PKAN

Pantothenate Kinase-Associated Neurodegeneration is one of the most common forms of NBIA. Approximately 30-35% of the NBIA population has PKAN.

It is caused by mutations in the PANK2 gene on chromosome 20. This gene provides the instruction for making an enzyme called pantothenate kinase. Researchers are investigating how this missing enzyme damages nerve cells in the brain and causes iron to build up.

There are two forms of PKAN: classic and atypical, although some people have symptoms that place them in between the two categories.

Classic PKAN

Individuals with classic disease have a more rapid progression of symptoms. According to published literature, classic PKAN develops before 6 years of age in 90% of patients. The onset age, however, ranges from 6 months to 12 years, with an average onset occurring at 3 years and 4 months.

These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Eventually, falling becomes more common. Because they have trouble protecting themselves during falls, affected children may have repeated injuries to the face and chin.

Many individuals with the classic form of PKAN require a wheelchair by their mid-teens. Most lose the ability to move or walk independently between 10 and 15 years after the beginning of symptoms. Also by this time, they may have enough trouble with chewing and swallowing that a feeding tube becomes necessary.

Dystonia, a movement disorder that causes the muscles to contract and spasm involuntarily, is always present and usually an early manifestation of PKAN. Head and limb dystonia are frequent and may lead to recurrent trauma to the tongue from tongue biting or from the direct impact of falls. Botulinum toxin can be effective in managing oral dystonia and is a first-line treatment to consider. In some extreme cases, removal of all teeth may be necessary. In addition, bone fractures have been reported from the combination of extreme bone stress and osteopenia.

Patients are at risk of premature death. The dystonia can result in swallowing difficulty and poor nutrition. Such secondary effects are more likely to cause premature death than the primary neurodegenerative process. However, life span varies among affected PKAN individuals. With improvements in medical care, more are living into adulthood.

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Atypical PKAN

The atypical form of PKAN usually occurs after age 10 and within the first three decades of life. The average age for developing symptoms is 13. The disease progresses more slowly than classic PKAN and generally is less severe.

The symptoms vary among individuals and are more different than those of early-onset disease. The inability to walk typically occurs 15 to 40 years after symptoms develop. Speech is affected early on. Common speech problems are repeating words or phrases (palilalia), rapid speech (tachylalia) and slurring words (dysarthria).

Psychiatric symptoms are more commonly observed in atypical PKAN and can include impulsive behavior, violent outbursts, depression and rapid mood swings. Movement problems are common, although they develop later. Patients often are described as having been clumsy in childhood and adolescence. Similar to Parkinson’s disease, “freezing” while walking may occur, especially when turning a corner or encountering surface variations. Shaking or tremors also have been reported.

Degeneration of the retina may occur, though much less often than with classic PKAN.

Clinical Diagnosis

PKAN is suspected when magnetic resonance imaging (MRI) changes are seen in an individual with typical PKAN symptoms.

All individuals with PKAN have high levels of brain iron, mainly in the globus pallidus. PKAN has a unique characteristic seen on an MRI. 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, called "the eye of the tiger" sign, pictured below. It is rarely seen in other forms of NBIA.

The sign sometimes is absent in early-disease stages. In the Dominican Republic, where over 20 affected individuals have been diagnosed with PKAN and have the same PANK2 mutation, it has been reported that many of these individuals lacked the eye of the tiger, despite their similarities to others in this group.

Some cases with a purported but not actual eye of the tiger sign will be found to instead have Mitochondrial-membrane Protein-Associated Neurodegeneration or MPAN, a different, less-common form of NBIA.

The movement disorder seen in PKAN individuals may include one or more of the following: dystonia, rigidity or choreoanthetosis (twisting and writhing). Other common features include involvement of the corticospinal tract, which is responsible for conducting impulses from the brain to the spinal cord, extensor toe signs that indicate damage to the central nervous system and spasticity, along with retinal degeneration or optic atrophy. Seizures are rare.

When PKAN is suspected, genetic testing is recommended to confirm the diagnosis.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with PKAN, the following evaluations are recommended:

Neurologic examination for dystonia, rigidity, choreoathetosis and spasticity, including evaluation of walking and speech
An eye exam for evidence of retinopathy and optic atrophy
Screening to assess if there are delays in development, with referral for more formal testing if delay is indicated
Assessment for physical therapy, occupational therapy, and/or speech therapy
Medical genetics consultation

Treatment of Dystonia

Dystonia is a movement disorder in which your muscles contract involuntarily, causing repetitive or twisting movements. This is the most debilitating and distressing symptom of the disease. Dystonia and spasticity are usually managed with different drugs such as anticholinergics, benzodiazepines and other anti-spasticity agents. For focal dystonia, which is dystonia in one part of the body, botulinum toxin (Botox) injections can also provide targeted relief of dystonia and spasticity. The first-line drugs that are most commonly effective in PKAN are trihexyphenidyl, clonazepam and baclofen. Second-line drugs for PKAN include clonidine, gabapentin, tetrabenazine and pregabalin. Physical and occupational therapy can be useful to maintain normal joint mobility for as long as possible, particularly for those who are only mildly symptomatic. Some of the most commonly used treatments for dystonia are baclofen, deep brain stimulation (DBS) and Botox.

Baclofen Pump: One of the most consistent forms of relief from dystonia is baclofen. This medication is first taken orally, but a baclofen pump may be an option for some individuals. An evaluation can be done to determine the likelihood a patient would respond positively to a pump, which is surgically implanted under the skin of the abdomen.

DBS: Deep brain stimulation is another option used to treat dystonia in NBIA individuals. It involves the placement of electrodes in the brain, which are attached to wires leading to a battery-operated neurostimulator implanted in the chest. The neurostimulator sends pulses to targeted areas in 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 is the most commonly performed surgical treatment for Parkinson's disease.

Botox: Injection of botulinum toxin into muscles affected by dystonia can provide relief for several months at a time. Botox helps relieve involuntary contractions causing pain, twisting, abnormal posture or changes in a person's voice or speech, by causing temporary weakness in those muscles. 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. Resistance to Botox is a phenomenon, which may cause the treatment to lose its effectiveness over time. It occurs because the body makes antibodies to combat the toxin.

Please see our Medical Information section for more in-depth information on these therapies.

What to Expect

PKAN is a progressive disorder. Affected individuals may experience episodes of rapid deterioration, often lasting one to two months, interspersed with longer periods of stability. Reasons for this are not clearly understood.

As the disease progresses, episodes of extreme distress may last for days or weeks. It is especially important during these episodes to evaluate for causes of pain so it can be treated. These may include occult GI bleeding, urinary tract infections and bone fractures. Individuals with PKAN are at an especially high risk for fractures without apparent trauma because of osteopenia and stress on long bones from dystonia.

About two out of three individuals with PKAN develop retinal degeneration, a cohort of debilitating conditions characterized by the progressive loss of photoreceptors and neuronal remodeling (the crucial step in sculpting the mature brain). It is more common in classic PKAN. Loss of peripheral vision may contribute to falling and gait problems in the early stages of PKAN. The retinal degeneration follows a typical clinical course, with nyctalopia (night blindness) followed by progressive loss of peripheral visual fields and sometimes eventual blindness. Evaluation by electroretinogram often detects retinal changes that are asymptomatic. Individuals with a normal eye examination at the time of diagnosis generally do not develop retinopathy later. Optic atrophy is only found in 3% of patients and has not been observed in atypical PKAN.

Swallowing evaluation and regular dietary assessments are needed to assure adequate nutrition. Once the individual can no longer maintain an adequate diet orally, a gastrostomy (feeding) tube becomes necessary.

The following should be performed on a regular basis: monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status; eye assessment; oral assessment for consequences of trauma; assessment of walking and speech abilities.

Two of the main resources for the clinical information are the PKAN - Best Practices which was created in collaboration with many different scientists and clinicians, and PKAN - GeneReviews. GeneReviews is primarily for the use of genetics professionals so the terminology and information may be difficult for the general public to understand.

Metabolism & Energy Requirements in people with PKAN

Patient & Family Experience with PKAN

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Genetics

PKAN is an inherited autosomal recessive disorder. Because most 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 pass their changed genes on to their child.

There is a one in four chance that two carriers would have an affected child. The chances are two in four that the couple will have a child who also is a carrier; and they are one in four the child won’t have the gene mutation.

Carrier testing for at-risk relatives and prenatal testing can be obtained if both disease-causing mutations have been identified in an affected family member.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies can be done by analyzing DNA extracted from fetal cells in amniocentesis (usually performed at 15 to 18 weeks of gestation) or chorionic villus sampling (usually performed at 10 to 12 weeks of gestation).

Preimplantation genetic diagnosis, used to identify genetic defects in embryos created through in vitro fertilization (IVF),may be an option when the disease-causing mutations have been identified.

Natural History Studies

TIRCON International NBIA Registry

The TIRCON International NBIA Registry was created under an EU grant called Treat Iron-Related Childhood-Onset Neurodegeneration. Grant funding ran from 2011 to 2015, and the project is housed at Ludwig Maximilian University of Munich, Germany. The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 12 countries currently take part in the registry by entering their patient data. There are over 700 entries consisting of NBIA patients and controls as of July 2020. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data is available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry.

PKANReady

The Oregon Health and Science University has a registry and natural history study that involves patients or guardians entering data remotely by phone, paper or online. It involves the retrospective use of medical records as well as listing PKAN milestones and patient (or parent) reported outcome measures.

The research team plans to use Latent Growth Models (LGM) in which latent growth curves will model disease progression. Understanding the progression of the disease and how it manifests in different cases will increase the knowledge of the disease and ultimately help researchers identify important aspects of the disease to study and treat. PKAN families wishing to participate can find more information and register at PKANready.

PKAN Clinical Trials

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies.

The PANK2 mutation is thought to result in the reductions of cellular coenzyme A (CoA). CoA is cell autonomous and thus any effective PKAN therapy must penetrate both cellular membranes and the blood-brain barrier (BBB). This presents a challenge in finding a suitable drug that can perform these functions.

Another challenge faced by PKAN researchers has been finding a suitable model on which to perform preliminary research. Using other species as models for the disease causes limitations on the implications of the research. In particular, PKAN researchers have lacked a compelling mammalian model in which an abnormality can be specifically attributed to a defect in PANK2. The state of the models is central to the development of therapeutic treatments.

CoA Therapeutics Discontinues BBP-671 Development for PKAN

Published papers on this work:

2016 - Allosteric Regulation of Mammalian Pantothenate Kinase

2018 - A therapeutic approach to pantothenate kinase associated neurodegeneration

Clinical Trials with Negative Results

Deferiprone Clinical Trial

Iron chelating drugs were thought to be a potential PKAN therapy by removing excess iron from the brain. A long-term deferiprone (iron chelator) study with 88 participants was done from June 2014 to March 2018 through an international trial conducted at clinical centers in the US, Germany, Italy and the United States under a 5.2 million euros (approx 7 million USD) EU grant called Treat Iron-Related Childhood-Onset Neurodegeneration, or TIRCON. This study showed that while the drug successfully reduced the amount of accumulated iron in the brain for PKAN individuals regardless of onset age, the treatment was not effective for PKAN patients in a statistically significant way. The study found a slight indication that deferiprone may slow the progression of the disorder in older patients with later-onset, or atypical PKAN.

Published papers on this work:

2019 - Safety and efficacy of deferiprone for pantothenate kinase-associated neurodegeneration: a randomised, double-blind, controlled trial and an open-label extension study

Retrophin Clinical Trial of Fosmetpantotenate

Seventy-eight PKAN individuals completed a 24-week randomized, double-blind study, meaning that neither the patients nor the doctors knew who was randomly selected to get the drug or placebo. Although the drug was observed to be safe and generally well-tolerated, the study found that it did not meet its primary or secondary endpoints, or outcome measures.

First, the study found no differences between those who received the drug and those who got the placebo. That determination was based on the extent to which individuals improved over the 24-week trial, based on a scale that measures activities of daily living, such as walking, eating and dressing. Those measures were specifically adapted for PKAN individuals using Part II of the comprehensive and widely referenced Unified Parkinson’s Disease Rating Scale.

Second, the study found no measurable change on the same scale’s Part III score, which evaluates motor function, including slowness, stiffness and balance.

No data suggested that a longer course of treatment would change the outcomes, nor were there any differences seen between classic and later-onset PKAN individuals taking part in the trial.

Published papers on this work:

2020 - Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase–Associated Neurodegeneration

2019 - The Fosmetpantotenate Replacement Therapy (FORT) randomized, double-blind, Placebo-controlled pivotal trial: Study design and development methodology of a novel primary efficacy outcome in patients with pantothenate kinase-associated neurodegeneration

Press Release with Results:

2019 - Retrophin Announces Topline Results from Phase 3 FORT Study of Fosmetpantotenate in Patients with PKAN

More information on PKAN and some of the latest research for this disorder can be found at https://nbiascientificsymposium.org for day 1 of the 7th International Symposium on NBIA & Related Disorders held September 30 – October 3, 2020.