Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1) and formerly called Hallervorden–Spatz syndrome (use of this eponym is somewhat discouraged due to Hallervorden and Spatz's affiliation with the Nazi regime and the ethically questionable manner in which they acted ), is a degenerative disease of the brain that can lead to parkinsonism, dystonia, dementia, and ultimately death. Neurodegeneration in PKAN is accompanied by an excess of iron that progressively builds up in the brain.
Symptoms typically begin in childhood and are progressive, often resulting in death by early adulthood. Symptoms of PKAN begin before middle childhood, and most often are noticed before ten years of age. Symptoms include:
- dystonia (repetitive uncontrollable muscle contractions that may cause jerking or twisting of certain muscle groups)
- dysphagia & dysarthria due to muscle groups involved in speech being involved
- rigidity/stiffness of limbs
- writhing movements
- Rigidity (neurology)
- seizures (rare)
- toe walking
- retinitis pigmentosa, another degenerative disease that affects the individual’s retina, often causing alteration of retinal color and progressive deterioration of the retina at first causing night blindness and later resulting in a complete loss of vision.
25% of individuals experience an uncharacteristic form of PKAN that develops post-10 years of age and follows a slower, more gradual pace of deterioration than those pre-10 years of age. These individuals face significant speech deficits as well as psychiatric and behavioral disturbances.
Being a progressive, degenerative nerve illness, PKAN leads to early immobility and often death by early adulthood. Death occurs prematurely due to infections such as pneumonia, and the disease in itself is technically not life limiting.
PKAN is inherited and is called an 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.
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 may be an option when the disease-causing mutations have been identified.
PKAN is suspected when magnetic resonance imaging (MRI) changes are seen in an individual with symptoms typically seen in this disease.
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. It is rarely seen in other forms of NBIA.
The sign sometimes is absent in the early stages of disease. In the Dominican Republic, where 21 affected individuals have been diagnosed with PKAN and have the same PANK2 mutation, it has been reported that six individuals lacked the ‘eye of the tiger sign’ despite their similarities to others in this group.
Some cases with a purported ‘eye of the tiger’ sign will be found to have Mitochondrial-membrane Protein-Associated Neurodegeneration or MPAN, a different form of NBIA that can look similar to PKAN when comparing scans.
Another hallmark feature is the presence of a movement disorder, including one or more of the following: dystonia, rigidity or choreoanthetosis (twisting and writhing). Other common features include corticospinal tract involvement 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.
Treatment of Dystonia
This is the most debilitating and distressing symptom of the disease. Therapies that are used with varying success include botox injected into the muscles; oral baclofen and trihexyphenidyl; intrathecal baclofen; deep brain stimulation; and physical and occupational therapy as indicated, particularly for those who are only mildly symptomatic. Therapies to maintain normal joint mobility for as long as possible may be useful.
Treatments Under Investigation
Iron Chelation: Interest in this therapy has re-emerged as data on deferiprone (Ferriprox®) have been collected on affected individuals. Iron chelating agents have been tried in the past without clear benefit. Until recently, trials were limited by the development of iron deficiency in the rest of the body before any clinical neurologic benefits were evident. Unlike earlier drugs, deferiprone crosses the blood-brain barrier and removes iron from the brain cells.
One small phase II pilot trial has been performed to assess deferiprone in the PKAN population. Deferiprone was tolerated well in the nine affected individuals who completed the study, and there was a statistically significant reduction of iron in the pallida by MRI evaluation. However, there was no change in their clinical status. The authors suggested that a longer trial period may be necessary to produce clinical benefit.
An international clinical trial with longer duration is underway. Please see our Research section for more information on a Phase III clinical trial of deferiprone.
Pantothenate and pantothenate derivatives: The possibility of the existence of enzyme activity in some individuals with PKAN raises the possibility of treatment using high-dose pantothenate, the PANK2 enzyme substrate. Pantothenate has no known toxicity in humans. High oral doses of pantothenic acid or calcium pantothenate (≤10 g/day for several weeks) do not appear to be toxic to humans. We don’t yet know how effective pantothenate supplementation is in ameliorating symptoms. Some individuals with an atypical disease course have anecdotally reported improvements in dysarthria, gait imbalance and a sense of well-being when taking pantothenate.
Clinical studies are underway to investigate the potential of a form of pantothenate, which is pantethine and pantethine derivatives, to treat PKAN. Studies with fruitflys show that when pantethine is provided in their food, they live longer and have a lower rate of nervous system decline.
In a grant provided by the NBIA Disorders Association, Dr. Ody Sibon from the University Medical Center Groningen, in Groningen, Netherlands, is testing pantethine derivatives to see if they are more stable in the human digestive system and blood. Also, as part of the European Union grant called Treat Iron-Related Childhood-Onset Neurodegeneration, or TIRCON, pantethine derivatives are being tested as a possible treatment for PKAN. Please see our Research section for more information on TIRCON.
Brain Imaging: Researchers at the Oregon Health & Science University have begun a brain imaging study to explore brain blood flow, called perfusion, in PKAN. They hope to gain new insights into how the disease progresses. For more information on this study, please see our Research section under Clinical Trials.
- NBIA Disorders Association: http://www.nbiadisorders.org/
- NBIA Alliance: http://www.nbiaalliance.org
- NBIA Cure: http://nbiacure.org/