Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a rare, inherited neurological disorder affecting the brain and nervous system. It is the most common type of neurodegeneration with brain iron accumulation (NBIA), characterized by abnormal iron deposits in specific brain regions. PKAN leads to movement problems and other neurological challenges, impacting quality of life.
The Genetic and Biological Basis
PKAN arises from genetic changes in the PANK2 gene, located on chromosome 20. This gene provides instructions for making pantothenate kinase 2, an enzyme active in the mitochondria, the cell’s energy-producing parts. Pantothenate kinase 2 initiates the creation of coenzyme A (CoA), a molecule involved in many cellular metabolic processes, including energy and lipid metabolism.
When mutations occur in both copies of the PANK2 gene, inherited from each parent, the enzyme’s function is disrupted. This inheritance pattern is autosomal recessive, meaning a child must receive one mutated gene copy from each parent to develop the disorder. Parents who carry one mutated gene copy typically do not show symptoms themselves. A deficiency of functional pantothenate kinase 2 can lead to a buildup of compounds like cysteine and disrupt CoA metabolism in the brain. This disruption contributes to the accumulation of iron in specific brain regions, particularly the globus pallidus.
Signs and Symptoms
PKAN presents in two main forms: classical and atypical. Classical PKAN typically appears in early childhood, often before age six, with a mean onset around 3.4 years. This form progresses more rapidly. Early signs include impaired gait and falling, often due to involuntary muscle contractions (dystonia), rigidity, and spasticity. Speech difficulties (dysarthria) and swallowing problems (dysphagia) are also frequently observed.
Atypical PKAN usually has a later onset, often in the second or third decade of life (average age 13 years). This form progresses more slowly with different prominent symptoms. Speech problems are common, sometimes including rapid speech or word repetition. Individuals with atypical PKAN may also experience psychiatric issues such as depression, emotional lability, impulsivity, or violent outbursts. Movement difficulties occur, but tend to develop later and are often less severe than in the classical form.
Pigmentary retinal degeneration can occur in some individuals with PKAN, particularly those with the classical form (about two-thirds of cases). This eye condition can lead to night blindness, progressive loss of peripheral vision, and in some instances, eventual blindness. Though less common in atypical PKAN, retinal changes can still be present.
Diagnostic Process
Diagnosing PKAN involves clinical evaluation, imaging, and genetic tests. A brain Magnetic Resonance Imaging (MRI) scan is a key diagnostic tool, often revealing the distinctive “eye-of-the-tiger” sign. This sign appears on T2-weighted MRI images as a central bright area surrounded by a dark rim in the globus pallidus. The bright area indicates tissue damage and fluid, while the dark rim signifies abnormal iron deposits.
While the “eye-of-the-tiger” sign is highly suggestive of PKAN, it is not always present, especially in early stages, and can occasionally be seen in other conditions. Therefore, definitive diagnosis relies on molecular genetic testing. This testing identifies specific mutations in both copies of the PANK2 gene, confirming the disorder’s genetic cause. Genetic analysis is the standard of care for a suspected diagnosis, even when MRI findings are inconclusive.
Management and Therapeutic Approaches
There is no cure for PKAN; management focuses on addressing symptoms and improving quality of life. Medications manage movement disorders like dystonia and parkinsonism. Baclofen (oral or intrathecal pump) and anticholinergics like trihexyphenidyl can reduce muscle spasms and rigidity. Botulinum toxin injections also provide targeted relief for severe focal dystonia.
Physical, occupational, and speech therapies maintain function and independence. Physical therapy improves gait, balance, and mobility, while occupational therapy assists with daily living activities like dressing and eating. Speech therapy addresses communication and swallowing problems, with assistive communication devices or feeding tubes potentially used in advanced cases.
For severe dystonia unresponsive to medication, Deep Brain Stimulation (DBS) may be considered. This surgical procedure involves implanting electrodes in specific brain areas, such as the globus pallidus, to deliver electrical pulses that regulate abnormal brain activity. While DBS can significantly improve dystonia, particularly in atypical PKAN, its long-term effectiveness on disability can vary.
Early investigations explored iron chelation therapy, using agents like deferiprone, to reduce brain iron accumulation. Although some studies showed decreased brain iron levels, these therapies have not consistently demonstrated significant clinical benefit in slowing disease progression for most patients. Research into new therapies, including those that aim to bypass the enzyme defect by supplementing CoA pathway intermediates or through gene therapy, is ongoing.
Progression and Long-Term Outlook
PKAN progression varies considerably between classical and atypical forms. Classical PKAN generally has a more rapid course, with individuals experiencing a faster decline in motor skills. Many children with classical PKAN may require a wheelchair by their mid-teens, with loss of independent ambulation typically occurring within 10 to 15 years of symptom onset. While cognitive abilities tend to be preserved longer than motor function in classical cases, swallowing difficulties can lead to issues like aspiration pneumonia.
In contrast, atypical PKAN typically progresses more slowly, with symptoms worsening gradually over several years, even decades. Individuals with atypical PKAN may remain able to walk and maintain independence for 15 to 40 years after symptom onset. Episodes of rapid decline (weeks to months) can occur in both forms, interspersed with longer periods of relative stability. Lifespan for individuals with PKAN is variable; premature death can occur due to secondary complications like infections or nutritional deficiencies, rather than the primary neurological symptoms.