What is Pantothenate Kinase-Associated Neurodegeneration (PKAN) (Pantothenate Kinase-Associated Neurodegeneration (PKAN))?
Pantothenate kinase-associated neurodegeneration (PKAN), which used to be known as Hallervorden-Spatz disease, is a rare brain disorder that is passed down through families (autosomal recessive). This condition is marked by the excess build-up of iron in certain areas of the brain and it gradually results in movement problems (extrapyramidal dysfunction) and severe memory loss (dementia). This means that affected people may experience difficulties with voluntary movements and mental functions over time.
What Causes Pantothenate Kinase-Associated Neurodegeneration (PKAN) (Pantothenate Kinase-Associated Neurodegeneration (PKAN))?
PKAN is a brain condition first recognized in 1922 by two German doctors, Hallervorden and Spatz. They found that it was linked to a buildup of iron in the brain. PKAN is related to a group of conditions called neurodegeneration with brain iron accumulation (NBIA), which all involve iron buildup in a part of the brain called the basal ganglia. This can lead to varied problems with the nervous system.
There are at least ten known genes that, when they change, can lead to different specific diseases within this group.
Despite much research, the exact cause of PKAN is still not entirely understood. Some scientists believe it might be linked to issues with oxidation of lipofuscin, a type of waste product in cells, to neuromelanin, a pigment found in certain areas of the brain, as well as a lack of cysteine dioxygenase, an enzyme that plays an important role in maintaining healthy iron levels in the body.
In people with PKAN, parts of the brain, the globus pallidus and the substantia nigra (areas known to have more iron even in healthy individuals), can end up with excessive iron buildup.
Inherited cases of PKAN are often due to changes in a gene called PANK2. These changes lead to problems with the processing of coenzyme A, a molecule that helps break down substances in the body. The result is a lack of a critical enzyme (pantothenate kinase) and a buildup of cysteine (a type of amino acid) in the basal ganglia, where iron builds up. This buildup of cysteine and other compounds can lock up the iron and cause it to oxidize, leading to the production of harmful free radicals.
Looking at the brain tissues of people with PKAN often reveals a rust-brown discoloration in the globus pallidus and substantia nigra, due to iron buildup. The size of these parts of the brain can also be reduced. Further, severe cases might present overall shrinking of brain tissues.
Risk Factors and Frequency for Pantothenate Kinase-Associated Neurodegeneration (PKAN) (Pantothenate Kinase-Associated Neurodegeneration (PKAN))
Pantothenate kinase-associated neurodegeneration (PKAN) is a condition with a prevalence rate of 1 to 9 cases per one million people, as per some studies. It usually shows up in individuals between the ages of 7 and 15. However, it should be noted that PKAN can occur at any age, including infancy and adulthood.
Signs and Symptoms of Pantothenate Kinase-Associated Neurodegeneration (PKAN) (Pantothenate Kinase-Associated Neurodegeneration (PKAN))
PKAN is a condition that involves the worsening of motor functions, typically beginning in early childhood. Symptoms can differ from person to person, but usually include a range of neurological issues.
Common symptoms of PKAN look like this:
- Loss of motor control, including involuntary muscle spasms and twisting
- Muscle rigidity and spasms
- Speech disturbances, which can occur early on
- Difficulty swallowing, usually due to muscle stiffness
- Memory loss problems, often seen in most PKAN patients
- Vision issues, although it’s rare for this to be the first sign of the disease
- Seizures, which have been frequently noted
Other features may include a feeling of internal restlessness which can be perceived as nervousness or anxiety, problems related to vision loss, and psychiatric issues. About a quarter of PKAN patients develop symptoms later in life, typically in their second or third decade, with a slower progression of the disease and prominent speech and psychiatric issues.
To diagnose PKAN , certain criteria must be met. These include:
Mandatory signs:
- Onset in the first two decades of life
- Progressive symptoms that result in the inability to walk within 10-15 years (for the classic form) or 15-40 years (for the atypical form) of the disease’s onset.
- The presence of motor system dysfunction, which can include loss of motor control, muscle rigidity, and involuntary movements.
Supporting features may include:
- Dysfunction of the nerve pathways that control voluntary movement
- Progressive mental deterioration
- Eye disorders such as retinitis pigmentosa and/or optic atrophy
- Seizures
- A family history that suggests inherited genetic disorders
- Abnormal brain images, showing clear involvement of the basal ganglia
- Abnormalities in cell structures in circulating blood cells
- Changes in the shape of red blood cells
Testing for Pantothenate Kinase-Associated Neurodegeneration (PKAN) (Pantothenate Kinase-Associated Neurodegeneration (PKAN))
Your doctor may order a kind of scan called a CT (Computed Tomography) to help understand your condition better. For a disease known as PKAN (Pantothenate kinase-associated neurodegeneration), a CT scan doesn’t typically provide much information. However, it can sometimes show certain changes in parts of the brain called the basal ganglia, or even some shrinkage of the brain.
The best imaging tool for diagnosing PKAN or any form of neurodegeneration with brain iron accumulation (NBIA), which is a group of diseases linked to iron build-up in the brain, is an MRI (Magnetic Resonance Imaging) of the brain. An MRI provides clearer pictures of the parts of the brain where there are increased iron deposits, mainly the globi pallidi, the pars reticulata of the substantia nigra, and the red nuclei.
A distinctive sign called the “eye of the tiger” is often a clear indication of PKAN. This sign appears as two symmetrical spots in a certain part of the brain (the anteromedial globus pallidus), showing up as brightly colored signals surrounded by a darker area on an MRI scan. It’s important to note that this sign is found only in patients with certain genetic changes (PANK2 mutations).
Another type of MRI scan, called SWI/T2*, may also be used. It provides even more detail about the areas involved by highlighting them as low signals because of iron build-up. MR spectroscopy, a special type of MRI, can provide additional information about changes in the brain’s chemical composition.
SPECT (Single Photon Emission Computed Tomography) scanning is another test that can be used, though it’s not common in routine clinical practice.
If your family has a history of PKAN, and you are planning a pregnancy, there are tests that can be done during pregnancy to check if your baby might be at risk. These include amniocentesis (testing fluid from around the baby) or chorionic villus sampling (testing tissue from the placenta). Both of these procedures are usually done during the first few months of pregnancy. This is made possible if specific genetic issues (pathogenic variants) are known in your family, allowing for targeted testing.
Treatment Options for Pantothenate Kinase-Associated Neurodegeneration (PKAN) (Pantothenate Kinase-Associated Neurodegeneration (PKAN))
Hellervorden Spatz disease, or PKAN, is treated mainly by addressing the symptoms. Tremors, movements of the body that you can’t control, respond well to medicines that interact with dopamine, a chemical in your brain that affects movement. Rigidity (stiff muscles) and spasticity (tight, stiff muscles that can’t stretch normally) can be managed using a combination of dopamine and anticholinergic agents. Anticholinergic agents are drugs that block certain nerve impulses, helping reduce muscle stiffness and spasms. A medication called Baclofen, which can be taken orally or injected into your spinal fluid, can also help relieve these symptoms and give some improvement to dystonia, a condition that causes involuntary muscle contractions.
Intramuscular botulinum toxin, known as Botox, can be used to help relax overactive muscles. In some cases, benzodiazepines, a type of sedative, have been utilized to manage uncontrolled, slow movements. Excessive drooling may be controlled with medications like methscopolamine bromide. Misspoken speech (dysarthria) might improve with medications used for stiffness and tight muscles.
In advanced cases, various strategies can help promote the function and communication skills. These include physical and speech therapies, swallowing evaluation, dietary assessment, feeding through a tube inserted into the stomach (gastrostomy tube feeding), and the use of computer-assisted devices.
Dementia, or a decline in mental ability severe enough to interfere with daily life, is a slowly progressing condition and typically does not improve with treatment. In patients who repeatedly bite their tongue due to severe uncontrolled facial muscle contractions, bite blocks or full-mouth dental extraction might be the only effective solutions. Systemic chelating agents, such as desferrioxamine, have been tried to remove excess iron from the brain, but this hasn’t been proven to help. There’s ongoing research exploring whether high doses of pantothenate and coenzyme A can be beneficial, but currently, there is no conclusive data.
What else can Pantothenate Kinase-Associated Neurodegeneration (PKAN) (Pantothenate Kinase-Associated Neurodegeneration (PKAN)) be?
When diagnosing certain conditions, doctors have to consider other diseases that may have similar symptoms. These include:
- GM gangliosidoses
- Huntington disease
- Juvenile neuronal ceroid lipofuscinosis
- Machado-Joseph disease
- Neuroacanthocytosis
- Neuronal ceroid lipofuscinosis
- Wilson disease
