye of the tiger” sign on MRI.

If no gene change or only one gene change is found through sequence analysis of the PANK2 gene, then genetic testing may proceed to deletion/duplication analysis. Among individuals who go forward with deletion/duplication analysis, a gene change will be found in approximately 3-5% of cases.

Very rarely, an individual with the signs and symptoms of PKAN will have only one or even no PANK2 gene changes identified. This can happen because genetic testing is not perfect and has certain limitations. It does not mean the person does not have PKAN; it may just mean we do not yet have the technology to find the hidden gene change. In these cases it becomes very important to have doctors experienced with PKAN review the MRI and the person’s symptoms very carefully to be as sure as possible of the diagnosis.

MANAGEMENT

decor-medical6There is no standard treatment for classic PKAN. Diagnosed individuals are managed by a team of medical professionals that recommends treatments based on current symptoms.

After diagnosis, individuals with classic PKAN are recommended to get the following evaluations to determine the extent of their disease:

  • Neurologic examination for dystonia, rigidity, choreoathetosis, and spasticity
  • Neurologic evaluation of ambulation (walking) and speech
  • Ophthalmologic assessment for evidence of retinal disease
  • Developmental assessment
  • Assessment for physical therapy, occupational therapy, and/or speech therapy
  • Medical genetics consultation
  • Consider whether a consultation for nutrition and/or swallowing is appropriate

The most commonly treated PKAN symptom is dystonia (involuntarily muscle contraction and spasms), which can be debilitating and distressing to affected individuals and their caregivers. The therapies for managing dystonia vary in method and success rate.

Therapies to manage dystonia can include:
  • Intramuscular botulinum toxin
    • Botox is injected in spastic, dystonic muscles to help them relax for a period of time
  • Artane (trihexyphenidyl), taken orally, usually divided into multiple doses each day
  • Baclofen (oral or intrathecal)
    • One of the main drugs used to treat PKAN dystonia, usually first taken orally and divided into several doses each day
    • In the intrathecal method, an implanted baclofen pump delivers medication directly into the spinal fluid
  • Deep brain stimulation
    • Used increasingly more often in NBIA and has some evidence for benefit
    • A stimulator sends electrical impulses to the affected brain region to help muscles relax
    • It involves surgical implantation of a lead, extension and battery pack (IPG)
      • The lead contains 4 electrodes and is implanted in the globus pallidus region of the brain
      • The extension connects the lead to the battery pack (IPG)
      • The IPG is a battery-powered neurostimulator that is placed in the abdomen (or in some cases below the clavicle)
  • Physical and occupational therapy
    • May or may not be indicated for those who are only mildly symptomatic
    • Therapies to maintain normal joint mobility for as long as possible may be useful
    • Speech therapy is often indicated for PKAN-related dysarthria

Even after a diagnosis has been made and the appropriate therapies have been started, it is recommended to continue long-term surveillance to decrease the impact of PKAN symptoms and increase quality of life.

Long-term surveillance for PKAN can include:
  • Evaluation for treatable causes of pain during episodes of extreme distress
    • Occult gastrointestinal bleeding (bleeding not visible to patient or doctor)
    • Urinary tract infections
    • Occult bone fractures (fractures that don’t appear in x-rays)
      • Individuals with PKAN have an especially high risk for fractures without apparent trauma
  • Nutrition
    • Monitoring of height and weight in children
    • Evaluation of swallowing difficulties due to head and neck dystonia
    • Oral assessment for signs of trauma
    • Nutritional supplements and gastric (tube) feeding (if needed)
  • Routine eye exams
  • Regular assessments of ambulation and speech abilities

PROGRESSION

Classic PKAN is a progressive condition in which an individual typically does not regain skills that have been lost. Individuals who start showing symptoms at an earlier age typically decline at a more rapid rate. As PKAN advances, features such as dystonia and spasticity have a negative impact on an individual’s ability to walk. Most children who develop symptoms at an early age use wheelchairs by their mid-teens.

PKAN does not progress at a consistent rate. Individuals with classic PKAN can have episodes lasting weeks to months where they decline rapidly, followed by longer periods when they are stable. At this point in time, a reason or trigger for the periods of decline has not been found.

The average life span varies for individuals with classic PKAN. Premature death is more likely to be caused by secondary effects, such as nutrition-related immunodeficiency and aspiration pneumonia, than due to the original symptoms. For example, orofacial dystonia can lead to swallowing difficulty and poor nutrition.

Due to improvements in medical care, more affected individuals are now living into adulthood.

HARP SYNDROME

HARP syndrome is a condition that was described in a few families prior to the discovery of the PANK2 gene. The letters H.A.R.P. refer to the main symptoms, which are also key features of PKAN:

  • Hypoprebetalipoproteinemia (low levels of LDL cholesterol)
  • Acanthocytosis (red blood cells shaped like spurs)
  • Retinitis pigmentosa (progressive vision loss due to damage of the retina)
  • Pallidal degeneration (damage in the part of the brain involved in voluntary movement)

After finding the PANK2 gene, it was recognized that HARP is a form of PKAN.

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