PKAN

What Causes Pantothenate Kinase-Associated Neurodegeneration (PKAN)?

PKAN is caused by an abnormal change (mutation) in a gene called the PANK2 gene. This gene carries instructions for making an enzyme crucial in the process of energy production inside cells. The PANK2 gene mutations interfere with the production of the enzyme. As a result, cells cannot function properly, and harmful substances, including iron, build up.

This dysfunction causes ongoing damage to cells in the brain and central nervous system, but scientists don’t yet know precisely how the destructive process leads to the symptoms of PKAN.

Is Pantothenate Kinase-Associated Neurodegeneration (PKAN) Hereditary?

PKAN is an inherited disorder. The disorder-causing PKAN2 gene mutations are inherited in an autosomal recessive pattern. This means that a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People who have only one copy of the mutated gene will not develop PKAN but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with PKAN with each pregnancy. Half of their pregnancies will produce a carrier, and a quarter of the pregnancies will produce a child with no mutated genes.

How Is Pantothenate Kinase-Associated Neurodegeneration (PKAN) Detected?

Because movement-related symptoms are usually the first signs of classic PKAN in young children, the early signs are sometimes overlooked because they may appear to be simple clumsiness.

In atypical PKAN, other neurological effects besides movement-related symptoms are more commonly the first signs. Early symptoms may include:

• Repeating words or phrases abnormally
• Abnormally rapid speech
• Depression
• Moodiness
• Anger
• Violent outbursts

PKAN can be detected via genetic testing before birth. These tests may be recommended if the parents are known carriers of PKAN2 mutations.

How Is Pantothenate Kinase-Associated Neurodegeneration (PKAN) Diagnosed?

A doctor may suspect PKAN when a child exhibits symptoms characteristic of the disorder or has a family history of PKAN. The diagnostic process usually includes:

• Assessment of the child’s medical and family history
• Physical and neurological exams
• Magnetic resonance imaging (MRI) to look for a unique signature in the brain called an “eye of the tiger sign” (a dark area with a bright spot in the center that indicates an accumulation of iron)
• Genetic testing to look for disorder-causing PKAN2 mutations

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Pantothenate Kinase-Associated Neurodegeneration (PKAN) Treated?

PKAN has no cure, and the progression of its symptoms generally cannot be reversed. Treatments and therapies aim to lessen the impact of symptoms and prevent complications. Common treatments and therapies include:

• Medications such as baclofen, trihexyphenidyl, botulinum toxin, and clonazepam to help with muscle rigidity
• Anti-seizure medications
• Deep brain stimulation (DBS)
• Feeding assistance, including feeding tubes
• Physical therapy

How Does Pantothenate Kinase-Associated Neurodegeneration (PKAN) Progress?

PKAN is a progressive disorder, and symptoms worsen over time. Progression of classic PKAN is usually rapid, with loss of the ability to walk within 10-15 after the initial onset of symptoms. Progression of atypical PKAN is generally slower, and patients may not lose the ability to walk until 15-40 years after the beginning of symptoms.

Other long-term complications of PKAN may include:

• Loss of control of voluntary movement
• Loss of speech
• Difficulty swallowing
• Malnutrition
• Vision impairments such as loss of peripheral vision
• Acid reflux
• Chronic constipation
• Depression
• Extreme mood swings
• Dementia
• Choking or aspiration of fluids or food, which can lead to pneumonia

The long-term outlook for people with PKAN varies depending on the severity of symptoms and the speed of the disorder’s progression. However, in all cases, life expectancy is less than average.

How Is Pantothenate Kinase-Associated Neurodegeneration (PKAN) Prevented?

There is no known way to prevent PKAN when the disorder-causing gene mutations are present. Therefore, parents with a family history of the disorder or who have had another child with PKAN are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) Caregiver Tips

• Caring for someone with PKAN is more than a full-time job, and you’re going to need help with everything you’re asked to do. Still, caregivers often have a hard time accepting help when it’s offered. You’ll be doing the best for your child and yourself if you let your family and friends give you a hand.
• Take a break. If it’s difficult to accept help, it’s even more difficult to step away from caregiving from time to time. However, you put your own health at risk if you don’t attend to yourself occasionally, too. Don’t feel guilty about it. You’ll be a better caregiver when your physical and mental health needs are taken care of.
• Find sources of support in other families living with PKAN. The NBIA Disorders Association administers a network of families affected by PKAN and other NBIA disorders, along with a library of educational materials and other support resources.

Some people with PKAN also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with PKAN:

• People with atypical PKAN are at increased risk for depression.
• Some people with atypical PKAN experience dementia.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) Brain Science

Scientists do not yet precisely understand how mutations in the PKAN2 genes lead to the symptoms of PKAN. The gene is responsible for producing an enzyme called pantothenate kinase, which is vital in the metabolism of pantothenate (vitamin B5). Metabolizing vitamin B5 produces a substance called coenzyme A, which is essential for proper cell function.

Mutations of the PKAN2 gene result in ineffective production of pantothenate kinase, which interferes with the critical process of making coenzyme A. Without coenzyme A, harmful substances, including iron, accumulate inside cells and cause progressive damage. These substances seem to have a significantly damaging effect on cells in the globus pallidus and the substantia nigra in the brain. These structures are part of the basal ganglia, an area of the brain responsible for functions such as voluntary movement, learning, eye movement, and emotion.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) Research

Title: Brain Perfusion in Pantothenate Kinase-associated Neurodegeneration (PKAN)

Stage: Completed

Principal investigator: Susan J. Hayflick, MD

Oregon Health and Science University

Portland, OR 

The purpose of this study is to learn whether blood flow in the brain is normal in people with pantothenate kinase-associated neurodegeneration (PKAN). Specifically, preliminary data suggest a region of the brain called the globus pallidus (GP), a key region affected by PKAN, may have reduced blood flow. Standard MRI and perfusion scanning techniques will be used to learn about cerebral blood flow in the globus pallidus and compare it to blood flow in other brain regions and healthy controls.

Title: Long-term Deferiprone Treatment in Patients With Pantothenate Kinase-Associated Neurodegeneration (TIRCON-EXT)

Stage: Completed

Principal investigator:  Elliott Vichinsky, MD

UCSF Benioff Children’s Hospital Oakland

Oakland, CA

Patients with PKAN will be treated with the iron chelator deferiprone for 18 months. Only patients who have completed the earlier study TIRCON2012V1 (NCT01741532), a double-blind placebo-controlled trial in which participants were randomized to receive either deferiprone or placebo for 18 months, are eligible to enroll.

TIRCON2012V1-EXT is a multi-center, single-arm, open-label study. All patients who completed the earlier study TIRCON2012V1 (NCT01741532) are eligible to take part. In the initial study, patients were randomized in a 2:1 ratio to receive 18 months of treatment with either the iron chelator deferiprone or placebo, respectively. In this extension study, all participants will receive deferiprone for 18 months. Thus, depending on which product was received earlier, patients will be on deferiprone for a total of either 1.5 years or three years. As in the earlier study, assessments will be carried out every six months to look at the drug’s safety and see if patients are showing any improvement in dystonia and other symptoms of PKAN.

Title: NBIAready: Online Collection of Natural History Patient-reported Outcome Measures

Stage: Recruiting

Principal investigator: Susan J. Hayflick, MD

Oregon Health and Science University

Portland, OR

This study aims to learn more about Neurodegeneration with Brain Iron Accumulation (NBIA) Disorders. Data is being collected on three types of NBIA disorders: Pantothenate Kinase-Associated Neurodegeneration (PKAN), PLA2G6-associated Neurodegeneration (PLAN), and Beta-propeller Protein-associated Neurodegeneration (BPAN). The study will (1) collect information about how symptoms and findings in NBIA change over time and (2) identify measures of NBIA that can be used in future clinical trials. In addition, participants will follow links to a secure website every six months for 5-10 years to electronically complete a set of rating scales related to their NBIA disorder.